We tested for differences in breastfeeding time using the subsample for which breastfeeding was observed (n = 176). Children who consumed one of the three FBFs had lower odds of consuming household grains, roots and tubers compared with the LNS consumers . Consumption of other foods, dietary diversity and breastfeeding did not differ significantly at the 5% significance level. FBFs displaced the household's own cereals more than LNS, with no difference in the child's consumption of other more nutrient‐rich family foods. Given limited stomach capacity and feeding time, providing fortified cereals may help improve children's overall diet quality in settings where children would otherwise be fed nutrient‐poor root crops or cereal grains.Lipid‐based nutritional supplements (LNS) and fortified blended flours (FBF) are widely used to increase the nutrient density of children's diets and improve their health, but their effectiveness could be modified by displacement of other foods. We reanalysed data from a cost‐effectiveness trial comparing impacts on anthropometry of three FBFs  and one LNS (Ready‐to‐use Supplementary Food [RUSF]) among infants aged 7–23 months in Burkina Faso. Using dietary diversity data from a single 24‐h recall period ( Infants need higher nutrient density than the foods used for family diets in low‐income countries, due to small stomach size and rapid growth velocity.Foods that are premixed with fortificants can meet infant needs, but their effectiveness is modified by displacement of other food.We find that supplementation with a fortified flour for porridge leads to lower odds of also feeding plain cereal, compared with supplementation with a lipid‐based fortified nut butter.Fortified cereals can improve diet quality more effectively than other supplementation strategies, by displacing plain cereal without altering breastfeeding or other intake.11.1Growth faltering often occurs during complementary feeding around 6 to 20 months of age, when the child is transitioning from exclusive breastfeeding to the family diet Dewey, . ComplemIn West Africa, and Burkina Faso particularly, where the agro‐ecological and demographic characteristics of the region make it difficult to grow or trade a variety of crops, suboptimal complementary feeding is common , showed no significant displacement of breastmilk by LNS  or were conducted in heavily controlled environments in which caregivers were monitored closely by research staff; we have found no studies that have assessed displacement in the context of a ‘true‐to‐life’ blanket supplementary feeding program aimed at preventing stunting and wasting. The conditions and motivations of the caregivers that decide which foods to give to children or how often to breastfeed may be different for those with healthy children in a prevention program than those with sick children in a treatment program. In addition, we are aware of no studies that have investigated which specific food groups get displaced by food supplementation. This question is important in understanding caregivers' feeding behaviours when different types of supplementary foods are provided.We reanalysed data from a trial comparing the cost‐effectiveness of three FBFs and one LNS in the prevention of stunting and wasting to explore differential effects of these supplementary foods on displacement of breastfeeding or household complementary foods and investigate which specific food groups get displaced, if any. We hypothesized that because the LNS is a product that does not physically resemble ordinary household staple cereals such as millet or sorghum flours, it may be considered a novelty item, and will thus not displace these staples, but may displace household nutrient‐dense foods  or breastmilk. The FBFs, however, bear a close physical resemblance to the most common ordinary household staple cereals in Burkina Faso, although in reality they are much more nutrient‐dense because they have enhanced micronutrient and macronutrient profiles. Supplementation with an FBF may lead caregivers to substitute the FBF for their normal household cereal grains, which would increase nutrient‐density, because the FBF contains extra micronutrient and macronutrient.22.1Dietary diversity data from a single 24‐h recall and direct observations of breastfeeding time over a 4‐day period were collected from children 7–23 months during a supplementary feeding program cost‐effectiveness trial conducted in Sanmatenga Province, Burkina Faso. Details of the trial methods and results are described elsewhere  delivered with Fortified Vegetable Oil (FVO) Milling, , Corn So2.2n = 1,591) and 4‐day in‐home observations on a subset of those interviewed (n = 176). Random numbers were generated to select caregivers from the larger pool of participants. During interviews, in addition to answering questions about perceptions and use of the study foods, caregivers were asked to report everything their child consumed during the previous 24‐h period , and enumerators coded the reported foods into a grid of 30 food groups, adapted from that used by the Demographic and Health Surveys  wherever they went during the observation period, even if this meant going outside the home. The observer would start a timer any time the child was put to the caregiver's breast and stop the timer once the child was removed from the breast. Caregivers participating in observations were administered their in‐depth interviews the morning after the last full day of observation, so the interview responses and 24‐h recalls for these respondents pertain to the last day in which the observer was present in the household. All study children were breastfed during the observation period .2.3Outcomes: Relevant food groups from the 30‐item questionnaire were recoded into the seven categories of the WHO indicator for infant and young child minimum dietary diversity score (IYCMDD): grains, roots and tubers; legumes and nuts; dairy products ; flesh foods ; eggs; vitamin A‐rich fruits and vegetables and other fruits and vegetables Table  World H. Note thCovariates: Child age was categorized based on the WHO recommendation that the IYCMDD indicator be disaggregated and reported for age groups: 6–11, 12–17 and 18–23 months. Though children were enrolled in the blanket supplementary feeding trial study at 6 months, the first interviews were conducted when children had been enrolled at least 1 month, so the youngest children in this subsample are 7 months old. The Household Food Insecurity Access Scale (HFIAS) Coates,  was used2.4We built several models to test our hypotheses about displacement of household staple cereals, nutrient‐dense foods or breastmilk as a result of supplementation with the four different supplementary foods, focusing on the differences between the three FBFs and the LNS. Separate models were built using dichotomous outcome variables indicating consumption of each of the seven food groups that comprise the IYCMDD. In addition, a composite score for dietary diversity was modelled as a continuous outcome. To investigate breastfeeding displacement, the main outcome was breastfeeding time during the 24‐h recall period in which dietary data were collected (breastfeeding time on Day 4 of the in‐home observation).R2, residual sum of squares) no longer improved. In general, variables were also kept in the model if the point estimates for study arm changed by more than 10% with their addition; however, age was kept in the models regardless, due to its biological importance.For each of the nine study outcomes, we looked at both intention to treat models where the main independent variable was assignment to study arm, and average treatment effect models in which only children who had reportedly consumed the ration during the 24‐h recall period for dietary data collection were included. Logistic regression models were estimated for dichotomous outcomes using maximum likelihood estimation procedures, and ordinary least squares linear regression models were used for continuous outcomes. The distribution of continuous variables was assessed for normality using measures of skewness and kurtosis, and if the variables were found to be skewed, models were assessed both with and without extreme outliers, as robustness checks. Model selection was done using a forward selection method, starting with no covariates and adding them in one by one until the metrics indicating model fit ; thus, all model results are presented without interaction terms. The only food groups for which there were significant differences in consumption prevalence among study arms were grains, roots and tubers; vitamin A‐rich fruits and vegetables and other fruits and vegetables. Results from both intention‐to‐treat and average treatment effect models are consistent in showing that consumption of the grains, roots and tubers food group, which is almost entirely made up of cereals in this sample, was significantly lower among ration consumers in the FBF arms  than those in the LNS (RUSF) arm. The average treatment effect models showed significantly lower odds of grains, roots and tuber consumption among those that consumed CSB+ w/oil  and CSWB w/oil  and borderline lower odds (p < 0.1) among consumers of SC+  compared with consumers of RUSF. Consumers of SC+ also had lower odds of consuming vitamin A‐rich fruits and vegetables , but borderline higher odds of consuming other fruits and vegetables  compared with RUSF consumers.Comparisons of model coefficients from the average treatment effect models for each food group are displayed in Figure Adjusted models for the four remaining food groups  mostly show null results. Intention‐to‐treat models show lower odds of consuming both legumes and nuts  and dairy  among those assigned to the CSB+ w/oil arm; however, these significant effects are not seen in the average treatment effect models among actual consumers of CSB+ w/oil. In addition, results for both dairy and eggs should be interpreted with caution due to the homogeneity in the outcome; only 2%–7% of study participants consumed items from these food groups, depending on the study arm.3.4Results from linear regressions modelling the effects of supplement type on an overall dietary diversity score are presented in Table 3.5p < 0.1), representing a 26% shorter breastfeeding time than the average time of 52.9 min; however, this should be interpreted with caution as the result is not significant at the 5% level, and the CI crosses the null value and is quite large due to the small sample size for these models.Table 4In this reanalysis of data from a supplementary feeding cost‐effectiveness trial, we found that supplementation with different FBFs appears to displace household cereal consumption significantly when compared to supplementation with an LNS. The relationship is strongest for two of the three FBFs tested, CSB+ w/oil and CSWB w/oil. While there is some evidence that the third FBF tested, SC+, may also displace more vitamin A‐rich fruits and vegetables than the LNS product tested, children who consumed SC+ were also more likely to eat other fruits and vegetables, indicating that those who consumed SC+ consumed similar amounts of fruits and vegetables as those in the other study arms, but consumed different types. None of the remaining food groups that make up the IYCMDD showed compelling evidence of differential displacement by the FBFs compared with the LNS product (RUSF).Our results add nuance to previous literature showing that FBFs displace more complementary foods than LNS by offering insight into which food groups are being displaced  in dietary diversity that we observed in conjunction with consumption of CSB+ w/oil and CSWB w/oil may also be due to the exclusion of household cereals from the diets of children who consume those FBFs and the replacement of these cereals with the FBFs. Current literature by Campbell et al.  demonstrThough our sample size is quite small for breastfeeding