Unfinished, rationed, missed, or otherwise undone nursing care is a phenomenon observed across health‐care settings worldwide. Irrespective of differing terminology, it has repeatedly been linked to adverse outcomes for both patients and nursing staff. With growing numbers of publications on the topic, scholars have acknowledged persistent barriers to meaningful comparison across studies, settings, and health‐care systems. The aim of this study was thus to develop a guideline to strengthen transparent reporting in research on unfinished nursing care. An international four‐person steering group led a consensus process including a two‐round online Delphi survey and a workshop with 38 international experts. The study was embedded in the RANCARE COST Action: Rationing Missed Nursing Care: An international and multidimensional Problem. Participation was voluntary. The resulting 40‐item RANCARE guideline provides recommendations for transparent and comprehensive reporting on unfinished nursing care regarding conceptualization, measurement, contextual information, and data analyses. By increasing the transparency and comprehensiveness in reporting of studies on unfinished nursing care, the RANCARE guideline supports efficient use of the research results, for example, allowing researchers and nurses to take purposeful actions, with the goal of improving the safety and quality of health‐care services. To address some of the known limitations of self‐reported measures, more novel approaches have recently been reported, such as the use of a single‐item measure ”—a 4‐year international networking activity aiming to advance a cross‐national discussion on unfinished nursing care with implications for practice, professional development, and education . Lastly, the list of eligible participants was screened for by the authors and potentially extended by hand with a snowballing approach. All eligible participants were invited via email.The Strengthening tRansparent reporting of reseArch on uNfinished nursing CARE (RANCARE) guideline was developed following steps outlined by the EQUATOR network  .n = 61 items, capturing methodological or conceptual barriers in research on unfinished nursing care, which were introduced for feedback on their relevance (“How do you rate the relevance of this item for inclusion in the RANCARE guideline?”) and clarity (“How do you rate the clarity of wording of this item?”) in the Delphi survey. Rating of each item was made on a scale from 1 = extremely irrelevant/unclear to 9 = extremely relevant/clear, with a given middle of 5 = uncertain. Consensus on items was defined a priori according to the RAND/UCLA Appropriateness Method  completed the first Delphi round, with 38 (30%) eventually finishing both rounds. Twenty‐six also joined the face‐to‐face workshop. The majority of participants were females (76%) and had a background in nursing (70%) or psychology (11%), followed by educational sciences (5%), business and economics (5%) or midwifery, sociology and health systems (each 3%). Seventy‐five percentage of participants had more than 5 years' professional experience; 30% had >20 years. Eighty percentage held doctoral degrees, with two‐thirds holding positions as assistant, associate, or full professor.n = 61 items reached consensus  regarding relevance and clarity on 98% of the items in the first Delphi round. Fifty percentage of participants provided additional feedback through comments. With respect to the comments' significance, the steering group agreed to adjust and refine the items for further discussion during the face‐to‐face workshop. The main feedback obtained both from Round 1 and during the workshop included removing redundant items, clarifying both the format and potential applications for qualitative research as well as incorporating examples.The initial item list of Based on results from the first Delphi round and the workshop, we sent a list of 38 revised guideline items in Delphi Round 2 for rating on relevance (1–9), clarity (1–9) and we added the self‐developed question, whether the item should be included (yes/no), to allow for a clear decision. For each item, the median rating was ≥7 without disagreement on either relevance or clarity and therefore included in the guideline. Furthermore, 17 (45%) items were rated by >90% of participants as to be included. The remaining 21 (55%) items were rated for inclusion by ≥75% of participants. With all items' acceptance confirmed, the Delphi survey was terminated. Substantial comment‐based feedback was implemented , resulting in the final version of the guideline.4The components of the final RANCARE guideline consist of 40 items that address key elements influencing the reporting of quantitative research on unfinished nursing care  is set on the estimate of unfinished nursing care. Researchers should describe their measurement in as much detail as possible. This should include information on the scoring method applied as well as justification for aggregating values to a higher level; survey studies should clearly describe the recall periods .With 446 entries currently listed in the EQUATOR network library for reporting guidelines , there is arguably a need to justify the development of yet another guideline. In recent years, reporting guidelines have increasingly been developed to improve the reporting of content‐related aspects for specific research fields, rather than just targeting a study design. For instance, the TIDieR‐checklist extends CONSORT  for improved reporting of interventions . As this guideline's aim is to facilitate comparison between studies, this primary iteration of the RANCARE guideline deals entirely with quantitative research, using either traditional self‐report survey methodology or novel data generation mechanisms like the electronic health record. Given the complexity of unfinished nursing care, we acknowledge the need to address qualitative study designs and would plan to address this limitation in future iterations. Still, with its overlap of items from other guidelines such as STROBE or CONSORT, this version can be widely applied for observational or interventional study designs. And while the full item set has been compiled to support detailed reporting on unfinished nursing care, items can be used individually if this phenomenon is treated as an antecedent or co‐variable.unfinished nursing care as an umbrella term to ensure inclusion of all related concepts. While our inclusion of nursing within this term acknowledges nurses' crucial roles within health‐care delivery, we also acknowledge that healthcare is multidisciplinary and encourage researchers of other disciplines to use the RANCARE guideline. Rather than focusing on one specific concept or terminology, the RANCARE guideline can provide guidance to all research investigating unfinished, rationed, missed, omitted, compromised, or underused care ‐Req‐2018‐00399.


