A collection of primitive operations for molecular diagram sketching has been developed. These primitives compose a concise set of operations which can be used to construct publication-quality 2 D coordinates for molecular structures using a bare minimum of input bandwidth. The input requirements for each primitive consist of a small number of discrete choices, which means that these primitives can be used to form the basis of a user interface which does not require an accurate pointing device. This is particularly relevant to software designed for contemporary mobile platforms. The reduction of input bandwidth is accomplished by using algorithmic methods for anticipating probable geometries during the sketching process, and by intelligent use of template grafting. The algorithms and their uses are described in detail. Molecular structure diagrams have been the mainstay of chemical communication since molecules began to be rationalised as Lewis structures. The basic ideas involved in representing structures have proven to be remarkably resilient -3. WhileIn recent decades, the process of creating molecular structure diagrams has steadily shifted towards use of computer software, which is now used exclusively for publications, and is in the process of replacing hand-drawings by way of electronic lab notebooks . There iThe subject of this work is a slightly different perspective on the drawing of a 2 D molecular structure diagram. Assuming that the composition of the molecule is known, and the desired output is an arrangement of atoms and bonds onto a flat surface, the process of building up the diagram can be described as a series of primitive unit steps, leading to a molecular connection table, with 2 D coordinates for each atom .In this work, we will explore an alphabet of primitives which has been chosen for the following properties:- small number of operation types- minimal degrees of freedom for input- opportunities for automated inferenceThe primary motivation for abstracting the sketching process in such a way is the emergence of new hardware devices which are highly constrained in terms of user input, such as smartphones, tablets and netbooks. These devices often lack an accurate pointing device. Mobile devices with touch screens, for example, are effective for selecting objects, but they are much less effective for the precise positioning operations upon which conventional molecule drawing software relies. Mobile devices which lack a touch screen offer merely a keypad and directional cursor keys.By describing all of the unit primitives needed to produce a molecular structure diagram in such a way that none of them requires precise user-supplied position information, structure sketching becomes possible for environments in which the user input is limited to little more than a series of menu choices.The objective of this work is to describe a collection of primitive drawing operations which provides a comprehensive set of editing capabilities. These can be used to compose complex diagrams with minimal effort on behalf of the operator.Ideally, each primitive would be able to examine the molecule diagram thus far, determine what it is the user wants changed, and execute the change. In practice, several additional fields are required for most operations. The unit primitives which are described in this work operate as sequences of:subject- select action- select result- select subject is an annotation to the existing structure, which consists of:The - current atom or current bond- a set of selected atomssubject atoms is defined as a set of:At any time there may be a current atom or a current bond, but not both. Each atom of the existing structure is either selected or unselected. In the text that follows, the term - all selected atoms, if there are any;or: the current atom, if there is one;- or: the two atoms of the current bond, if there is one;- else: an empty set.- action is the choice of primitive to apply to the current subject.The results. The list of results should be sorted so that the most plausible result is first, and the remaining possibilities in order of decreasing relevance.For many primitives, there is just one possible outcome when applied to a particular subject, e.g. changing atoms to a specific element, for which it is appropriate to design the primitive to have an unambiguous effect. For some of the more complicated primitives, there could be more than one possible outcome, e.g. attaching a template with multiple possible geometries. In these cases, the primitive may choose to generate a number of When this scheme is mapped to a practical implementation of a user interface, the sequence can be described as:- select the atoms or bonds of interest- pick the action from a menu- if there is more than one result, and the best suggestion is not the desired one, pick from the list of possibilitiesThe remainder of this section describes a minimal set of primitive classes which provide enough functionality to assemble a fully-featured molecular drawing package.Atom modification primitives are mostly straightforward and unambiguous, such as changing an element label, or altering atom-centred properties such as charge or radical count. The number of primitives required depends on the number of editable atom properties used to describe the molecular structure. The following primitive classes are representative.A new atom is created. Its position is determined automatically. If the structure already contains one or more atoms, it is along the top and to the right of the existing atoms.One primitive is required for each element of the periodic table. The new atom will have the corresponding label, with default values for all other properties, and no bonds.Add Atom primitive.The subject atoms have their atomic symbol changed. One primitive is required for each element of the periodic table. If there is no subject, then this primitive should be mapped to the corresponding Variations on this primitive should allow arbitrary values to be entered via an input dialog, for symbols which are not atomic elements, such as abbreviations or Markush structures.The subject atoms have their ionic charge set to a specific value, such as 0, -1, +1, etc. The primitives in this class can either specify exact values for the charge, or they can be increment/decrement operations.radical count) set to a specific value, where 0 is for diamagnetic atoms, 1 is for radicals, 2 is for carbene-like species, etc. One primitive is needed for each available value.The subject atoms have the number of unpaired electrons .New Bond with Order, in the Geometry section, which creates a new atom and a new bond.If the subject contains a single atom, this primitive is mapped to If the subject contains two atoms, and they are not currently bonded to each other, a new bond with the requested order is added between them.Otherwise, all bonds between any two atoms within the subject set are set to the indicated bond order. Any of these bonds which previously had a specific stereo style is reset to the default non-stereochemical bond type.This class contains one primitive for each explicit bond stereo-style supported by the molecular datastructure, which includes: inclined bonds (upward wedge); declined bonds (hashed wedge); and unknown stereochemistry (often drawn as a wavy line). When used correctly, these types are sufficient to unambiguously resolve most kinds of stereoisomerism.Set Bond Order class, if the subject contains a single atom, this primitive is mapped to New Bond with Stereo Style, in the Geometry section.Similarly to the If the subject contains two atoms which are not currently bonded to each other, a new bond of order 1 and the indicated stereo style is created. In the case of inclined or declined wedge bonds, the direction is arbitrary, and is defined by the current atom order.Otherwise, all bonds between any two atoms within the subject set become the focus of the operation: the bond stereo style is set to the indicated type. If the indicated type is inclined or declined, then any of the affected bonds which are already of this type have their  order reversed, which inverts the meaning of the wedge, potentially altering the stereochemistry.Of all the subject atoms, any pairwise combination of two atoms which are not already bonded is considered. If there are any such atom pairs whose bond distances are approximately within the default bond distance (see Appendix 1) then all of these pairs are joined by adding a single bond between each pair.If there are unbonded pairs, but none of them are close enough to the default bond distance, then only the closest pair of atoms is connected.Any bond for which both the participating atoms are a part of the subject is deleted. The atoms themselves are not otherwise modified.Removal of atoms and bonds is straightforward, and requires only a small amount of logic to interpret the subject and apply the action to the molecule connection table.All of the atoms in the subject set are deleted, as are any bonds which are connected to them.Any bond which is between two atoms within the subject set is deleted. The atoms themselves are not modified.All atoms and bonds are deleted.Each atom in the subject set is examined to see if it is particularly close to any other atom in the structure, typically set to a tolerance level which is significantly shorter than the default bond distance (see Appendix 1). For each of the subject atoms, a list is made of all other atoms to which the distance falls within the tolerance. From this list, one atom is selected to be retained, using the merging rules described in Appendix 2. The coordinates of the retained atom are set to the average position of the atoms in the list.While the unit primitives for grafting new fragments onto an existing molecular sketch are entirely sufficient for building up many complex molecules, there will always be structures which need to be fine tuned, or drawn with nonstandard parameters. This is often the case around heavily congested atoms for which there is no non-overlapping planar layout that adheres to common conventions.Detailed control over individual atom positions is straightforward to implement, but care is needed to ensure that the primitives accomplish common tasks with a minimal number of invocations.The subject atoms are moved in a specific direction. There are twelve primitives in this class: four directions  by three extents .The small and large nudges offset the X or Y coordinates of the subject atoms in the given direction by an offset, such as 0.1 or 0.5 Å.When moving to the furthest extent, the distance needed to move the subject atoms 1 Å beyond any of the other atoms in the molecule is calculated, and used as the offset.Two primitives are defined for this class: grow and shrink, which correspond to scaling factors of 1.25 and 0.8, respectively.If the subject contains any selected atoms, then a central point is determined from the average positions of the selected atoms, unless there is also a current atom or bond, in which case its central position is used instead. Each of the subject atoms has its position recalculated by scaling its distance from