observations, and we only have data on breastfeeding times during the 12‐h observation period from 6:00–18:00, which limits interpretation of these results, our results show borderline significant reductions in breastfeeding time among consumers of CSWB w/oil and nonstatistically significant reductions in breastfeeding time among consumers of the other two FBFs compared with the LNS products. As with interpretation of the dietary diversity score results, we are limited to the comparison of FBFs to the LNS product and cannot draw any conclusions about absolute displacement of breastmilk by food supplements compared to a pure control group. These results, however, align with previous literature showing no significant displacement of breastmilk by LNS foods  than does the LNS product. This could have implications in terms of the effectiveness of supplementary feeding programs. While both the current and previous studies have shown that FBFs displace more household foods than LNS, it is reassuring that the only household foods that are being displaced appear to be household cereals which are likely inferior in nutritional quality to the FBFs that replace them. This provides a likely mechanism by which FBFs can be as effective as LNS products in preventing stunting and wasting, as was demonstrated by the primary results of the cost‐effectiveness trial from which these secondary analyses were derived (Cliffer et al., While our study was limited in that we were not able to calculate specific quantities of foods consumed, but rather used dichotomous indicators of consumption of the food groups, nor were we able to compare with a pure control group, the results are helpful to supplementary feeding programmers who need to decide which products to program for prevention and treatment of undernutrition. Future studies should investigate any potential consequences of displacement of household cereals and estimate the quantities of each food group that could be displaced by supplementary foods.None of the authors report conflicts of interest.BR designed original study; IC and WM designed re‐analysis. IC conducted research, analysed data, wrote the paper. WM and BR critically reviewed the paper. IC had primary responsibility for final content. All authors have read and approved the final manuscript.


Accessory pathways are present in 1 in 300 young individuals. They are often asymptomatic and potentially lethal arrhythmias may be the first presentation. During long‐term follow‐up, up to 20% of asymptomatic individuals with pre‐excitation go on to develop an arrhythmia and the absence of traditional clinical and electrophysiological high‐risk markers does not guarantee the “safe” nature of an accessory pathway. The widespread availability of permanent cure for the condition at low risk by catheter ablation, creates an incentive to screen for accessory pathways with a 12‐lead ECG, particularly in individuals who are perceived to be at increased risk, such as athletes and high‐risk professions. We review the existing literature on the assessment and management of accessory pathways (Wolff‐Parkinson‐White [WPW] syndrome) and discuss its implications for the young athletic population. Due to the requirement for cardiac screening with a 12‐lead ECG in most athletic disciplines and associated sporting organizations, a pre‐excitation pattern may be identified in otherwise healthy individuals. This review aims to address in a systematic way the assessment and management of WPW, with particular emphasis on the athletic population.2For the purpose of this review, a search for available literature between 1930 and 2020 was conducted, using PUBMED, using the key words: Wolff‐Parkinson‐White, pre‐excitation, athletes, accessory pathway, sudden cardiac death, life‐threatening events, screening, and ablation. A summary of the key studies included in the review is outlined in Table 3Drs Louis Wolff, John Parkinson, and Paul Dudley White described what they believed was an association between left bundle branch block and supraventricular tachycardia.An accessory pathway provides an additional route for conduction from atrium to ventricle and vice versa, bypassing the His‐Purkinje system and AV node; it is therefore often also called a “bypass tract.” The presence of an accessory pathway leaves the patient vulnerable to two forms of arrhythmia: re‐entrant arrhythmias due to the second route of conduction and accelerated conduction of atrial arrhythmias because the pathway bypasses the protection of the AV node. Pre‐excited atrial arrhythmias, particularly atrial fibrillation (AF) can be lethal. The atrial fibrillation cycle length (CL) is variable and short, typically between 150 and 250 ms. But the atrial rate of up to 300 beats per minute can, in some cases, be transmitted directly to the ventricles producing ventricular fibrillation and sudden cardiac death (SCD).The prevalence of WPW in the general population is estimated at 0.1 to 4.5 per 1000 individuals.Most individuals with pre‐excitation never experience an arrhythmia.4Accessory pathways can be found at any point around the AV ring: left lateral locations are most common, septal and right sided ones slightly less so; they have even been described in the aorto‐mitral continuity. A small proportion run from the compact AV node to the ventricle via the fascicle or directly  and a few have decremental conduction properties like the tissue of the AV node (Mahaim fibres), but most are just strands of myocardium that traverse the AV groove and have conduction properties similar to atrial myocardium.The most important electrophysiological properties of a pathway are its anterograde effective refractory period (RP) and its directionality.manifest accessory pathway is one that conducts anterogradely and often can conduct bi‐directionally (both anterograde and retrograde). A concealed AP cannot conduct anterogradely and so there is no evidence of pre‐excitation on the ECG. The absence of anterograde conduction makes such a pathway incapable of causing sudden death by pre‐excited AF. Latent pre‐excitation refers to anterograde pathway conduction unmasked by certain conditions of the atria and/or the AV node but not seen on the ECG at other times because normal conduction reaches the ventricles before conduction via the pathway. Delaying conduction via the AV node, for example by administering adenosine, can reveal the pathway; pre‐excitation can also be unmasked by premature atrial complexes or by the occurrence of AF.As the electrophysiological property and behavior of an AP may vary, the terms manifest, latent and concealed have been used to describe and clarify this. A 5In classical times, Pheidippides' death after the battle of Marathon was not questioned;Wolff‐Parkinson‐White accounts for 1% of SCD in the athletic population based on a long‐term registry but this is likely to be an underestimate due to lack of ECG screening.Athletic activity accentuates the risk of pre‐excitation related SCD; in one survey, two thirds of the study population suffered from an aborted VF cardiac arrest during exercise or under emotional stressParticipation in organized athletics presents an opportunity, as screening is used to exclude a variety of conditions, and pre‐excitation can be detected and treated as a result. Because athletic training and competitions are organized by schools, societies and companies, a duty of care is created that involves organizations with the logistical capacity to deliver screening and alongside this be sensitive to the associated ethical and legal considerations.6A study by Malhotra et al.Screening for the conditions that predispose to SCD in athletes often includes a resting 12‐lead ECG alongside a focused history and a clinical examination. However, the screening protocol can vary depending on the type of organization providing it. In the case of manifest pre‐excitation, the diagnosis derives from the ECG. Good history‐taking and clinical judgement remains important not only for risk stratification purposes, but also because symptoms may be the only evidence of latent or concealed pre‐excitation. The symptoms that are most strongly suggestive of arrhythmias are recurrent syncope, pre‐syncope and sustained palpitation, particularly when associated with exercise. To make the screening process more challenging, athletes may not report or under report symptoms for fear of interruption to their training, funding or other impact to their career.The electrocardiographic hallmarks of pre‐excitation are a PR interval shorter than 120 ms and a slurred upstroke to the QRS complex known as a delta wave for its shape. The degree to which pre‐excitation is evident depends on the relative time taken for a sinus beat to conduct to the ventricle via the accessory pathway and via the conduction system. Activation takes so long to reach a pathway in a left lateral location that AV nodal conduction will often beat it, masking its presence. A patient with WPW may therefore have a perfectly normal ECG even with a rapidly conducting pathway with a short anterograde RP  provides a robust measure of the anterograde effective refractory period of any pathway and is the best verified method of risk stratification.88.1Offering blanket suppression of arrhythmic potential by long‐term medication is inappropriate due to the very low rate of clinical success, the long‐term risk of adverse effects including lethal arrhythmias provoked by prolongation of the QT interval or slowing of conduction, and interference with the athlete achieving his/her athletic potential. In general, regular anti‐arrhythmic medication should only be considered in symptomatic patients as short‐term instruments of symptom control if ablation is not immediately available,8.2The cure rate of accessory pathways by ablation now approaches 100%, with more than 90% of patients obtaining permanent cure on a first attempt Figure .36, 3The safety profile of catheter ablation treatment has been documented by Garg et al.Septal pathways accounted for approximately 25% of a series of 1969 cases undergoing EPS.Compared to RF, cryotherapy has the advantage of partial reversibility: Tissue that is cooled ceases to conduct long before it sustains permanent injury. For this reason, cryotherapy is often chosen when the pathway lies within 5 mm of the His bundle or the compact AV node.An EPS study with a view to ablation is recommended in all symptomatic individuals.asymptomatic athletic individual, the question asked is whether there is a case for completely non‐invasive management. Risk assessment of the AP must take place before the athlete can be deemed “cleared” in preparticipation. An EPS ± ablation is considered first line investigation in the majority of cases and a referral to cardiac electrophysiology is therefore recommended in all, including asymptomatic individuals.When pre‐excitation is identified in a young and P < .001) over a period of 5 years.A small randomized controlled trial on asymptomatic pre‐excitation found that the group who received ablation had fewer arrhythmic events compared to the control group (7% vs 77%; A recent systematic review of the management of asymptomatic children with pre‐excitation found that management for this age group follows similar principles to those in adults. Raposo et al.Etheridge et al. reported on 96 children with WPW who had a life‐threatening event.8.3The 2019 ESC guidelines for the management of patients with supraventricular tachycardia provide a good summary of the acute and long‐term management of WPW.9Cardiac screening in the young and athletic cohort may uncover pre‐excitation. Evidence of an accessory pathway is significant even if the individual is asymptomatic at the time. The condition is potentially lethal if unrecognized but is amenable to a safe and permanent cure once diagnosed.Figure S1Click here for additional data file.Figure S2Click here for additional data file.