Regulation of protein synthesis is a vital step in controlling gene expression, especially during development. Over the last 10 years, it has become clear that rather than being homogeneous machines responsible for mRNA translation, ribosomes are highly heterogeneous and can play an active part in translational regulation. These “specialized ribosomes” comprise of specific protein and/or rRNA components, which are required for the translation of particular mRNAs. However, while there is extensive evidence for ribosome heterogeneity, support for specialized functions is limited. Recent work in a variety of developmental model organisms has shed some light on the biological relevance of ribosome heterogeneity. Tissue‐specific expression of ribosomal components along with phenotypic analysis of ribosomal gene mutations indicate that ribosome heterogeneity and potentially specialization are common in key development processes like embryogenesis, spermatogenesis, oogenesis, body patterning, and neurogenesis. Several examples of ribosome specialization have now been proposed but strong links between ribosome heterogeneity, translation of specific mRNAs by defined mechanisms, and role of these translation events remain elusive. Furthermore, several studies have indicated that heterogeneous ribosome populations are a product of tissue‐specific expression rather than specialized function and that ribosomal protein phenotypes are the result of extra‐ribosomal function or overall reduced ribosome levels. Many important questions still need to be addressed in order to determine the functional importance of ribosome heterogeneity to development and disease, which is likely to vary across systems. It will be essential to dissect these issues to fully understand diseases caused by disruptions to ribosomal composition, such as ribosomopathies.Translation > Translation RegulationTranslation > Ribosome Structure/FunctionRNA in Disease and Development > RNA in DevelopmentThis article is categorized under: Ribosome heterogeneity is found across a variety of species and its potential importance to development is being assessed to determine if these ribosomes are specialized. Dissecting the biological function of “specialized ribosomes,” particularly through development, will be essential in determining where different ribosome populations exhibit distinct functions and whether these are important to cellular and organismal health.Drosophila melanogaster  recHOX mRNA 5′‐UTRs appear to contain internal ribosome entry site (IRES)‐like elements that help recruit ribosomes via RPL38  prevalence of tissue‐specific RP expression of particular RPs, and (ii) distinctive phenotypes when specific RP genes are disrupted Dinman, . Both th4.1ASH1 mRNA in Saccharomyces cerevisiae suggest that paralogs can be functionally different, contribute to ability to regulate ribosome structure and therefore function as a result of differences in their amino acid sequence  and Arabidopsis] have also been found to have tissue‐specific expression of RPs. For example, there is specific expression of RPS5A/uS7A, RPS18A/uS13A and RPS16B/uS9B paralogs in apical and root meristems while other paralogs within the family are expressed in specific nonproliferating tissues   and RPS19/eS19, which is mutated in 25% of patients , which results from haploinsufficiencies in several different RP genes  and null mutations  suggesting functional redundancy  RPs of na Table . RPL9B a8.4Although there is clear evidence that a major driving force behind the retention of RP‐paralogs is to maintain high translational output, there are also hints of unique roles for RPs during development. Understanding why some paralogs are only expressed in a subset of nonproliferating tissues will be key to understanding the extent to which the ribosome sufficiency theory and GDBH explain ribosome heterogeneity. In addition, phenotypic analysis of all members within the gene family is necessary to assess the differential contributions of protein paralogs. Furthermore, many RPs have only been characterized under control conditions but evidence is accumulating for ribosomal heterogeneity during stress response (Martinez‐Seidel et al., 9The most significant outstanding question is: Do different ribosome populations actually possess specialized functions? At the center of this is whether these ribosomes translate different mRNA pools. This has been one of the most technically challenging aspects of the field, especially in the context of developmental biology. The Barna group has employed an impressive combination of TRAP‐Seq and Ribo‐Seq to identify which mRNAs different RP‐containing ribosomes are bound to and translating. This level of detail has only been achieved in a very limited setting because the amount of material required for these approaches makes it technically challenging in a developmental setting.If specialized ribosomes exist, then how do they mechanistically affect translation? So far only one mechanism has been characterized and this is the recruitment of specific mRNAs through elements in their 5′‐UTRs via specific RPs to groups of specialized ribosomes. The underlying mechanisms by which specialized ribosomes can regulate specific pools of mRNAs have yet to be discovered. We, and others, have