the central point by the scaling factor associated with the primitive.Scale Bond primitive.If there are no selected atoms, but there is a current bond, then this primitive is mapped to the corresponding Scale Atoms class, two primitives are defined: grow and shrink, which correspond to scaling factors of 1.25 and 0.8, respectively.As for the The subject must include two atoms which are bonded to each other. Each side of the bond is assigned a weighting of 0, 0.5 or 1.If the bond is acyclic, then the atoms of the connected components on either side of the bond are counted. If one side forms a component with more atoms than the other, then the smaller side is assigned a weighting of 1 and the larger side a weighting of 0. If both sides have the same size, or the bond is cyclic, then both sides are assigned a weighting of 0.5.The bond length is scaled according to the scaling factor assigned to the primitive, and the weights that are assigned to both sides, i.e. if a side has a weighting of 0 it does not move. For acyclic bonds, when moving one side of the bond, all other atoms associated with that side are moved as well. For cyclic bonds, only the two atoms that make up the bond are extended.Figure Two primitives are defined for this class: horizontal and vertical flip.If the subject contains some number of selected atoms, then these atoms are flipped about the indicated axis. The origin of the axis is calculated as the average position of the selected atoms, unless there is also a current atom or bond, in which case its central position is used instead.If the subject only contains a current atom or bond, then the whole connected component is used as the subject. If the subject is empty, then all atoms are used as the subject.Primitives in this class are defined to be common rotation increments, such as ± 1°, ± 5°, ± 15° and ± 30°.The position of the rotation centre is determined by the average position of the selected atoms, unless there is also a current atom or bond, in which case its central position is used instead. A further special case is defined: if there are no selected atoms, but there is a current bond, and one end of the bond is terminal, then the terminal atom is rotated about the position defined by the non-terminal end of the bond.Because the information provided to the unit primitives cannot include spatial information such as bond direction, a crucial part of the design of the primitives is based on perception of atom geometry.One of the most important sketching primitives is the ability to create a new atom which is bonded to an existing atom. With a traditional user interface this is done by using the mouse to drag a bond line in a particular direction, thus specifying bond angle and distance. Lacking such input, it is necessary for algorithms to be able to estimate the geometry of the atom, and from it, the most likely directions for a new bond.Fortunately there are only a handful of geometry templates which are commonly observed in molecular diagrams, for atoms in environments which are not constrained by rings or heavy congestion. In this work, seven geometry templates are used. These are shown in Figure Most atom environments, when unconstrained, are drawn with complete or partial occupancy of one of these geometries. By examining the immediate bonding environment of an atom, it is often possible to make a reasonable estimate as to which of these geometry templates is most appropriate - and more importantly, which would be most appropriate in the context of adding an additional bond to a new atom. The process of assigning probable geometry based on topology and partial geometry is explained in Appendix 3.When creating a new bond with a known bond order, the first step is to consider the subject atom with an additional bond with the requested order, connected to a newly created neutral carbon atom. In its new circumstances, the subject atom may have some number of preferred geometries. Consider the following cases shown in Figure In the examples shown in Figure Appendix 3 describes in detail the process of determining potential new bond angles. Once the list of angles has been generated, it is necessary to select one. For each of the angles, a point position is calculated by extending to the default bond length. The molecular congestion at each of these points is calculated (see Appendix 4), and the point which has the lowest congestion is used. A new carbon atom is created at this position, and a bond is created between the subject atom and the new atom.New Bond with Order, given that the bond order is 1. The newly created bond has the indicated stereochemical style, e.g. inclined, declined or unknown. For wedge bonds, the atom direction emanates from the subject atom.The new atom position is determined using the same method as for This class has one primitive for each of the 7 available geometries, which are shown in Figure New Bond with Order, but more specific: if the current geometry about the subject atom does not match the indicated geometry with one angle missing, then the operation will instead be mapped to the corresponding Set Geometry primitive. If it does match, then all of the angles which are implied by matching the partial geometry are scored by calculating the congestion at the point of the implied new atom (see Appendix 4). The angle which corresponds to an atom with the least congestion is used to create the new atom and bond.The implementation is related to that of This class has one primitive for each of the 7 available geometries, as shown in Figure Each of the subject atoms is examined in the context of the requested geometry type. If the current geometry about the atom matches the requested geometry, with some number of missing bonds, then this primitive has no effect. If a partial match is not possible, the geometry about the atom will be refitted, if possible, in order to make it compliant with the requested geometry.New Bond with Geometry. In Figure This primitive class is complementary with For each pairwise combination of an existing bond and a bond from the geometry template, the template is rotated so that the two angles match. Of the remaining existing bonds, the angles are rotated so that they align with the closest angle from the rotated geometry template.Cases which require moving of a bond which is part of a ring system are disallowed. If there are multiple ways to refit the geometry, that with the smallest overall angular displacement is chosen. If the geometry template is asymmetric, the process is repeated with its mirror image.One of the caveats of the methods by which the primitives select a new bond geometry is that there are often multiple choices which are quite similarly valid. Selecting the least congested position is the desired result more often than chance, but it is not uncommon for a more congested position to be preferred.For this primitive, the subject must indicate a bond, and only one side of the bond must be terminal. The non-terminal end of the bond is examined, and its most likely bond geometry is estimated, as if the selected bond were not present (see Appendix 3). If no compatible geometry is found, or the only compatible geometry contains no available positions, this operation is not carried out.Any missing angles, which are non-degenerate and differ from the original bond angle, are considered to be viable new angles for the selected bond. Two examples are shown in Figure The grafting of predefined template fragments onto an existing molecular structure is a vital part of the sketching process. Chemical structures include a number of diagram motifs which occur throughout the field, e.g. small rings of sizes 3 through 6 are all but ubiquitous, and rings which are neither square nor hexagonal are difficult to draw precisely. Besides rings and fused ring systems, there are a number of chains, branched chains, larger rings and functional groups which are particularly common. Almost all molecule structure drawing software has some number of predrawn templates, which can be added to the structure as a separate component, or attached to an existing component. Suggested default templates can be found in the Supplementary Information.With a few exceptions, the algorithms needed for fusing an arbitrary structure with an arbitrary template fragment are non-trivial. Given the information allocated to the unit primitives described in this work, it is possible to specify information about the attachment site on the current structure, but not any information about which part of the template itself should be involved in the joining process.Because practicing chemists often work on a series of projects for which particular structural motifs are frequently encountered, but not all of them are common throughout chemistry as a whole, it is also important to ensure that the list of available templates can be extended easily.copy and cut actions that have become a standard part of the desktop metaphor place a single template onto the clipboard, and paste reads the template back out and applies it, using the same algorithm as is used for grafting predefined templates. The clipboard therefore shares the same primitive classes as the template functionality.A standard convenience feature made available by almost all molecular drawing programs is the ability to copy portions of the current molecule onto a temporary container, often referred to as the clipboard, then paste them back later. For the purposes of this work, the clipboard should be considered as a single temporary template, i.e. the This primitive class describes two operations: copying a molecular fragment to a temporary container, such as the system clipboard, and copying a molecular fragment to a persistent collection of fragments, such as a group of templates.The template fragment itself is generated by considering the subject atoms to define a substructure, which is excised from the current structure.If the subject atoms make up whole connected components, i.e. they are not bonded to any atoms which are not part of the subject, then the template fragment is taken to be the substructure in its entirety.guide atoms for the primitive classes which make use of them, which is described below.Otherwise, all atoms which are immediately connected to one or more of the subject atoms are also included in the template fragment, but have their atom type converted into a placeholder atom label. In the examples shown in Figure A logical primitive is defined for each template that is available to the user, including the clipboard, if it contains a suitable molecular structure. The template fragment is an implicit parameter of the primitive. When the operation is instigated, several classes of behaviour will be investigated, depending on the nature of the template fragment and the subject.The objective of the grafting procedure is to produce a list of putative new structures, each of which is a plausible way in which the template might be appended to the existing structure. Each of the following primitive classes is given an opportunity to generate some number of potential new structures, if appropriate.guide atoms. The presence of these