We review the field of organic–inorganic nanocomposites with a focus on materials that exhibit a significant degree of electronic coupling across the hybrid interface. These nanocomposites undergo a variety of charge and energy transfer processes, enabling optoelectronic applications in devices which exploit singlet fission, triplet energy harvesting, photon upconversion or hot charge carrier transfer. We discuss the physical chemistry of the most common organic and inorganic components. Based on those we derive synthesis and assembly strategies and design criteria on material and device level with a focus on photovoltaics, spin memories or optical upconverters. We conclude that future research in the field should be directed towards an improved understanding of the binding motif and molecular orientation at the hybrid interface. This Review provides an overview of the field of organic–inorganic nanocomposites with a focus on materials that exhibit a significant degree of electronic coupling across the hybrid interface. The characteristic properties of these nanocomposites pave the way to potential optoelectronic applications in devices which exploit singlet fission, triplet energy harvesting, photon upconversion or hot charge carrier transfer. In order for this to occur, both constituents of the composite are usually semiconductors, metals or conjugated organic π‐systems. As charge carriers or energy are exchanged, fundamental questions arise as to the direction, the efficiency and the speed of this transfer. Since exchanged charges carry magnetic momentum, another important question is the nature and fate of their spin in the process. The lifetime, dipole strength and degeneracy of excitons with different spin configurations are so distinct in inorganic vs. organic matter that the hybrid interface becomes a unique feature in any nanocomposite where the photophysical properties of both constituents merge into something potentially new. Studying charge and energy transfer in COINs exposes the effect of the interface, increases the chances that its role becomes predominant for the overall physical properties of the system, thus directly addressing the core hypothesis above. The four major applications to date of tailored charge or energy transfer in COINs are singlet fission, triplet energy harvesting, photon upconversion and hot electron transfer.[With the ability to mix organic and inorganic compounds on the nanometer scale, the field of “hybrid organic‐inorganic nanostructures” evolved since the 1980s.transfer.8, 12 We argue here that advances in the chemistry of nanocomposites enable the rational design of solid‐state COIN films which explicitly target one of the four above‐mentioned major applications towards an improved optoelectronic device performance. A key factor is the ability to graft organic π‐systems directly to the surface of inorganic nanostructures, for instance by functional groups with strong electron donor/acceptor capabilities and thermodynamically favorable surface ligand exchange reactions.1.1This article is structured as follows: We begin with a short account of the most common inorganic (section 2) and organic (section 3) material classes from which COINs are typically formed. A special focus is the inorganic‐organic interface: After discussing the general role of surface ligands (section 3.1) we focus on π‐systems (section 3.2) and polymers (section 3.3) as ligands, and finally examine the coupling of conjugated organic systems to nanocrystals (section 3.4). In section 4, we detail the four main applications of charge and energy transfer across the hybrid interface in COINs, namely singlet fission, triplet harvesting, photon upconversion and hot electron transfer. For each application, we summarize the key criteria to be fulfilled by a COIN in order to excel in a specific application. In section 5, we outline tools for the characterization and fabrication of COIN‐based optoelectronic. This leads to the proposal of fabrication strategies in section 6 for COIN‐based devices geared towards photovoltaics, photodetection, spin memories and light emitting diodes. We conclude with an outlook on future challenges and directions for the field in section 7.2This section summarizes the most important inorganic nanostructures with which COINs have been reported up until now. While their general properties are described in the text, Table 2.1J) of a few 10 meV  or even less (in III–V QDs).kbT at not very low temperatures, QDs act as spin mixers with fast thermalization of spins.J=±2 and referred to as “dark”, manifesting in long lifetimes and low quantum yield at low temperature, when thermalization of spins is inhibited.Quantum dots (QDs) are inorganic semiconductor crystallites which are confined in all three dimensions to length scales smaller than the exciton Bohr radius. Since most inorganic materials exhibit relatively large dielectric constants, strong dielectric screening is present in QDs. This invokes small exciton binding energies  profoundly impacts the surface state density, while the number of X‐ (e.g. carboxylic acids) or L‐type ligands (e.g. amines) does not.The most common passivation scheme for colloidal ODs, however, is passivation by organic molecules tethered to the QD surface.In the context of this review, surface defects are also important as they often form a reservoir for excitons at the organic/inorganic interface before charge or energy transfer occurs. X‐type pentacene derivatives tethered to the surface of PbS quantum dots have been shown to induce defects, which localize triplet excitons at the surface of the quantum dots for 100 s ns, before the triplets are transferred to the organic π‐system.2.22  have values in the range of ≈300–600 meV so that excitonic features are prominent at room temperature.[The rise of two‐dimensional (2D) materials with outstanding electronic properties has started with the ongoing research on graphene 15 years ago, and in recent years ultrathin 2D semiconducting materials with well‐defined band gaps have likewise moved into focus.perature.65, 66While deposition and exfoliation routes for the production of layered 2D van der Waals semiconductors are widely used, colloidal synthesis methods for obtaining ultrathin 2D semiconductors have opened up a promising alternative to the classical exfoliation and deposition methods.67, 682.3Metal nanostructures possess excellent light harvesting properties, due to the phenomenon of localized surface plasmon resonance (LSPR).Compared to lithographic fabrication methods, wet‐chemical synthesis offers a cost‐efficient and scalable way to produce defined nanocrystals.Besides tuning at the single‐particle level, the plasmonic coupling of nanoparticles provides an additional way to further enhance and control these effects. The plasmonic coupling leads to new emerging properties such as strong electromagnetic field enhancement,Due to the aforementioned properties, plasmonic nanocrystals facilitate a variety of applications including electronics (e.g. plasmonic solar cells),3This section focuses on the qualities of the organic ligands found in COINs. It will discuss the general nomenclature of the ligand shell , carboxyls (R‐COOH), and phosphines (PR3); and for semiconducting QDs thiols, carboxyls, phosphine oxide (P(O)R3), and phosphonyls (PO(OR)2). Several general rules apply: The interaction between the particle surface and the anchor group can be ionic or covalent and can have different degrees of dipolar (dative) character. Green's classification distinguishes X‐type ligands with a strong covalent character (e.g. thiols on CdSe), L‐type ligands bonding in a donor‐acceptor fashion via a lone pair donated by the anchor group (e.g. Au‐NR2), and Z‐type ligands accepting electron pairs from the surface (e.g. CdCl2).3 hybridized carbon atomsThe structure of surface ligands can be formally divided in (1) anchor group, 2) ligand core and (3) termini . In general, to replace the ligands already present on the surface, the anchor group of the incoming ligands needs to have a higher affinity and bind more strongly to the surface, yet different synthetic strategies can be used to overcome this rule, e.g using sacrificial intermediate ligands in a two‐step protocol. The binding affinity of diethylamine (DEA) is pH‐switchable: The native amine is a strong ligand, while the protonated form interacts only weakly with the gold surface. This allows to replace strong surface ligands using the amine, before exchanging the protonated form with a weak ligand in a second step.The ligand core determines the properties of the organic ligand. Saturated chains, for example, alkyl or ethylene glycol chains, are primarily used for solvation and colloidal stabilization. As these chains are insulating, interaction between NCs depends on the length of the ligand core, and shorter cores generally lead to stronger coupling.Finally, the ligand termini can be used as reactive sites, for example, to tune the interaction of NCs with cells or functional surfaces, or to modify the hydrophilicity of the colloidal NPs.3.2τ<200 ps) with yields approaching 200 %. Both transfer directions are Dexter‐type, requiring orbital overlap and thus exhibiting an exponential distance dependence.[Organic semiconductors are electroactive themselves and their low dielectric constants lead to the formation of strongly bound Frenkel type excitons. NCs can serve as sensitizers for molecular triplet states via triplet energy transfer processes, or alternatively, the triplet exciton is transferred from the organic π‐system to the inorganic NP, for example, from tetracene to a PbS NC.pendence.25, 26Efficient exciton dissociation and charge separation in NC‐organic hybrid materials requires an alignment of the positions of the frontier orbitals of the organic π‐system and the electronic states available at the NC surface: For the combination of an organic donor and a NC acceptor, the NC′s LUMO level must be below the LUMO level of the organic ligand , a chromophore in an excited singlet state S1 shares its excitation energy with a neighboring ground‐state chromophore, resulting in the conversion of both into excited triplet states T1 , each high‐energy photon absorbed by the organic SF component would generate two triplet excitons, which would then be converted to two low energy photons and absorbed by a conventional PV cell, doubling photocurrent harnessed from the high‐energy part of the solar spectrum. SF‐PMs could break the Shockley‐Queisser limit for the silicon band gap and increase the efficiency of the best Si PV cells available today from 26.7 % to 32.5 %.E(S1) is higher than ‐ and yet well matched to ‐ the sum of the two triplet energies E(T1) is limited:Still, SF requires a suitable organic chromophore, and the number of molecule classes known to meet the fundamental requirement that the singlet excitation energy 3/TIPS‐pentacene bilayer system, SF generated triplet states of the pentacene can be transferred to the conduction band of the perovskite.Disregarding the case of an all‐organic process taking place at an inorganic surface, and focusing on SF events across the interface, two directions of energy transfer are possible: From the organic component to the inorganic, and vice versa. In the first case, organic chromophores absorb light to yield a singlet state, and after SF the resulting triplets are transferred to NCs, which in turn emit two photons. Combining pentacene with PbSe NCs of different sizes (and band‐gaps) allowed to pinpoint the triplet energy of the chromophore between 0.85 eV and 1.00 eV in operating devices.3 NCs.3 NCs:SF) of 145 %.From a fundamental point of view, the NC to organic transfer direction is especially interesting: The NC band gap can be tuned, and even energetically high‐lying naphthalene triplets are accessible via visible‐light‐driven TET from CsPbBr4.2spin mixers at room temperature with fast thermalization of spins, which renders them good triplet sensitizers but poor acceptors with low spin stability.Triplet excitons are referred to as “dark excitons” as selection rules require the simultaneous flip of one carrier's spin during recombination, which is unlikely, and results in very low emission yields.Following these general considerations, combining QD‐based triplet sensitizers and organic π‐systems for the long‐lived storage of excitons with triplet spin into COINs enable exciting new possibilities for optoelectronics . With QDs as the sensitizer, intersystem crossing occurs so readily that triplet generation is usually not the rate limiting step. For efficient triplet harvesting to occur, the exciton recombination rate in the QD needs to be slower than the rate of TET. This can be ensured by passivation of deep trap states, for instance by one of the core–shell structures outlined in section 2.1. We suggest that the utilization of type‐II core/shell QDs as the sensitizer is particularly promising due to the greatly prolonged exciton lifetimes.Due to their low transition dipole moment, TET between the sensitizer and the acceptor is dominated by the Dexter mechanism, where two individual charges are consecutively transferred and spin is exchanged. According to Marcus theory, the Dexter rate for this exchange is given as Eq. :(1)τTET-ϵ is the coupling energy between the sensitizer and the acceptor, λ is the Marcus’ reorganization energy and ΔV is the energy offset between the triplet state of the sensitizer vs. that of the acceptor. In the weak coupling regime , the coupling energy may be approximated as [Eq. Here, d as Eq. (2)ϵ=ΔVπem* is the effective mass of the transferred charge and d is the distance between the sensitizer and the acceptor.V, and decreasing m* of the transferred charges, λ as well as d.where We arrive at the following key properties for COINs to be fulfilled for efficient triplet exciton harvesting:For the sensitizer, these are long exciton lifetimes, high lying triplet states, a large extinction coefficient and long‐range order in thin films. For the acceptor, a low‐lying triplet state, strong binding affinity to the sensitizer with a rigid binding motif, for example, by multidenticity, short binding distance as well as long‐range order and iso‐orientation are required.4.3sensitizing system absorbing the lower energy photons and the activator/annihilator system from which anti‐Stokes emission takes place. For radiative recombination PU discussed here, three general methods are possible  is a nonlinear process occurring at low photoexcitation densities in which multiple (at least two) photons of lower energy (longer wavelength) are sequentially converted into a photon of higher energy (shorter wavelength), which is apparent by Anti‐Stokes emission from the sample.137 In te Figure :Energy transfer upconversion (ETU)Triplet‐triplet annihilation upconversion (TTAU)Cooperative sensitization upconversion (CSU)two successive energy transfer steps. If sensitizer and activator units are very similar, they can undergo cross‐relaxation photon upconversion , followed by an energy transfer between two excited NCs, which in turn leads to charge transfer to an excited state of the coupled molecule from which upconverted photons are emitted. The charge transfer in CSU occurs within a range of tens to hundreds of ps, outpacing the TTAU process by at least one order of magnitude.Note, that a distinction between ETU and CSU is often complicated and upconverting systems can involve all three processes.PU is very efficient in solution,143 but Thus, concepts for further advancing PU rates and efficiencies include, for example, the utilization of ultrafast hot‐electron mediated PU of plasmonic (nano)structures, which could be coupled to semiconducting NCs or organic π‐systems for efficient emission.4.4After LSPR excitation in plasmonic nanostructures, electron movement in the metal is quickly damped by electron scattering associated with dissipation. Consequently, the excited plasmon mode is lossy and fast decaying (femtosecond range).147 ReceIn the following section, we thus focus on the mechanism of hot carrier generation by light adsorption in plasmonic metal nanostructures and their transfer to other materials such as semiconductor solids or adsorbates. In addition, we address the requirements for efficient transfer of hot charge carriers and derive design criteria for nanostructures.The relaxation process after LSPR excitation can be either radiative by re‐emitting photons or non‐radiative Besides the excitation wavelength and particle size, the particle shape also affects the yield of hot charge carriers. Experimental and theoretical studies of Au/TiO2 structures have shown that the catalytic efficiency (hot charge carrier generation) is strongly dependent on the EM field enhancement of the plasmonic component.Geometry as well has a major impact on the required match of momentum:Concerning life‐times, as depicted in Figure As shown by Wu et al., an effective transfer rate can be achieved within the given time (<100 fs) by ensuring a strong electronic interaction between the metal structure and a semiconductor material.Similar to inorganic semiconductor materials, two mechanisms for hot charge transfer to adsorbed molecules, such as those in section 3, are known  is an excellent tool for studying photophysics on an ultrafast time scale in the materials and material combinations mentioned above . This is important for resolving the underlying photoexcitation processes, including charge carrier generation, migration and recombination dynamics as well as energy transfer and change of charge carrier spins in “real time”. Samples to be characterized are typically measured in solution or as thin solid films at ambient temperature . Thin COIN films exhibit sizes of several hundreds of μm so that a probe beam spot size of <0.5 μm and a pump beam spot size of >1 μm are sufficient to probe the sample accordingly. Multiple sample areas are spectroscopically characterized independently to ensure sufficient statistics. While excellent reviews on ultrafast spectroscopy exist,5.1.1pump‐probe experiment, the sample is photoexcited with an optical pump pulsetrain of an ultrafast laser source (≈100 fs), while a delayed probe pulsetrain enables monitoring of the sample PL at different times after photoexcitation. TRPL measurements with a time resolution down to ps can be