atoms introduces opportunities for special behaviour. Using guide atoms is a way to reduce the degrees of freedom when it comes to the possible types of outcomes, which is useful when a template was designed with the intention of using a specific attachment mode. It is also necessary when the attachment modes favour nonstandard bond distances or angles, which would not ordinarily be generated by the geometry perception algorithms.As described previously, templates may have special When there are no subject atoms, adding a template to the current structure is straightforward. It needs to be placed in an area where its atoms and bonds do not interfere with any that already exist, e.g. to the right and centre of the current structure.All possible rotations of increments of 30° and 45° are included in the list of output structures. If the template contains guide atoms, they are stripped out.If there is one subject atom, this primitive applies. If the template contains guide atoms, they are stripped out.New structures are generated using the following overall sequence:Mirror to be the mirror image equivalent of the Template.1. Define N, in the template fragment.2. Loop over each atom, Template, N}.3. Direct Connect {Mirror, N}.4. Direct Connect {Template, N}.5. Bridge Connect {Mirror, N}.6. Bridge Connect {let x = -x. If there are any bonds with inclined or declined stereochemistry, these are interchanged.The connections are repeated with the mirror image of the template structure, in case it is not symmetrical. Generation of the mirror image is done by inverting one of the axes, e.g. N) of the template fragment, and finding suitable angles by which to rotate the fragment. Bridge connection involves creating a new bond between the two atoms, rather than mapping them onto each other.There are two main methods used for grafting templates using a single atom as the frame of reference. Direct connection involves overlaying the subject atom of the initial structure with the iterated atom . The template fragment is translated so that atom N is superimposed on top of the subject atom from the starting structure. The template fragment is rotated by θ1-θ2+180°, about the atom N. The two fragments are then combined, and the result recorded.Both sets of angles are iterated over .3. Loop over each atom, 1 Nso that the direction of the 1N2 Nvector matches that of the first two subject atoms.4. Rotate the template fragment about 5. Match all remaining atoms.In step 4, the position of the first subject atom is used as the axis of rotation, so that the directions of the first two atoms are aligned. In the example shown in Figure 2 Nfrom the template fragment does not now overlap the position of the second subject atom, then the graft is rejected. Once the first two atoms are aligned and matched, the remaining subject atoms are each required to overlap with one of the template atoms. If any of them do not, the graft is rejected.If the position of the atom Once all of the atoms are matched, the fragments are merged, as described in Appendix 2, and a new structure is added to the list.If there is one subject atom, and the template contains one guide atom, and the guide atom has one adjacent neighbour, this primitive applies.bridge connect variant of the Graft with Atom Connection primitive, except with less degrees of freedom, because there is only one applicable template atom, and the projection direction and magnitude is defined by the guide atom.Grafting a template containing a single guide atom to a single subject atom has a similar effect to the The list of projection angles emerging from the subject atom is calculated. These angles are matched against the angle formed from the guide to its neighbour. In the example shown in Figure The bond distance is taken from the distance between the guide atom and its neighbour, rather than using the default bond distance. As with the other grafting primitives, the process is repeated with the mirror image of the template fragment. Once the grafting is complete, the bond connecting the guide atom to the rest of the template fragment is attached to the subject atom, and the guide atom is deleted. The remaining atoms are merged together if there is any overlap.The main benefit of this primitive arises when a template is to be affixed using an irregular or non-obvious geometry, but it is also a way to ensure that a specific template connection point is used preferentially.If there are two subject atoms, and they are bonded to each other, and the template contains one guide atom, and the guide atom has one adjacent neighbour, this primitive applies.The template grafting is done by mapping the subject bond and the template fragment bond to each other. There are 4 base permutations, obtained by using the template fragment vs. its mirror image, and aligning the matched bonds in both parallel and anti-parallel fashion.There is a further bifurcation if the two bonds differ in length: in one case the guide atom is mapped onto the first subject atom, and in the other case the atom adjacent to the guide atom is mapped onto the second subject atom, which is illustrated in Figure Graft with One Guide Atom primitive, because both of the connection angles and the bond distance can be defined prior to the grafting process, which is particularly useful if the subject contains an irregular geometry or nondefault bond distance.This primitive is useful as a constrained case of the If there is at least one subject atom, and the template contains at least one guide atom, this primitive applies in the following cases:1. There is one subject atom and one guide atom, and the guide atom has more than one neighbour.2. There are 2 or more subject atoms, and the number of guide atoms is equal to the number of subject atoms.Graft with One Guide Atom primitive. Bond angle projections are generated from the source atom. For the template fragment, a median angle is generated, by considering the angles between the guide atom and the atoms adjacent to it. In the example shown in Figure The first case is dealt with in a similar way to the Graft with Multiple Connections, except that the guide atoms are used to map the template fragment. As shown in Figure The second case is handled using the same technique as for When any successful matches are found, in which all of the guide atoms can be mapped onto a subject atom, the structures are merged together and the guide atoms are deleted.After each of the primitives described above has had its chance to generate some number of putative new structures, the result list is processed. First, the list is trimmed such that whenever any two structures are found to be equivalent, one of the structures is removed from the list. The method used to decide whether two structures are equivalent is described in Appendix 5.Once the unique set of structures is obtained, they must then be scored. The objective of scoring is to present the most feasible fused structures first, such that the user is most likely to see the desired result presented first and foremost. In cases where it is clear that some structures are significantly more reasonable than others , then some of the results can be omitted.The score for each grafted template result is computed by adding the following terms, where lower is better:1. The total congestion of the molecule (see Appendix 4).2. +1 for each atom that was merged with another atom due to positional overlap.3, sp2 or sp hybridised, and received a new bond which was not positioned at an angle 120° (sp3 and sp2) or 180° (sp) from its neighbours, with a tolerance of 5°.3. +50 for each atom of element type C, N, O, P or S which is clearly sp4. +1000 for every carbon or nitrogen atom with a total bond order of 5 or more.5. -1 for every guide atom involved in the grafting process.The scoring system heavily favours regular bond angles, prefers to add new atoms in less congested orientations, and encourages avoidance of certain types of impossible structures.If the best available structure has a score of less than 1000, then all structures with a score of 1000 or more are excluded.Once the scoring is complete, the structures are ordered so that the results with the lowest scores are shown first. For user interface purposes, it is appropriate to allow the user to traverse the list of potential structures, and select the desired result, if there is more than one. The best scoring result is frequently the intended result of the operation.The unit primitives which have been described thus far provide a way to draw or modify structure diagrams with a small number of steps and a much lower input bandwidth than would be required from a conventional software package which relies on a pixel-perfect pointing device, such as a mouse or trackpad. The following examples illustrate the steps required in order to draw three molecules from scratch, using the primitives described in this work.The first example, shown in Figure Graft with No Connections: benzenea. New Bond with Order: 1b. New Bond with Order: 2c. Switch Geometryd. New Bond with Order: 1e. Set Element Label: Of. New Bond with Order: 1g. Set Element Label: Oh. Graft with Atom Connection: acetyli. ingenol [The natural product ingenol  can be dGraft with No Connections: cycloheptanea. Graft with Multiple Connections: cycloheptaneb. Delete Atomsc. Graft with Bond Connection: cyclopentaned. Graft with Bond Connection: cyclopropanee. New Bond with Order: 2f. Flip Atoms: vertical. Note that the two atoms making up the double bond are selected, while the source of the terminal bond is the current atom.g. Set Stereo Style: inclinedh. Set Stereo Style: inclined. Note that this reverses the direction of the already extant wedge.i. Set Bond Order: 2j. New Bond with Order: 1k. New Bond with Stereo Style: inclinedl. New Bond with Stereo Style: declinedm. New Bond with Geometry: tetrahedral (variant #1). Note this primitive is issued twice, in order to create two new bonds.n. New Bond with Order: 1o. Set Element Label: Op. Set Element Label: Hq. The gold-based catalytic intermediate for a carboxylation reaction  is drawnGraft with Atom Connection: cyclopropanea. Set Bond Order: 2b. Set Element Label: Nc. New Bond with Order: 1d. Graft with Atom Connection: benzenee. New Bond with Stereo Style: declinedf. New Bond with Stereo Style: inclinedg. New Bond with Order: 1. Note this primitive is issued twice, in order to create two new bonds for each of the selected atoms.h. Create Template: copy to clipboard.i. Graft with One Guide Atom: paste from clipboard.j. Scale Atoms: growk. New Bond with Geometry: linearl. Set Element Label: Om. New Bond with Geometry: linearn. Graft with Bond Connection: acetylo. Graft with Atom Connection: cyclopentadienep. Set Element Label: Nq. Set Element Label: Or. A collection of unit primitives for sketching molecular diagrams has been described. It is complete, such that complex molecules can be drawn by stringing together a series of these primitives. It is efficient, insofar as the more regular components of a chemical structure can be drawn using a small number of primitives, since only a very small amount of information must be transmitted from