conducted with a Streak camera, an ultrafast detector capturing the sample emission.In TRPLS, the radiative recombination  of photoexcited charge carriers (excitons) in samples  is spectrally and temporally resolved. In a typical 5.1.2pump pulsetrain, while a delayed probe pulsetrain is used to study the evolution of photoexcited charge carrier dynamics at different times after photoexcitation. The temporal and spectroscopic time evolution of the change in absorption of the sample is used to draw conclusions about the origin and fate of the photoexcited charge carriers, as well as their decay dynamics.In TAS, samples are likewise photoexcited with a short Recent investigations of different COINs with TAS have successfully proven chemical and electronic coupling, polaron formation, upconversion by TTA and CSU, ultrafast energy and charge transfer and underline the versatility of the method.1435.2Colloidal self‐assembly is a thermodynamically driven process in which defined building blocks  are spontaneously organized into ordered structures.For well‐controlled colloidal self‐assembly both geometry and surface properties are crucial.5.2.12.Periodic superstructures of nanocrystals can be achieved via interface‐mediated assembly , tailoring the triplet transfer rate is of paramount importance for all device applications. For triplet‐triplet annihilation and spin storage, the focus should be on fast and one‐way triplet transfer onto the acceptor, where the spins exhibit long lifetimes. Therefore, a large negative energy offset between the triplet state of the sensitizer vs. that of the acceptor is important. Based on the criteria for TET following Marcus theory in section 4.2, a small effective mass for the hole and electron in the sensitizer as well as low reorganization energy are also desirable. These criteria can be met by decreasing the NC size and maximizing the quantum confinement.COINs with large areas of structural periodicities and long‐range order, such as those depicted in Figure Optimizing the orbital overlap is more complex as this depends to a large degree on the exact binding motif of the molecules to the NC surface, which is unclear in most cases. For metal phthalocyanines, optical spectroscopy has suggested that the molecular π‐system forms small stacks of H‐aggregates, which separate adjacent NCs.Fast radiative or non‐radiative recombination of triplets are among the most important challenges for devices, which rely on long lifetimes and diffusion lengths for efficient triplet harvesting. To overcome the inherent “spin‐mixing” behavior of NCs, operating at low temperature (≈10 K), where the triplet state is stabilized will be mandatory for applications requiring a high spin purity and maximized lifetimes, such as spin memories. Another factor with deleterious consequences for the spin purity are dangling bonds and other surface defects, which can invoke spin flipping due to the interaction with the unpaired electrons in dangling bonds and are, thus, to be avoided.Figure 6.3As has been described in the previous sections, close contact between the organic‐inorganic moieties of a COIN is the key for efficient coupling and PU. If ETU is favored, energy level alignment of the sensitizers has to be selected such that their (first) excited state is close to the first excited state of the activator to enable efficient Förster resonance energy transfer (FRET). However, a spectral overlap of the acceptor emission and the sensitizer absorption could lead to downconversion from the sensitizer. This has to be avoided.6.4As described in section 3.5, plasmonic nanostructures are able to convert absorbed light into electrical energy by the excitation of hot charge carriers. Thus, the plasmon‐induced hot carrier generation is a promising tool for energy conversion processes in photovoltaics or photochemistry.In the simplest case, the plasmonic nanostructure is implemented as an active layer in the solar cell  in perovskite solar cells. By coupling plasmon hot spots with photonic lattice effects, the absorption of the solar cell and the generation of hot carriers can be significantly increased. In addition, the direct coupling between the plasmonic component and the semiconductor material allows better charge separation.7vice versa are combined to a highly asymmetric interface. Utilizing this asymmetry in the preferred direction enables several optoelectronic applications with high efficiency, of which we have specifically highlighted photon upconversion, singlet fission, triplet exciton and hot electron harvesting. Additional opportunities which we have omitted due to limitations of space include light emitting diodes and photochemical reactions.We began this review with a hypothesis originating from the 1980s that biphasic nanocomposites can exhibit emergent properties which are more than the sum of the individual contributions if the effect of the interface becomes predominant. The large body of work discussed here shows that maximizing the interfacial area and controlling electronic coupling in such hybrid nanocomposites indeed fulfills this promise. Enabling charge or energy transfer across the interface enhances the importance of the phase boundary, providing additional optoelectronic functionalities. Tailoring the transfer direction exploits the vast differences between inorganic and organic nanostructures in terms of their behavior as sensitizer or acceptor agents during the transfer. The largest advantages of hybrid nanocomposites over single‐phase materials arise if two components with excellent acceptor/poor sensitizer properties and The opportunities arising from coupled organic‐inorganic nanostructures have become possible largely due to the development of chemical strategies to tailor the interfaces in the composites. This includes the surface chemistry of the nanostructures, an understanding of the correlation between it and the electronic structure as well as the development of methods to monitor this correlation. There have also been large improvements in controlling the micro‐ and macroscopic structure of the composites, for instance by self‐assembly and templating. Perhaps the largest challenge for chemists in the future is understanding and tailoring the structure and binding situation at the hybrid interface itself. Very limited knowledge exists to date about the precise binding motif, the orientation of the organic entity to the surface of the nanostructure and possible polymorphs and variances for a given combination. Considering the large dependence of the optoelectronic effects discussed here on orbital overlap, regioregularity and interchromophoric distance, it is highly likely that excelling in controlling the structure at the interface provides room for substantial further device improvements.The authors declare no conflict of interest.Anja Maria Steiner received her Master's degree in 2015 from the University of Bayreuth, where she studied Polymer Science. She is currently a Ph.D. student at the Leibniz‐Institut für Polymerforschung Dresden under supervision of Prof. Dr. Andreas Fery. Her research interests mainly focus on the synthesis, assembly and characterization of nanoparticle systems.Franziska Lissel is a TUD Young Investigator and a Liebig Fellow of the Chemical Industry Fund (FCI) heading the Functional Electronic Materials group within the Leibniz‐Institute of Polymer Research. Her group investigates the covalent introduction of redox‐active metalcenters into conjugated polymer backbones, the development of polymeric MALDI matrices, new concepts for stretchable polymer electronics, and molecular switches. Previously, she was associated with Prof. Z. Bao (Stanford), and obtained her Ph.D. with Prof. H. Berke (Zürich 2014).Andreas Fery did his PhD at the MPI for Colloids and Interfaces (MPIKG)/Potsdam University in 2000. After a post‐doc at Institute Curie, he became group leader MPIKG. In 2007 he joined Bayreuth University as professor. Since 2015 he is head of the institute for Physical Chemistry/Polymer Physics at the Leibniz Institut für Polymerforschung Dresden. He is interested in colloid and interface science with a focus on colloidal interactions and colloidal self‐assembly of functional materials such as plasmonic metal surfaces.Jannika Lauth obtained her Ph.D. in 2014 at the University of Hamburg with Prof. H. Weller. She joined TU Delft as a postdoctoral fellow with Prof. L.D.A. Siebbeles working on ultrafast laser spectroscopic methods. Since 2019 she is a research group leader at the Physical Chemistry and Electrochemistry Institute of the Leibniz University of Hannover. Her group is combining colloidal synthesis methods (for 2D semiconductors) with assessing the materials’ potential for optoelectronics by ultrafast transient absorption spectroscopy.Marcus Scheele obtained his PhD at the University of Hamburg in 2011. After a postdoctoral visit at UC Berkeley, he led an Emmy Noether group at the University of Tuebingen and was appointed as a Heisenberg Professor for Physical Chemistry in 2020. His group investigates the physical chemistry of hybrid semiconductor mesocrystals and their application for fast optical data communication.


Most clinical guidelines are developed by high‐income country institutions with little consideration given to either the evidence base for interventions in low‐ and middle‐income countries (LMICs), or the specific challenges LMIC health systems may face in implementing recommendations. The aim of this study was to prioritize topics for future global surgery guidelines and then to develop a guideline for the top ranked topic.A Delphi exercise identified and prioritized topics for guideline development. Once the top priority topic had been identified, relevant existing guidelines were identified and their recommendations were extracted. Recommendations were shortlisted if they were supported by at least two separate guidelines. Following two voting rounds, the final recommendations were agreed by an international guideline panel. The final recommendations were stratified by the guideline panel as essential (baseline measures that should be implemented as a priority) or desirable .Prevention of surgical‐site infection (SSI) after abdominal surgery was identified as the highest priority topic for guideline development. The international guideline panel reached consensus on nine essential clinical recommendations for prevention of SSI. These included recommendations concerning preoperative body wash, use of prophylactic antibiotics, decontamination of scrub teams' hands, use of antiseptic solutions for surgical site preparation and perioperative supplemental oxygenation. In addition, three desirable clinical recommendations and four recommendations for future research were agreed.This process led to the development of a global surgery guideline for the prevention of SSI that is both clinically relevant and implementable in LMICs. A global surgery guideline for the prevention of surgical‐site infection has been developed that is both clinically relevant and implementable in low‐ and middle‐income countries (LMICs). This guideline includes nine essential and three desirable clinical recommendations.Usable worldwide Clinical guidelines produce evidence‐based recommendations that aim to standardize patient care by identifying best practice. Implementation of clinical guidelines into routine practice has the potential to reduce complications, mortality and costsTo increase the likelihood of guidelines being adopted internationally, particular consideration needs to be given to the specific resource and logistical challenges LMIC health systems may face in implementing recommendationsThe aim of this study was to prioritize topics for future global surgery guidelines and then to develop a guideline for the top ranked topic. Development of new clinical guidelines is expensive and time‐consuming. Rather than commissioning entirely new guidelines, the National Institute for Health Research (NIHR) Global Health Research Unit on Global Surgery (GSU) network aimed to build on existing HIC guidelines by adapting these to LMIC settings.AppendixA three‐round Delphi exercise was conducted among the international NIHR‐GSU network to prioritize topics for global surgery guidelines. In the first round, collaborators proposed guideline topics. In the second round, an international panel shortlisted the top 12 proposed guideline topics. An anonymous online vote by LMIC stakeholders then prioritized the shortlisted topics in the third round. The full methodology for the prioritization exercise is reported in TableThis highest‐priority guideline was taken forward into development of a full guideline, in keeping with the International Standards for Clinical Practice GuidelinesTableEach recommendation made by the eligible guidelines was extracted into a spreadsheet and coded by intervention to facilitate further analysis. Recommendations were longlisted if they were endorsed by at least two separate guidelines, with at least one of these having reported moderate or strong evidence to support the recommendation ?Is this recommendation appropriate to your setting (yes or no)?Would implementing this recommendation in your setting be easy or difficult?Consultant (attending) surgeons, representing LMICs, who had participated in the in‐person voting were invited to participate in the second stage and were e‐mailed a link to an online survey. To ensure balance in country representation, two senior Rwandan surgeons were invited to participate from among the Rwandan surgeons who had participated in the in‐person voting. The survey was open from 8 to 18 November 2018. Participants were asked three binary questions about each of the revised recommendations:Respondents were invited to enter free‐text comments to justify their decisions. Recommendations identified as appropriate by fewer than 75 per cent of participants were preplanned to be eliminated, unless it was possible to reword them to address concerns raised in free‐text comments.A search of the WHO International Clinical Trials Registry Platform was undertaken to identify ongoing RCTs relating to the recommendations being taken forward to the third stage. The search was completed on 5 June 2019 using the keywords ‘wound infection’ and ‘surgical site infection’. Only RCTs with sample sizes greater than 150 patients were included.To accept it with its current wording.To accept it after rewording aimed at either reducing its ambiguity, or maximizing its relevance. When appropriate, the panel combined separate draft statements into single recommendations.To change it to a research recommendation. Research recommendations were made if relevant ongoing trials were identified, and the panel agreed that the outcome of these trials should be awaited before making a recommendation. In addition, if the panel agreed that it was not possible to make a decision based on the existing evidence base, a recommendation was made regarding the need for future research.To eliminate it entirely.An international guideline panel met in person on 17 June 2019 in Dubai, United Arab Emirates. The panel included senior surgeons and methodologists. The panel's deliberations were led by the same individuals who had co‐chaired discussion in stage 1. The results of the voting in stage 2 informed the guideline panel's discussions. For each draft recommendation the panel formed a consensus on which of the following decisions to take:Finalized recommendations were additionally stratified as: essential – the panel agreed that these recommendations are baseline measures required for safe surgery and should be implemented as a priority across all hospitals performing surgery; or desirable – the panel recognized that at present some hospitals lack resources to implement these recommendations, but agreed that all hospitals performing surgery should plan their future implementation.Fig. TableA total of 56 surgeons from across 15 LMICs proposed 34 guideline topics. The top 12 topics were shortlisted, and these were then prioritized in an online vote by 736 participants representing 82 LMICs. The overall top ranked topic  screening, mechanical bowel preparation for colorectal surgery, incise drapes and antibiotic‐impregnated drapes, antiseptic‐coated sutures and iodophor wound lavage. In keeping with the predefined criteria, these six recommendations were eliminated, along with another recommendation that was no longer relevant following rejection of MRSA screening. A recommendation for using either plain or antimicrobial soap was supported by 85 per cent of respondents, but subsequent discussion identified that many clinicians found this recommendation too non‐specific, so a committee decision was made to eliminate it.Of the total 31 draft recommendations, six were supported by fewer than half the participating LMIC clinicians , with 13 countries represented. Overall, 17 of the 19 draft recommendations in stage 2 had agreement from at least 75 per cent of respondents regarding their appropriateness to LMIC settings , lower–middle‐income countries  and upper–middle‐income countries  across Africa, South Asia and Latin America. LMIC participants were regional research network leaders. Although most were not based in rural or district hospital settings, they did have substantial insights into the needs of those settings.SSI is the commonest postoperative complication in abdominal surgeryThe WHO Surgical Safety Checklist has been disseminated widely, and has been demonstrated to reduce postoperative morbidity and mortalityAppendix S1. Supporting InformationClick here for additional data file.A PDF of the summary recommendations is available and free to download in the Supporting Information section online.Click here for additional data file.