the user in order for the algorithms to infer the intent. Less regular features can be created by manipulating atom positions or angles using a variety of low level primitives, but a number of implicit shortcuts can be exploited to keep repetitive actions to a minimum.Several representative examples have been shown, which illustrate the relatively small number of steps and low information content necessary to draw complex molecular geometries, and obtain publication-quality depiction layout coordinates.The primitives described in this work provide the tools needed to build a user interface in which input is limited to selecting atoms and picking from menu choices. The interface can expose the primitives by several means, such as menu bars, icon toolbars, keyboard shortcuts, etc. As long as all of the primitives are conveniently available, the user interface will provide a complete and efficient molecule drawing tool.These primitives have been implemented in a commercial software product called the Mobile Molecular DataSheet (MMDS), which is available for BlackBerry smartphones and iPhone/iPod/iPad devices . Both veWhile the motivation for this work arose from the need to provide molecular sketching capabilities on mobile devices with tiny screens and lack of accurate pointing devices, the set of primitives has applicability outside of this niche.One analogous situation is found in web-based applications where the capabilities of the browser must be assumed to be a lowest common denominator, which requires that the web server do most of the work . Under tde novo series [The primitives described in this work were designed for the purpose of using them to compose a user interface, but they may find applicability as part of scripted processes. For example, when producing a series of chemical structures as part of a combinatorial library ,21 or soo series -24, it mBecause a molecular sketch does not correspond to a physical model, the 2 D coordinates of the atoms are chosen so that they can be presented on a screen or a piece of paper, in such a way that chemists can quickly perceive the structural features and be able to ascertain stereochemistry from the layout and additional annotations.The choice of units for the coordinates is arbitrary, but in this work, Angstroms are used. The default unit of distance between any two atoms is 1.5 Å, which applies regardless of atom and bond type.overlapping. Some of the algorithms described in this work consider overlapping atoms as a cue to merge two atoms together. Otherwise, the presence of overlapping atoms is generally considered to be an error state, since this makes visual perception of a diagram difficult.Any two atoms that are closer than 0.2 Å are considered to be The template grafting algorithms described in this work mostly operate by joining specific atoms together. While these atoms are merged, bonded or deleted according to the algorithm, there is also the possibility for additional atoms to overlap. This situation is dealt with according to the following steps.The composite structure is partitioned into its two sources, i.e. atoms that originated from the starting structure, and atoms that originated from the grafted fragment. Pairwise combinations of these atoms are examined to see if they overlap. When an overlap is found, one atom must be retained, and the other atom deleted. Before the other atom is deleted, its bonds must be reassigned to the retained atom.exotic each atom is, which is calculated by assigning one point for each condition that applies:The decision as to which atom to retain is made based on how - Having an element label other than carbon- Non-zero charge- Any unpaired electrons- Non-default isotope abundance- Specific non-automatic hydrogen countThe most exotic atom is retained, or the first one, if they are equally so.exoticness of a bond is assigned by one point for each of:During the merging process, it is possible to create duplicate bonds. A similar process is used to decide which bond to keep. The - Bond order other than 1- Any stereochemical assignmentAs for atoms, the first bond is retained in the event of a draw.Other primitives besides template grafting also have need to merge together atoms which happen to overlap. In these cases the same procedure is used, but without the partitioning.For many of the primitives described in this work, it is necessary to produce a list of potential angles for a new bond that will be created with a particular source atom and bond order in mind. When the list of angles produced contains the result which is desired by the user, the amount of effort required to draw the structure is considerably reduced.The following sequence is used to obtain a list of potential new bond angles:1. If the atom is isolated, return four angles, aligned on the X and Y axes.2. Match the atom's bond topology to likely geometry templates , classify as either s-block atoms, classify as either trigonal, square planar or either of the octahedral geometries.b. For trigonal, square planar or either of the tetrahedral geometries.c. If the atom is carbon, and the bonds are all single, classify as either trigonal.d. If the atom is carbon, and the bonds are not all single, classify as p-block, and in the first 3 rows, classify as being trigonal, either of the tetrahedral geometries, or square planar.d. If the atom is in the p-block, but not in the first 3 rows, classify as being any of the available geometries.f. If the atom is in the octahedral geometries.g. Otherwise, classify as either of the two Once the possible classifications have been enumerated, each of them is checked to see if there is any way the current geometry can match it, within a tolerance of 2°. The first postulated geometry to achieve a match is given precedence. All of the nondegenerate vacant bond directions implied by the ways in which it can match the input structure are returned as the resulting list of possible new bond geometries.If no matches were found, the list of current bond angles are sorted by bond angle. For each bond, the angle directly in between itself and the next angle in the list  is calculated and added to the result list.congestion to make decisions about where to place a new atom, bond or fragment, when an otherwise degenerate choice is available. The position which places new atoms as far away as possible from existing atoms is frequently preferable to the alternatives.A number of the primitives use The congestion at a specific point is calculated by:i iterates over each atom in the structure, and x and y denote the atomic position, where the subscripted variables are the positions of existing atoms.where The total congestion of a molecule is calculated by:i and j iterate over all unique pairs of atoms.where Two structures A and B are considered equivalent or not according to the following algorithm:1. If the number of atoms or bonds is different, the structures are different.2. The structures are translated so that their centre positions are the same. Each atom in structure A is mapped uniquely to the closest atom in structure B, which must be within 0.2 Å.3. If any atoms are not successfully mapped, the structures are different.4. Every atom in structure A must be mapped to an atom in structure B which has the same element label, charge, unpaired electron count, etc. If any mapped pair of atoms are not the same, the structures are different.a1 and a2, there must be a corresponding bond in structure B, between atoms b1 and b2, where a1:b1 and a2:b2 are mapped to each other. If the bond stereochemistry type is not a wedge bond (inclined or declined), the inverse mapping, a1:b2 and a2:b1, is also permitted. If no such pair can be found, the structures are different. The matched bonds must have the same order and stereochemistry type. If not, the structures are different.5. For every bond in structure A, between atoms 6. If no differences were found, the two structures are equivalent.This comparison considers alternate tautomers and Kekulé resonance forms to be different species, which is desirable for sketching purposes. The determination of the equivalence of two sketches, as described above, should not be confused with methods used to determine whether two connection tables represent the same molecule, such as unique SMILES  or InChIA list of template fragments grouped into categories is provided [Additional file Additional examples of diagram drawing using the primitives described in this work can be found online .The author is the founder and president of Molecular Materials Informatics, Inc., which produces the Mobile Molecular DataSheet, a working implementation of the primitives described in this manuscript. This publication is a disclosure of the algorithms that form the basis of a commercial product.Suggested default template fragments. A printable document containing diagrams of template fragments.Click here for fileSuggested default template fragments (SD files). A collection of MDL SD files, one per group, containing machine-readable data for each of the template fragments.Click here for file


Cardiovascular diseases (CVD) are the leading cause of death and the third cause of disability in Europe. Prevention programmes should include interventions aimed at a reduction of medical risk factors  as well as behavioural risk factors . The aim of this study is to investigate the effects of a multifaceted, multidisciplinary electronic prevention programme on cardiovascular risk factors.In a randomized controlled trial, one group will receive a maximal intervention (= intervention group). The intervention group will be compared to the control group receiving a minimal intervention. An inclusion of 350 patients in total, with a follow-up of 3 years is foreseen. The inclusion criteria are age between 25–65 and insured by the Onderlinge Ziekenkas, insuring for guaranteed income in case of illness for self-employed. The maximal intervention group receives several prevention consultations by their general practitioner (GP) using a new type of cardiovascular risk calculator with personalised feedback on behavioural risk factors. These patients receive a follow-up with intensive support of health behaviour change via different methods, i.e. a tailored website and personal advice of a multidisciplinary team . The aim of this strategy is to reduce cardiovascular risk factors according to the guidelines. The primary outcome measures will be cardiovascular risk factors. The secondary outcome measures are cardiovascular events, quality of life, costs and incremental cost effectiveness ratios. The control group receives prevention consultations using a new type of cardiovascular risk calculator and general feedback.This trial incorporates interventions by GPs and other health professionals aiming at a reduction of medical and behavioural cardiovascular risk factors. An assessment of clinical, psychological and economical outcome measures will be performed.ISRCTN23940498 In Europe, cardiovascular disease (CVD) is the leading cause of death (1.5 million deaths per year) and is an important source of disability . The incPreCardio is a randomized controlled trial. Approval was obtained from the ethics committee of the University Hasselt. A total of 350 subjects will be included in the study with a follow-up of 3 years. The inclusion criteria are age between 25–65 and insured by the Onderlinge Ziekenkas, insuring for guaranteed income in case of illness for self-employed. All study participants need to sign an informed consent and have access to the internet. Other eligitability criteria are not included.study participants will be recruited through various channels. Firstly, all potential participants are insured by "De Onderlinge Ziekenkas". This membership gives the study secretariat access to necessary contact information. Secondly, all of the insured are self-employed, most of them lawyers. This provides the study office with two advantages: (1) communication is possible at the worksite and (2) the prevention programme is even more tailored to the uniform target group. The announcement of the study was already made through mass-media announcement  but will be intensified at the worksites of the potential participants. Together with the involved Bars (of the province of Limburg in the East of Belgium) mass mailings and promotional activities at the worksite  will be organized. Thirdly, a large event will be organised for the participants of the intervention group and control group. Before joining these events a written informed consent, downloadable on a website with brief information, should be signed and mailed back to the study secretariat. At this large event general information about PreCardio will be given, a first screening and the ability to purchase health-related products.The general practitioners (GP) that will participate in the study are GPs of the province of Limburg, situated in the East of Belgium. They will be recruited with involvement of their own provincial general GP platform "Limburgs Huisartsenplatform" and provincial institutions involved in health "LOGOs". Together with the GP platform and the LOGOs mass mailings to GPs of Limburg will be organised. Moreover, minimal two information sessions for GPs will be organised in the university building with information about the study and education about a new type of cardiovascular risk calculator will be offered. All participating GPs need to sign an informed consent and have access to the internet for downloading an electronic cardiovascular risk screenings programme based on the European Guidelines for CVprevention. Th. Th15]. For physical activity assessment it is important that each study participant gives an estimate of the intensity, duration and frequency of the physical activity he has in daily life. For this purpose a Dutch translation and computerized version of the International Physical Activity Questionnaire (IPAQ) was chosen. This cor from 0.45 to 0.77), and adequate validity comparing the food-frequency questions with 7-day food records (Spearman r from 0.38 to 0.53)[To stimulate rapid assessment only data collection will be limited to fat intake and fruit and vegetable intake. For fat intake assessment a computerized fat intake questionnaire with a good reliability and adequate validity was chosen. For fru to 0.53).To obtain data about smoking behaviour, a short questionnaire regarding smoking from a national health questionnaire used by the federal government was selected. This quThe Dutch translation of the Short Form 36 (SF-36) will be used to measure Health Related Quality of Life (HRQoL). This version was successfully tested in a Belgian and Dutch population with a Chronbach's alpha coefficient ranging from 0.81 to 0.91,22.Stages of change is a construct from the TransTheoretical Model. The staAttitudes are an important element in the Theory of Planned Behaviour. As recoSelf-identity is seen as the extent to which people see them fulfilling different societal roles. In thisPerceived control over behaviour is related to self-efficacy, the two variables are significantly and highly correlated . HoweverSelf-efficacy is usually measured in terms of individuals' confidence in their ability to perform the behaviour . Self-efPeople are autonomously motivated if they experience a true sense of volition and choice and act because of the personal importance of the behaviour ,31. If pIntention to engage in a behaviour is a direct precursor to engaging in the behaviour itself . BehavioSocial support is an important variable influencing behaviour change. ConsequA step test will be used for assessment of physical fitness. The step test procedure used was modified from earlier procedures. The steThe interventions targeted on medical parameters include a first medical prevention consultation with the GP. In this medical prevention consultation the cardiovascular risk (risk on having a heart attack in the next 10 years) will be calculated using a new computer programme. This computer programme is called "Electronic Prevention Record" (EPR). Innovative about the EPR is its connection to "Electronic Medical Record" (EMR). The EMR is also a computer programme, a record about the medical history and treatment provided to the patient. In the province of Limburg, the setting for the PreCardio-study, 75% of the GPs use an EMR. In BelgAll data collected at the medical prevention consultation are stored in the EPR that is connected to the EMR Fig . Therapewithout tailored feedback and without reminder from study office). It is also used as a means for study measurements at certain times during the 3-year follow up  is about physical activity, fat intake and smoking and is modified for different measurements in time to avoid drop-out. However, the advice will always be formulated very abstract to avoid 'contamination' of the control group as was the case in another multiple risk factor cardiovascular intervention study[The website available for the control group is limited and contains information about the minimal intervention  walking aiming at a health benefit. The programme most in line with the PreCardio mission, namely CVD prevention, is the "Reduce my risk" programme. This programme is a fitness programme aimed at improving physical fitness through more intensive PA. The basis for the fitness programme is a specially developed algorithm linked to the step test used in the study Fig . Three dNext to the personalised website with tailored feedback, study participants of the intervention group are entitled to support from a multidisciplinary team. This multidisciplinary team includes: a cardiologist, a general practitioner, a psychologist, a physiotherapist and a dietician. Different media will be available for this personal contact: personal messages on the website, the forum on the website, e-mail, telephone and group sessions. The first types of media will be more frequently used than the latter, dependent on the stage of behaviour change patients are in. Moreover, the cost-effectiveness of the prevention programme must be guarded. The psychologist (= behaviour coach) can aid people more thoroughly with behaviour change, using the different manuals and behavioural (cognitive) therapy.At GP-level a tool for computer-assisted cardiovascular risk screening (EPR) will be implemented. Minimal two information sessions for GPs will be organised in a university building with information about the study and education about the EPR. GPs will have access to an informational website. This informational website contains information about CVD prevention in general with a summary of the latest guidelines . . Furthermore, it contains information about the PreCardio-study and the role of the GP in the study. On this website information about the EPR will be available . GPs are provided with information on behaviour change, including video registrations of motivational interviewing adaptations for PreCardio. In the section on behaviour change more information will be given about the stages of change and type D-personality as a risk factor for CVD. The website for GPs also contains an overview of the personalised website for patients from the intervention group. GPs have access to a forum where they can post messages to open a debate with their participating colleagues about CVD prevention or the PreCardio-study or messages with a question for the PreCardio-team. In other sections contact information and links to relevant websites can be found.et al found a mean systolic blood pressure of 125 mm/Hg (SD 14 mm/Hg)[®. A two group t-test with a 0,05 two-sided significance level will have 82% power to detect the difference between a Group 1 mean of 120 mm/Hg and a Group 2 mean of 125 mm/Hg, a difference in means of -5 mm/Hg, assuming that the common standard deviation is 14 mm/Hg, when the sample sizes in the two groups are 200 and 100, respectively . Other outcome measures were also used to determine the necessary sample size. A recent study about the effect of a computer-tailored intervention to reduce fat intake included at post-test a mean fat intake of 85 grams/day (SD 34.5 grams/day) [A power calculation was performed to determine the number of study participants needed to detect a significant effect of the PreCardio prevention programme. A t-test will be used to compare the means of the outcome measures from the intervention and the control group. The sample size calculation is based on the population standard deviation of the primary outcome measure. For PreCardio, this is, for instance, systolic blood pressure. Kelley 14 mm/Hg). The samams/day) . A two gams/day) . In thisams/day) . A two gA linear regression model will be employed to assess the effects of the prevention programme on change in overall cardiovascular risk from baseline to 3 year follow-up.Next to an effect evaluation a cost analysis will be performed. There are different costs that will be measured in the PreCardio-study: (1) One-time costs, this is the total cost for the implementation of the prevention programme ; (2) Costs for medical resource use ; (3) Continuous costs: (acute care) costs for CVD, costs for CVD morbidity and mortality, hospitalization costs (4) Administration costs; (5) Personnel costs ; (6) Travelling and time costs (e.g. study participant's time and GP time); (7) Indirect costs due to productivity loss; (8) Material costs and overhead. This study will be performed from a health service perspective.et al., SF-36 data were converted using a specific algorithm into health state utility values for the determination of incremental QALYs[In cost effectiveness analysis incremental cost-effectiveness ratios (ICER) are used as an economic outcome measure. An ICER can be calculated as incremental cost divided by incremental effectiveness . Incremetal QALYs,48.The PreCardio-study is a randomized controlled trial. However, the shared worksite setting could lead to an intervention contamination. In this regard, the failure to find significant effects from the Heartbeat Wales programme due to contamination of the reference area is relevant. PartialSeveral aspects of the PreCardio-study are noteworthy. Firstly, all interventions are based on recent guidelines and knowledge on CVD prevention. Moreover, this knowledge was taken as a basis to develop a new computer programme for GPs. After limited input, this programme automatically determines CVD risk and generates therapeutic goals according to this risk. Furthermore, tailored advice is provided to the study participant. The involvement of GPs in the PreCardio-study is paramount. Secondly, study participants are provided with a number of aids to support them with behaviour change. These include a personalised website with tailored feedback and personal support from a multidisciplinary team. Consequently, a reduction in medical and behavioural risk factors resulting in a reduction in overall CVD risk is expected.BMI, body mass index; BREQ-II, Behavioural Regulation Exercise Questionnaire II; CVD, cardiovascular diseases; EMR, electronic medical record; EPR, electronic prevention record; GP(s), general practitioner(s); HRQoL, Health Related Quality of Life; ICER, cost-effectiveness ratio; ICT, information and communication technology; IPAQ, International Physical Activity Questionnaire; MI, motivational interviewing; PA, physical activity; QALY, Quality Adjusted Life Year; SDT, Self-Determination Theory; SF-36, Short Form 36 TBP, Theory of Planned Behaviour.The author(s) declare that they have no competing interests.The PreCardio-study Protocol was written by prof dr Neree Claes (NC) and psychologist Nele Jacobs (NJ). Both authors have made substantial contributions to this protocol and performed a feasibility study prior to the development of this study protocol. NC, project manager, has elaborated the study design and co-authorised the manuscript. NJ drafted the manuscript and participated in the study design. Both authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