Understanding the geographic extent and connectivity of wildlife populations can provide important insights into the management of disease outbreaks but defining patterns of population structure is difficult for widely distributed species. Landscape genetic analyses are powerful methods for identifying cryptic structure and movement patterns that may be associated with spatial epizootic patterns in such cases.Odocoileus virginianus) in the Mid‐Atlantic region of the United States, a region where chronic wasting disease was first detected in 2009. The goal of this study was to evaluate the juxtaposition between population structure, landscape features that influence gene flow, and current disease management units.We characterized patterns of population substructure and connectivity using microsatellite genotypes from 2,222 white‐tailed deer (FST ≤ 0.041), but significant genetic differentiation. Genetic differentiation was lower and migration rates were higher among neighboring genetic clusters, indicating an underlying genetic cline. Genetic discontinuities were associated with topographic barriers, however.Clustering analyses identified four to five subpopulations in this region, the edges of which corresponded to ecophysiographic provinces. Subpopulations were further partitioned into 11 clusters with subtle (Resistance surface modeling indicated that gene flow was diffuse in homogenous landscapes, but the direction and extent of gene flow were influenced by forest cover, traffic volume, and elevational relief in subregions heterogeneous for these landscape features. Chronic wasting disease primarily occurred among genetic clusters within a single subpopulation and along corridors of high landscape connectivity.These results may suggest a possible correlation between population substructure, landscape connectivity, and the occurrence of diseases for widespread species. Considering these factors may be useful in delineating effective management units, although only the largest features produced appreciable differences in subpopulation structure. Disease mitigation strategies implemented at the scale of ecophysiographic provinces are likely to be more effective than those implemented at finer scales. We characterized the spatial population structure of white‐tailed deer in the Mid‐Atlantic region of the United States in order to evaluate the juxtaposition population structure, gene flow patterns, and chronic wasting disease cases in the region. We found evidence of four to five subpopulation units, the extents of which generally corresponded with ecophysiographic provinces, with 11 subtle genetic clusters nested hierarchically within subpopulation units. Landscape genetic analyses revealed corridors of high connectivity adjacent to ridges, roads, and open areas, which may indicate directed disease transmission in regions heterogeneous for these features. Since then, additional cases have been detected in free‐ranging herds in western Maryland and central Pennsylvania, but region‐wide prevalence rates in free‐ranging populations are still estimated to be low  was included on each plate in order to ensure amplicons were not contaminated by external sources of DNA and at least one previously genotyped sample was included as well to confirm reproducibility. We used GeneMarker (Softgenetics) to determine allele identity. Alleles were binned using the MsatAllele R package . Tissue digestions were incubated for a minimum of 4 hr to ensure samples were completely lysed, and DNA elutions were carried out with a single 150 µl volume of elution buffer to maximize DNA concentration. We quantified the concentration of extracted DNA (ng/µl) using a NanoDrop spectrophotometer (Thermo Fisher Scientific) and diluted samples to approximately 20 ng/µl. All samples were genotyped using 11 microsatellite loci previously shown to be effective for genotyping in this region  and delineate population structure. Geneland was chosen as the basis for analysis because it is suggested to be better able to identify cryptic genetic discontinuities than alternative clustering algorithms  and edge detection methods  in scenarios where gene flow is widespread and dispersal barriers are permeable to movement  iterations thinning after every 100th iteration, a maximum number of nuclei set to 6,666 (three times the number of samples), and a maximum rate of the Poisson process equal to 2,222 (the number of samples). All postprocess analyses were conducted with a burn‐in period of 1,000 iterations. Cluster assignment was determined using the single run with the highest average log posterior density , observed heterozygosity (HO), unbiased expected heterozygosity (HE), and the number of private alleles (PA) for each genetic cluster. Genetic connectivity among inferred genetic clusters was described using migration estimates from BayesAss  among individuals within genetic clusters, (b) among genetic clusters within larger subpopulation units determined from the hierarchical clustering analysis, and (c) among all subpopulation units. Hierarchical F‐statistics and covariance components were calculated using the poppr R package ; however, the MCMC output indicated poor convergence relative to the chain with the second‐best run  and heterozygosity  but a low number of private alleles . Average immigration rates among genetic clusters were high  and among all subpopulations within the region , the greatest amount of genetic variation was explained by comparisons made among individuals within genetic clusters . Visual inspection of the principal components plot and K‐means clustering of lag scores identified five genetic clusters that generally corresponded to subpopulation groupings identified in the hierarchical clustering analysis, although the central Ridge‐and‐Valley population was split into two clusters  relative to both the isolation‐by‐distance‐only model  and intercept‐only model . Landscape resistance was not spatially uniform and was focused in the southeastern portion of the study domain  occurred within the topographically heterogeneous Ridge‐and‐Valley province. Ridges can affect the extent and direction of deer movement in this region , or no known occurrence in free‐ranging populations (east). Because of the juxtaposition between hierarchical population structure and ecophysiographic provinces, surveillance and management interventions may be most effective if focused within ecophysiographic provinces with known disease occurrence. This may lead to a greater probability of detecting novel disease occurrences relative to random or spatially uniform sampling strategies implemented at broader or localized scales. Outbreaks in distinct genetic clusters may also have different origins and epizootiological patterns. For example, novel cases of chronic wasting disease in the Allegheny Plateau region had a higher probability of assignment and ancestry to captive deer populations than deer from other ecophysiographic provinces (Miller & Walter, While defining population substructure can aid in defining the extent of disease management efforts, landscape connectivity models may help to identify potential transmission corridors between infected and naïve groups (Paquette et al., 4.3Our results help to elucidate patterns of spatial substructure and genetic connectivity in a continuously distributed population of white‐tailed deer where chronic wasting disease is emerging. Population‐level trends may help to describe the relative risk of transmission and provide important insights into future epizootic patterns. Genetic samples from deer with chronic wasting disease were limited in this current study, however, and we did not have access to spatial records of chronic wasting disease from neighboring states with active infection, such as West Virginia. Continued genetic sampling and disease surveillance will clarify genetic cluster membership in areas where samples were currently unavailable and improve efforts to assess the association between subpopulation structure and chronic wasting disease occurrence. Integrating measures of population substructure and connectivity into diffusion models, such as those used in Hefley et al.  to prediIndividual‐based genetic analyses, such as ancestry and assignment analyses, will also allow for testing specific hypotheses regarding the origin of chronic wasting disease cases. For example, Miller and Walter  used simNone declared.WLM, DRD, and WDW collected genetic samples. WLM, CMM‐B, and WDW performed microsatellite genotyping. WLW and WDW analyzed the genetic and spatial data. All authors contributed to the preparation of this manuscript.Figure S1Click here for additional data file.Table S1Click here for additional data file.Table S2Click here for additional data file.Appendix S1Click here for additional data file.Appendix S2Click here for additional data file.


Growing literature continues to identify brain regions that are functionally altered in bipolar disorder. However, precise functional network correlates of bipolar disorder have yet to be determined due to inconsistent results. The overview of neurological alterations from a large‐scale network perspective may provide more comprehensive results and elucidate the neuropathology of bipolar disorder. Here, we critically review recent neuroimaging research on bipolar disorder using a network‐based approach.A systematic search was conducted on studies published from 2009 through 2019 in PubMed and Google Scholar. Articles that utilized functional magnetic resonance imaging technique to examine altered functional activity of major regions belonging to a large‐scale brain network in bipolar disorder were selected.A total of 49 studies were reviewed. Within‐network hypoconnectivity was reported in bipolar disorder at rest among the default mode, salience, and central executive networks. In contrast, when performing a cognitive task, hyperconnectivity among the central executive network was found. Internetwork functional connectivity in the brain of bipolar disorder was greater between the salience and default mode networks, while reduced between the salience and central executive networks at rest, compared to control.This systematic review suggests disruption in the functional activity of large‐scale brain networks at rest as well as during a task stimuli in bipolar disorder. Disrupted intra‐ and internetwork functional connectivity that are also associated with clinical symptoms suggest altered functional connectivity of and between large‐scale networks plays an important role in the pathophysiology of bipolar disorder. The investigation of the brain alterations with a large‐scale network perspective may provide a more comprehensive way in elucidating the neuropathology of a disorder. This systematic review evaluates recent literature and suggests alteration in the functional activity of large‐scale brain networks including the default mode, salience, and central executive networks in bipolar disorder. Furthermore, disrupted intra‐ and internetwork functional connectivity are also associated with clinical symptoms of bipolar disorder, which highlight the importance of large‐scale networks in the pathophysiology of bipolar disorder. Currently, functional connectivity of RSNs have been mostly explored to differentiate between bipolar disorder and other affective disorders such as unipolar depression  in English language, (b) primary target population of individuals with bipolar disorder, (c) brain functional magnetic resonance imaging data as one of the outcome variables, and (d) evaluates the functional connectivity or functional network of the brain. Any review papers, conference abstract, short communications were excluded.2.3For the current review, functional connectivity was defined as follows: (a) spatial or temporal alterations in blood oxygen level‐dependent (BOLD) signals , central executive network (CEN), and salience network (SAN) were most frequently used as a priori seeds in ROI‐based studies, and the same networks were also shown to undergo significant alteration in the majority of the ICA studies. Others that underwent significant alteration in functional connectivity included brain structures that make up the limbic network (LIM) and the cerebellar network (CBL).The remaining 9 studies explored brain functional connectivity in bipolar disorder through task‐based fMRI. Research on task‐based