Sex Hormones and Physical Exercise (SHAPE) study. Purpose of SHAPE study is to examine the effects of a 1-year moderate-to-vigorous intensity exercise programme on endogenous hormone levels associated with breast cancer among sedentary postmenopausal women and whether the amount of total body fat or abdominal fat mediates the effects.Physical activity has been associated with a decreased risk for breast cancer. The biological mechanismn(s) underlying the association between physical activity and breast cancer is not clear. Most prominent hypothesis is that physical activity may protect against breast cancer through reduced lifetime exposure to endogenous hormones either direct, or indirect by preventing overweight and abdominal adiposity. In order to get more insight in the causal pathway between physical activity and breast cancer risk, we designed the In the SHAPE study, 189 sedentary postmenopausal women, aged 50–69 years, are randomly allocated to an intervention or a control group. The intervention consists of an 1-year moderate-to-vigorous intensity aerobic and strenght training exercise programme. Partcipants allocated to the control group are requested to retain their habitual exercise pattern. Primary study parameters measured at baseline, at four months and at 12 months are: serum concentrations of endogenous estrogens, endogenous androgens, sex hormone binding globuline and insuline. Other study parameters include: amount of total and abdominal fat, weight, BMI, body fat distribution, physical fitness, blood pressure and lifestyle factors.This study will contribute to the body of evidence relating physical activity and breast cancer risk and will provide insight into possible mechanisms through which physical activity might be associated with reduced risk of breast cancer in postmenopausal women.NCT00359060 Most of the established risk factors for breast cancer, such as family history of the disease, early age at menarche, late age at menopause, late age at first childbirth or nulliparity are not, or not easily, amenable to intervention. Physical activity is a modifiable lifestyle characteristic that has been associated with breast cancer risk in various studies -22 and aFurthermore, both an early menarche and a late menopause increase risk, probably by increasing lifetime exposure to ovarian hormones ,34. SeveSo far, one study has reported on the effects of an exercise intervention on sex steroid concentration among postmenopausal women. This study observed that a 12-month moderate-intensity exercise intervention in sedentary, overweight women resulted in small but significant decreases in serum estrogens and androgens. These results were restricted to women who lost a certain amount of body fat.Sex Hormones and Physical Exercise (SHAPE) study. This study examines the effect of an exercise intervention on sex steroid hormones and insulin in sedentary postmenopausal women and investigates if the amount of total body fat or abdominal fat mediates the effect. If increase in physical activity has a beneficial effect on the sex hormone and metabolic profile of postmenopausal women, it will offer opportunities for breast cancer prevention programs. This paper presents the design and evaluation plan of the SHAPE study.In order to get more insight in the causal pathway between physical activity and breast cancer risk, we designed the The SHAPE study examines the effects of a 1-year moderate intensity exercise programme on endogenous hormone levels  associated with breast cancer among sedentary postmenopausal women. The study is designed as a single blind, randomised, controlled trial with two study arms.We chose to include only postmenopausal women because (a) there is more evidence for an inverse association between physical activity and breast cancer risk in postmenopausal women (b) the incidence of breast cancer is greatest in postmenopausal years (c) the major conversion locus of androgens into estrogens in postmenopausal women is fat tissue – a reduction in fat mass through exercise may be more likely to affect the relative concentrations of estrogens on postmenopausal women than in premenopausal women (d) there are no problems associated with measurements of hormones with timing of the menstrual cycle.The SHAPE study includes 189 healthy postmenopausal women aged 50 tot 69 year, who are sedentary and not currently using postmenopausal hormone replacement therapy. Postmenopausal status is defined as not having menstrual periods for at least 12 months. Being sedentary is defined as less than 2 hours per week of moderate sport activity  and not adherent to the international physical activity recommendation. The international physical activity recommendation states that every adult should accumulate 30 minutes or more of at least moderately intense physical activity for at least five days per week ,47. The Participants are recruited through a random selection out of the female inhabitants aging 50–69 years of the following middle sized municipalities in the centre of The Netherlands: Utrecht, Zeist, Bilthoven, Houten, Soest en IJsselstein. Potential candidates receive an invitation letter explaining the goal of the study and a short eligibility questionnaire. Next, the potential candidates are contacted by phone to explain further details and the inclusion criteria list is completed to screen eligibility. Additionally, interested and eligible women receive written study information and are asked to complete and sign an informed consent form. With the women who return their informed consent form an appointment for the baseline visit at our research unit is made. See Figure Eligible women are randomised into an intervention group or a control group. Randomisation is blocked on two categories of waist circumference: < 92 cm and ≥ 92 cm .Women in the intervention group participate in a combined endurance and strength training programme over a period of 12 months. The programme is organised in a way to optimise fat loss. The goal of the intervention programme is to have participants exercise at least 3 times per week  and to reach a training stimulus in each person. In general, implementation of the exercise goals is done slowly, to reduce chance of injury and to increase participants' adherence and sense of accomplishments.Twice a week the participants of the intervention group meet for an exercise session of one hour. Each group includes about 15–20 women. A qualified sports instructor facilitates the standardised group sessions according to a protocol. Group exercise takes place in six fitness centres located in the subjects' home town. Classes start with a 10-minute warming up: e.g. exercise to music routines and walking. Then the training is continued with moderate-to-vigorous level of aerobic exercise on 60 – 85% of the age-predicted maximum heart rate. The maximum heart rate is established as 220 minus the person's age in years. The participants receive heart rate monitors to control their training intensity. The training session ends with 25 minutes strength exercises and 5 minutes cooling down. The sport instructor registers the attendance of the subjects. Since it is important that the group exercise sessions are conducted uniformly in all centres, all instructors who participate in the SHAPE study are instructed extensively. In addition, the study coordinator (EM) performs several monitor visits per exercise group to control adherence to the protocol.Previous experience showed that group exercises are preferred by Dutch women of this age and are better adhered to in the short and long term . HoweverOnce a week the participants are asked to perform an individual home-based exercise session. They receive instructions during the group sessions. The home-based exercise programme consists of 30 minutes brisk walking or cycling with an intensity of moderate-to-vigorous intensity . Afterwards, the women record the type and duration of their activity in an exercise log, together with the mean heart rate during the training and the BORG-score (6–20) for exertion .Participants in the control group are requested to retain their habitual exercise pattern. They also receive newsletters. Although some control subjects may decide to increase their level of physical activity, we believe that it is unlikely that they will sustain in a similar level as the intervention group. Level of physical activity is measured frequently to monitor changes in physical activity (PASE questionnaire) during the course of the intervention.The study participants visit the research unit of the Julius Center at baseline, after 4 months and at the end of the study (See table Blood samples (30 ml per visit) are drawn between 9.00 and 11.00 AM after an overnight fast in order to determine serum concentrations of estradiol , estrone, estrone sulfate testosterone, androstenedione, insuline, glucose and sex hormone binding globulin. Blood samples are stored at -70°C. All samples from an individual subject are analysed in the same batch since the batch-to-batch variation can be higher than any woman's likely change in hormones over the year . Serum eThe laboratory "Stichting Huisartsenlaboratorium Oost" in Velp  performsBody weight and height (to the nearest 0.5 kg and 0.5 cm respectively) are measured while the subjects wear light clothes and no shoes using an analogue balance (SECA) and wall-mounted tape measure.Body fat distribution is measured by the waist- and hip circumference. Waist circumference (to the nearest 0.1 cm) was measured