fMRI focused on exploring the affective and cognitive symptoms of bipolar disorder through the selection of ROIs of the frontal cortex, specifically regions that make up the CEN. The nature of the tasks in these studies primarily included cognitive tasks such as those targeting working memory or affective tasks of negative and positive emotional stimuli.Among the literature reviewed, studies that report altered brain functional connectivity in bipolar disorder using detailed anatomical brain regions as according to the Montreal Neurological Institute (MNI) template and cluster size are summarized in Table 3.3For studies that used the hypothesis‐driven approach of ROI analyses, functional alteration of large‐scale brain networks were assessed based on the networks to which the a priori ROIs belong, as well as the brain regions that demonstrated significant temporal correlations with the selected seeds as assessed through fMRI data. A total of 30 studies underwent seed‐based ROI analyses as to investigate the altered functional connectivity in bipolar disorder, one of which explored the functional connectivity of networks using a graph theory‐based approach   was reported (Baker et al., Intranetwork functional connectivity of the SAN was also found to decrease at rest (Gong et al., For ROIs that make up large‐scale networks outside of the 3 major RSNs, individuals with bipolar disorder showed significantly lower nodal path length in the hippocampus, caudate, and fusiform gyri, which partially make up the LIM (Dvorak et al., 3.3.2The collective findings from the ROI‐based studies demonstrated distinct internetwork functional connectivity patterns among large‐scale functional networks in bipolar disorder compared to healthy control. A visual representation of the internetwork functional connectivity alterations of the 3 major large‐scale RSNs at rest for individuals with bipolar disorder, compared to the respective healthy control group, is shown in Figure Second, hyperconnectivity of the SAN‐DMN was reported. Specifically, increased functional connectivity was found between the insula of the SAN and mPFC of the DMN (Chai et al., Third, significantly altered functional connectivity of the SAN‐CEN was found (Pompei et al., Furthermore, large‐scale networks that were strengthened among each other which are the SAN and DMN each demonstrated increased functional connectivity with the LIM also (Favre et al., 3.4A total of 16 studies of the selected literature used the data‐driven approach of ICA analysis as to investigate the functional alteration of large‐scale brain networks. Of these, 10 studies explored the DMN, seven explored the CEN, 4 explored the SAN, and 8 investigated other miscellaneous functional network including the dorsal attention network, CBL, LIM, medial visual network, and sensorimotor network. A detailed summary of the ICA‐based and ALFF‐based studies reviewed is provided in Table 3.4.1Five studies reported altered functional connectivity within the DMN. Specifically, Calhoun and colleagues  performeBrandt and colleagues  performeOther large‐scale functional network that underwent intranetwork functional connectivity alterations in bipolar disorder included the increased functional connectivity of the sensorimotor network (Skåtun et al., 3.4.2Significant altered functional connectivity between the three large‐scale networks of the triple network model was most prevalent across ICA‐based studies. First, similar to findings from the ROI‐based analyses, increased functional coupling of the SAN‐DMN was found in bipolar disorder using a 20‐component ICA (Das et al., For the internetwork connectivity between networks of the triple network model and other large‐scale networks, He et al.  showed d3.5Three studies using ALFF as outcome measures to investigate functional brain network alteration were selected for review. Of these, Li, Liu, et al.  reportedApart from the triple network model, Jimenez et al.  used nin44.1The aim of the current systematic review was to examine the current trends in existing literature on network‐based study findings in bipolar disorder. Through a systematic search of literature, a total of 49 studies were reviewed, of which the methodologies and key findings were explored. A majority of the studies reviewed demonstrated altered functional connectivity of functional brain networks through the hypothesis‐driven approach of a priori ROI analyses, where brain regions that are most representative of a specific large‐scale network were selected as seeds. Other methodologies exploring the functional connectivity of the brain in bipolar disorder included the ICA, ALFF, and network‐based statistics.In general, in terms of intranetwork functional activity, patients with bipolar disorder generally show reduced functional connectivity within each of the triple network model which are major RSNs as according to previous literature Menon, . ReducedThe studies reviewed in the current article also provide supportive evidence for previous voxel‐based neuroimaging studies that demonstrated significant structural and functional alteration in bipolar disorder. In particular, brain regions that indicated significant altered functional connectivity between its subregional structures were similar to regions that underwent significant gray matter alteration in previous literature. To name a few, significant gray matter volume reduction was reported in the mPFC (Liu et al., Among these, the functional connectivity of the mPFC was particularly of interest across the studies reviewed. The mPFC has been described to play a crucial role in self‐reflection (Passingham et al., Another interpretation to the reduced connectivity within the mPFC and hyperconnectivity of the SAN‐DMN may follow the paradigm of attentional shift as described in the triple network model Menon, . AccordiFrom an internetwork perspective, the articles reviewed indicate a significant disruption across functional networks in bipolar disorder. Specifically, many of the studies demonstrated hyperconnectivity between the DMN and SAN at rest, while the relationship between the CEN‐SAN and CEN‐DMN indicated hypoconnectivity. Considering the anticorrelation nature of the CEN and DMN in normal healthy conditions Menon, , the wea4.2A few limitations should be noted. First, the current review provided an overview of functional brain alterations from a network perspective focusing on the triple network model, along with some of the other major networks such as the limbic network and cerebellar network. Due to this, the current review has simplified the names of the large‐scale networks of interest according to regions that overlap, including the converging of the anterior and posterior DMN, the SAN and the cingulo‐opercular network, the CEN and the frontoparietal control network, and the LIM with the rest of the basal ganglia. While the triple network model has been a growing interest in many disorders including PTSD (Lanius et al., Second, it is noteworthy that the current search strategy led to the inclusion of two main approaches to the investigation of functional alteration of the brain which are the ROI analyses and ICA analyses. While the two methods of analyses represent both the hypothesis‐driven and data‐driven approaches to exploring the functional connectivity of the brain, it is noteworthy that very few articles using other methods such as NBS of ALFF were included. Through ROI‐based studies, precise alteration among a priori seeds were precisely reported, highlighting the advantage of exploring functional deficits in regions that are known to be associated with the disorder. In contrast, ICA‐based analyses allow an overall view of brain connectivity (Vargas et al., Third, the current systematic review did not include other methods to investigate altered brain functional connectivity such as regional homogeneity or expansion of ROI‐based approaches using various atlases for parcellation of seed selection. The addition of supportive evidence through other methods as mentioned above may provide more conclusive patterns of altered intra‐ and internetwork functional connectivity in bipolar disorder.Fourth, it is noteworthy that 9 of the 49 studies currently reviewed investigated the functional connectivity of the brain in bipolar disorder using a task‐based fMRI study design. While this may be a small proportion compared to the majority of the studies reviewed which explored the neurological alterations of bipolar disorder through a resting‐state fMRI study design, research has shown that the two MRI acquisition techniques have very distinct functional characteristics (Friedman et al., Lastly, the current review article does not discuss the key findings while considering other additional factors associated with bipolar disorder, such as the segregation of results according to the state and mood of bipolar disorder, as well as medication status of the participants. In particular, it is noteworthy that while the majority of the studies discussed in this review provided some sort of information regarding the medication status and history of the bipolar disorder participants, only 4 of the studies reported medication status in a detailed manner where medication load was calculated in the form of ordinal data or composite scoring. While the state and mood of bipolar disorder as well as medication status may be important factors to consider in developing a more extensive and comprehensive understanding of bipolar disorder from a neurological perspective, they have not been actively discussed in this review due to the limited number of studies that provided the relevant data. For instance, previous research reported significant differences in the functional networks altered according to the type of bipolar disorder (Thomas et al., 5In conclusion, the current review suggests the functional activity of the triple network model at rest and at task‐based stimuli as potential neural correlates for bipolar disorder as compared to healthy individuals. While the current literature review was construed under the assumption that functional connectivity between two brain regions imply functional interactions between two brain networks to which each brain region belongs, the present approach enables the identification of potential networks of interest in revealing the neural correlates of bipolar disorder. The collective findings of recent literature indicated that individuals with bipolar disorder have overall weakened function of the task‐negative state, salience detection, and cognitive control at rest, which may result to the dysfunction in alternating between task‐positive and task‐negative states and lead to difficulties in affective and cognitive function. Furthermore, such weakened activity across the triple network model may potentially lead to a compensatory response between the task‐negative and salience networks at rest, and hyperconnectivity of the cognitive network when performing a task. Studies that used the hypothesis‐driven approach of ROI analysis were most prevalent and easily interpretable in terms of the functional relationship among key brain regions, while the majority of the ICA‐based studies provided supportive evidence of the ROI findings through a data‐driven approach at a network level. The current study may demonstrate the significance of network‐based perspectives in bipolar disorder, as it may provide more comprehensive results on the alterations of the brain and lessen the likelihood of errors in selection of regions of interest. The elucidation of the particular large‐scale networks as potential neural correlates of bipolar disorder may then be used as potential strategies to reduce misdiagnosis of bipolar disorder, help distinguish bipolar disorder from other comorbid illnesses and those with similar clinical symptomatology, as well as understanding the diagnostic state of the disorder. Further research on functional MRI studies using a network‐based approach, including longitudinal studies and interventive studies, may help determine the directionality of the tentative internetwork pathways speculated in this review.None declared.IKL developed the original idea of the study and supervised the study. SY and TDK retrieved the data. SY, TDK, and JK abstracted and analyzed the data. All the authors wrote and approved the manuscript.App S1Click here for additional data file.