standing at the midway between lower ribs and iliac crest. Hip circumference (to the nearest 0.1 cm) was measured standing over the buttocks. All measurements were taken in duplicate and averaged. Total body fat and body fat percentage are determined by using a whole-body DEXA scan . A whole body scan analyses body composition according to a three-compartment model: fat mass, lean tissue, and bone mineral content. The standard soft tissue analysis is performed using software supplied by the manufacturer. Total body fat is estimated for each subject in kilograms.Intra-abdominal fat is measured by abdominal ultrasound assessment . The ultrasound measure comprises the distance between the peritoneum and the lumbar spine at three predefined places. All measurements are performed longitudinally from one line over the abdomen halfway between the lower rib and iliac crest.Blood pressure is measured with an automatically tonometer (OMRON M4) after participants have been sitting quietly for at least five minutes.2 max). VO2 max is determined by a submaximal cycle test: the Fit Test programme on a Life Fitness cycle ergometer. The theory of the test is based on the Ästrand Rhyming Protocol [2 max estimate based on the subject's weight, age, gender, selected resistance, and steady-state heart rate. After the test, the subject pedals without resistance for 2 minutes to cool down.Fitness is measured by the maximal oxygen uptake  was 0.993 (P < 0.001). Other reliability indexes  were respectively 0.993, 0.532 ml/kg/min and 1.475 ml/kg/min. This reproducibility study showed that the Fit Test is a reproducible measure of submaximal work capacity.To assess reproducibility of the Fit Test, we tested 25 volunteers twice with an average period of 2.0 ± 1.5 days between the tests. Group means and standard deviations of the first and second VOA self-constructed questionnaire  is used to assess level of physical activity, diet, socio-demographic variables, smoking history, medical history and reproductive factors.The general physical activity questionnaire includes the Voorrips questionnaire measuring habitual activity in elderly subjects  and quesThe PASE  questionnaire  measuresDaily caloric intake, percent daily calories from fat, percent daily calories from carbohydrates and proteins is determined by a food frequency questionnaire ,58. The Medication use is asked each visit and registered by use of an internet database. This database is based on the current available medications and uses ATC codes.All randomised subjects will be analysed according to the intent-to-treat principle. The intention-to-treat principle will assess the intervention effect based on assigned treatment at the time of randomisation regardless of adherence. Demographics and baseline characteristics will be reported descriptively. We will assess whether life style factors that are potentially related to hormone levels might have changed differentially between exercisers and controls, including alcohol use and caloric intake. Differences between the treatment groups in primary and secondary efficacy parameters will be analysed by repeated measurement analyses in SAS and 95% confidence intervals will be calculated. We will also assess effect modification by change in intra-abdominal  and, among exercisers only, by adherence levels.In this paper, we present the rationale and design of the SHAPE trial which aims to get more insight in the biological mechanism underlying the observed effect between physical activity and breast cancer risk.The success of the study will depend to a large extent on adherence to the exercise protocol. Factors that enhance adherence to exercise programmes in The Netherlands are group exercise , a varied programme and a regular instructor . We incoIt is also of utmost importance that the control group is compliant with the study protocol, e.g., retaining their habitual lifestyle pattern. Women who are randomised to the control group might be disappointed about the assignment and may take up exercise or change their diet. We monitor the level of physical activity of all participants with questionnaires in order to get insight in the actual amount of physical activity and potential cross-over between both treatment arms. Changes in diet are monitored by a food frequency questionnaire.Six fitness centres and fourteen instructors participate in the SHAPE study. Although the exercise protocol is standardised as much as possible, the attitude and experience of the instructor might influence the actual performance of the participants. In the analysis, we will explore whether outcomes of participants within the same sporting centre are correlated (intracluster correlation). If there is evidence for intracluster correlation, we will account for this in the analysis.Because of the stringent in and exclusion criteria, the participants of the SHAPE study comprise a selected group of postmenopausal women. This type of preselection will not affect the validity of the study (no selection bias) because randomisation is aimed to ensure comparability of intervention and control group but it may limit the generalisability. For example, since we exclude lean women and women not using hormone replacement therapy, the results might not be generalised to these groups of women.So far, one study (PATH study) has been published on the effects of exercise interventions on sex steroid concentration in women . The PATIn summary, this paper shows the rationale and design of the SHAPE study. The SHAPE study aims to unravel the mechanisms underlying the association physical activity and breast cancer risk. Furthermore, this study evaluates the feasibility of delivering an exercise programme for postmenopausal women.2max, Maximum Oxygen Uptake; ATC, Anatomical Therapeutic Chemical Classification SystemBMI, Body Mass Index; DEXA, Dual-Energy X-ray Absorptiometry; SHBG, Sex Hormone Binding Globulin; VOThe author(s) declare that they have no competing interests.EMM, PHMP and AJS designed the study, participated in the coordination of the study and writing of the article. All authors provided comments on the draft and have read the paper.The pre-publication history for this paper can be accessed here:


Physical activity participation is low among blacks, and strategies are needed to successfully create immediate and sustained behavior change related to physical activity. Churches can play an important role in health promotion efforts among blacks because of their central role in spiritual guidance, communication, social support, and networking. This pilot study evaluated the feasibility and acceptability of implementing a physical activity program for sedentary black adults in churches.We used a preintervention/postintervention single-group design to evaluate the effect of a 3-month faith-based physical activity intervention on daily walking and moderate- and vigorous-intensity physical activity among sedentary blacks. Eighty-seven black adults participated in eight group sessions that included discussion of physical activity-related topics, an instructor-led physical activity session, and weekly incentives to promote physical activity. We used a questionnaire to assess moderate and vigorous physical activity in minutes per week at baseline and after 3 months. Walking was assessed weekly in steps per day by using a pedometer.2) reported 27 ± 54 and 10 ± 25 minutes per week in moderate-intensity and vigorous-intensity physical activity, respectively, and walked 4822 ± 2351 steps per day at baseline. After 12 weeks, moderate- and vigorous-intensity physical activity increased by 67 ± 78 and 44 ± 66 minutes per week, respectively (P ≤ .01), and daily walking increased by 1373 ± 728 steps per day (P < .001).Participants (mean age, 52 yrs; mean body mass index, 35 kg/mThese data suggest that a faith-based physical activity intervention may be an appropriate strategy for increasing physical activity among sedentary black adults. Future research will determine the impact of this program in a randomized, controlled design. The benefits of increased physical activity (PA) have been well documented -4, yet nThe purpose of this study was to develop and test a faith-based PA program to increase participation in daily walking and moderate- and vigorous-intensity physical activity , particularly in bouts lasting 10 minutes or longer, among sedentary black adults. This study was funded as a part of a career development grant. Data collected during this study were intended to serve as pilot data for a proposal for a larger randomized, controlled trial to test the faith-based PA program compared with a control group.We conducted this study in a suburban community in North Carolina from March through October 2005. In September and October 2004, nine local church pastors participated in in-depth interviews and provided input on the design, development, and implementation strategies for health promotion programs in churches in general and a faith-based PA program specifically. Pastors were recruited from a list of pastors who attended (or sent a representative to) at least one of two luncheons held for ministers in the local community to determine potential strategies for health promotion and disease prevention among blacks.Data from in-depth interviews suggested that, in general, health was viewed as a concept that encompassed spiritual, physical, mental, and emotional health. Pastors indicated that they play a role in the health of their church congregants by setting an example for healthy living, imparting the knowledge that wholeness and health are essential parts of Christian character that enable one to do God's bidding and that the body is God's temple. They advocate, encourage, and support efforts to engage in healthy behaviors and to implement health-related programming within the church. Pastors provided suggestions for why their congregants were not physically active  as well as feedback on ways to successfully implement a faith-based intervention .We used information from the in-depth interviews to shape the study design and session content of the faith-based PA intervention. Because the pilot study was designed to determine the feasibility and acceptability of the intervention strategy, a preintervention and postintervention study design with no control group was used. This design was deemed the most acceptable for church pastors and is in line with previous research suggesting that a no- or low-attention control would not be well received by this population . The intParticipants maintained weekly logs of pedometer step counts, which were used to self-monitor walking, and received a weekly summary to track walking progress throughout the study. We used incentives to encourage participants to increase their daily MPA to at least 30 minutes by engaging in moderate-intensity walking. Although participants were not given specific targets to increase their steps per day, they were advised of the 10,000 steps recommendation for daily walking  and wereWe hired group leaders to lead the weekly intervention sessions at churches. The following characteristics were considered desirable for group leaders: 1) having a working knowledge of general health and wellness but not being currently employed as a health educator, 2) being physically active but not exceptionally athletic, 3) having previous experience working with blacks and other groups in faith-based settings, 4) being comfortable speaking in group settings; and 5) not being a member of a church involved in the intervention. These criteria were selected to avoid hiring highly trained individuals, which might hamper the ability to disseminate this type of intervention to a larger audience, and to avoid potential biases by hiring church members because all four churches could not be represented in group leadership. Two black females were recruited as group leaders. Each group leader was assigned to lead sessions at two churches, depending on the time the church selected to hold the sessions and the availability of the group leader.Each church pastor also selected one church member to serve as a liaison between the church and the study staff and to attend to any church-related logistical issues. We paid church liaisons a modest honorarium for their participation in the study. In addition, church liaisons received a group leader training manual and session materials to facilitate continued implementation of the PA program after completion of the study. No additional incentives or compensation were provided to churches or pastors.or obtaining recommended MPA and VPA, but in bouts lasting less than 10 minutes, as assessed using a modified version of the International Physical Activity Questionnaire); 4) responding “no” to all questions on the Physical Activity Readiness Questionnaire (PAR-Q) or having obtained medical clearance; 5) having no other physical illnesses or disabilities limiting PA; and 6) being willing to commit to participating in weekly intervention sessions and all data collection visits. All individuals who attended an interest session received a pedometer, regardless of their eligibility for study participation. Eighty-seven participants met the eligibility criteria and were enrolled in the study.We selected a convenience sample of four churches that identified themselves as predominantly serving blacks and whose pastors participated in one of the previously mentioned ministers’ luncheons. Recruitment for study participants was at the churches’ discretion; it primarily consisted of making announcements during Sunday morning worship services and weekly activities and placing flyers throughout the church and in the Sunday bulletin. Interested individuals were invited to attend a general-interest session held at each church and led by the study’s principal investigator (MCW). Interest sessions were held during the time the church had selected for the weekly intervention sessions. This limited the number of individuals who would be unable to attend the sessions regularly. During the interest session, the principal investigator explained the study procedures and eligibility criteria and answered participant questions. At the end of the interest session, participants were screened for study eligibility using the following criteria: 1) being self-identified as black; 2) being 18 years of age or older; 3) not currently meeting recommendations for MPA or VPA ; thus, to maximize the sample size available for data analysis, we used the average number of steps per day across weeks. In addition, we analyzed steps per day categorically: less than 5000 steps per day (sedentary); 5000 to 7499 (low active); 7500 to 9999 (somewhat active), 10,000 to 12,499 (active), and 12,500 or more (highly active) .Moderate- and vigorous-intensity physical activity. Self-reported participation by minutes per week in MPA, VPA, and walking was assessed using a modified version of the International Physical Activity Questionnaire (IPAQ) (e (IPAQ) . The IPAParticipant characteristics and anthropometrics. At the baseline visit, we used a questionnaire to measure self-perceived general health and well-being and presence of chronic diseases. Using a digital scale, we weighed each participant twice and measured a third time if the two measures differed by more than 0.2 kg. Height was also measured twice to the nearest 0.5 cm using a height stadiometer and measured a third time if the two measures differed by more than 0.5 cm. The average of the two closest measures was used for height and weight. Body mass index (BMI) was calculated as weight (kg) divided by height (m2). Seated resting blood pressure was measured, in duplicate, using a digital Omron monitor after participants had been seated with legs uncrossed for at least 5 minutes. Blood pressure was measured a third time if the two measures differed by more than 4 mm Hg. The two closest measures were averaged and used for analyses.Statistical analysis. Statistical analyses were performed using SAS version 8.2  and SAS-callable SUDAAN software . We examined the magnitude of the intra-class correlation coefficient (ICC) among subjects from the same church, which was estimated to be 0.06. We used a SUDAAN modeling procedure with two levels of clustering  to account for the ICC among church members and temporal dependence in repeated observations obtained on the same individual. Working independence between participants from the same church was assumed, along with an exchangeable covariance structure for repeated measurements on the same individual. Least square means were obtained from the models along with standard errors, which were then converted into standard deviations for the adjusted mean changes.2; range, 16.1 to 63.3 kg/m2; 69% of participants had BMIs ≥30 kg/m2). All participants were black, most were female (89%), almost half (49%) were married, and most (96%) had a high school-level education or higher. Eighty-five percent of study participants reported at least one chronic health condition. Almost half (43%) of study participants reported using antihypertensive agents, and the mean systolic/diastolic blood pressure levels of study participants were in the borderline hypertension range (137 ± 23 mm Hg systolic and 84 ± 14 mm Hg diastolic). The four churches included in the intervention were similar across all baseline characteristics with the exception of education (P < .01).At baseline, participants (n = 87) were 52 ± 14 years of age  with an average BMI in the obese category . Most pP = .04). The increase in steps per day was 1373 ± 728 steps (a 28% increase) after 12 weeks to an average of 6148 ± 2534 steps per day (P < .01). Although our sample size was not large enough to detect statistically significant differences, we observed a decrease in the proportion of participants who were categorized as sedentary , and an increase in the proportion of participants who were classified as somewhat active . There was an increase from baseline to 4 weeks in the proportion of participants who were classified as active (from 1% to 4%), but no additional change was observed after 12 weeks (4% classified as active). Participants also reported increases in self-reported minutes per week in MPA  and VPA . Weight and BMI remained stable over the 12-week intervention (data not shown). Changes in systolic and diastolic blood pressure after 3 months were in the expected direction  but were not statistically significant (data not shown).Data on mean changes in study outcome variables are presented in We observed statistically significant increases in number of steps per day after 4 weeks and after 12 weeks, and significant changes in MPA and VPA after 12 weeks. We were encouraged to see that the proportion of participants who were classified as sedentary on the basis of previously published criteria for evaluating steps per day  decreaseFindings from our study regarding changes in PA among blacks are in line with, and in some cases show better results than, studies with similar time frames and study designs. An uncontrolled community-based walking program among 24 black breast-cancer survivors (aged 47 to 66 years) included eight 75-minute weekly sessions held at either a community center or a local church . The stuNot surprisingly, we did not observe significant changes in blood pressure in our study. The pilot study had a large enough sample to test meaningful differences in daily walking as assessed by a pedometer but was not large enough to be able to detect small changes in blood pressure. We were encouraged, however, to see trends in the appropriate direction for these variables. We were also not surprised that weight did not change in the current study. Hill et al suggest that small changes in behavior, such as adding an extra 2000 to 2500 steps per day, may prevent excess weight gain . ChangesOur study had a number of limitations. First, because we were unclear about the feasibility of the proposed study design and because of the reluctance in some faith-based communities to be part of a randomized study, particularly to a no-attention control group, we did not use a randomized, controlled design. We recognize the lack of a control group as a major limitation of the study. Second, this study's sample group was small; additional participants may have improved our ability to detect differences in clinical variables. Third, we did not have objective data for participation in MPA and VPA. We attempted to collect these data using accelerometers but encountered several issues related to adherence to the accelerometer data collection protocol and, thus, were not able to use these data for analyses. Finally, we are aware that participants who enrolled in our study might differ from the general population, from individuals who do not attend church, and from individuals who chose not to volunteer for the study.The study also had several strengths. Although we were unable to obtain an objective measure of MPA and VPA, we were able to collect this information using a self-reported questionnaire. Although self-reported PA data tend to be overestimated, increases in MPA and VPA in our study were in line with increases in objectively measured PA. We addressed some limitations of previous studies by incorporating tenets of the church and by involving the church in intervention development. Participants reported high satisfaction with the intervention, suggesting that this strategy might be successful in other black churches. At least one church used the materials to conduct a second set of intervention classes with new participants. Although we did not collect outcome data on the new participants, anecdotal evidence suggests that the program was well accepted in the second set of classes. Group leaders were able to implement the program on their own, suggesting that the program strategy may be sustainable. Finally, the current pilot study found that participants increased their number of steps per day and approached the level suggested to prevent weight gain .These data suggest that a faith-based PA intervention may be an appropriate strategy for increasing PA among sedentary black adults. Future research will determine the impact of this program compared with a control group. We plan to conduct a randomized, controlled trial to compare the faith-based PA intervention with a control condition.