tried to use cryo‐EM to shed light on how ribosome compositional changes might regulate translation but so far this has proved impossible given the technical limitations both dissecting subtle differences in 3D classifications and/or performing EM in purified individual ribosome populations.Are paralogous RPs functionally equivalent? We know that mutations in different members of an RP gene family can generate specific phenotypes, but this does not necessarily mean that the paralogs have disparate functions. Phenotypic differences could arise because of differences in transcript expression between tissues and not because they have different functions. Further work is required to dissect whether paralog‐containing ribosomes translate different mRNAs.Heterogeneous ribosome populations exist, but how are they generated? The most parsimonious theory is that different rRNAs and RPs combinations are generated during ribosome biogenesis. However, as described above, it has been shown that translation of RP mRNAs occurs close to synapses of neurons, a significant distance from the nucleus of the cell (Shigeoka et al., Can single ribosomes contain multiple combinations of alternative ribosomal components? Proteomics has been hugely informative in determining that ribosome heterogeneity is widespread but it is not yet understood if there is preference to have multiple alternative components in the same ribosome, that is, does paralog x in one protein preferentially occur with paralog y in another nearby protein. Native mass spectrometry of ribosomes will hopefully provide this important insight (van de Waterbeemd et al., Does ribosome heterogeneity exist within a cell? Another aspect of heterogeneity not yet fully understood is tissue specificity. Tissue‐specific expression of RPs has been well characterized but what is not yet clear is whether ribosome diversity occurs within a cell rather than in different cells within tissue? Profiling different cell populations within organisms will help address this.Since 2011 and the reemergence of the theory of specialized ribosomes there has been substantial evidence provided for ribosome heterogeneity. RNA‐Seq analysis indicated that different RP mRNAs were expressed at different time point during development and in different tissues. Cellular proteomics revealed that these transcriptional differences result in changes to protein abundance at the cellular level. In the last few years, more advanced proteomics studies have focused on purified translating ribosomes. Importantly, this revealed that the composition of ribosome itself varies, not just the cellular pool of RPs (Shi et al., In summary, developmental biology has provided substantial evidence for the specialized ribosome theory from phenotypes and tissue‐specific expression. Recent work has revealed diversity in ribosome composition through RPs, rRNA, modifications, and associated proteins. However, only limited evidence and examples have been discovered that indicate that this heterogeneity represents a potentially exciting new mode of post‐transcriptional regulation. It will be exciting to see how widespread translational regulation by specialized ribosomes turns out to be.Karl Norris: Writing‐original draft; writing‐review and editing. Tayah Hopes: Writing‐original draft; writing‐review and editing. Julie Aspden: Writing‐original draft; writing‐review and editing.Translation initiation by cap‐dependent ribosome recruitment: Recent insights and open questionsLocal translation of mRNAs in neural developmentGuarding the ‘translation apparatus’: defective ribosome biogenesis and the p53 signaling pathway


Z scores (WAZ) > −2 SD] and undernourished [weight for length (WLZ) or WAZ scores ≤ −2 SD] children aged 6–24 months from seven clinics in low‐income areas of Nairobi. Structured interviews were used to identify exposure to socioeconomic, water and hygiene, infant feeding, dietary and behavioural risks . We recruited 92 wasted WLZ ≤ −2 SD, 133 stunted (length for age Z scores LAZ ≤ −2 SD) and 172 healthy (LAZ and WLZ > 2SD) children. Nearly all children were exposed to hygiene risks (90%) and low dietary diversity (95%) regardless of nutritional status. Stunted children were more likely to be exposed to socio‐economic risks . Compared with healthy children, wasted and stunted children were more likely to be exposed to infant feeding  and behaviour risks . Overall, wasted and stunted children were twice as likely to be exposed to more than three risks . They were also more likely to be exposed to more than three modifiable risks . Wasting and stunting are associated with exposure to multiple risk factors, many of which are potentially modifiable using targeted advice.We aimed to describe the co‐occurrence of known risk factors for undernutrition and the prevalence of modifiable risks in wasted, stunted and healthy children. Quota sampling was used to recruit healthy [weight for age  Most of the undernourished children were exposed to feeding issues such as problems with breast feeding, late complementary feeding, low meal frequency and food refusal, which have the potential to be modified via advice and support.Undernourished children were exposed to a variable number and combination of risk factors, which suggests that an individualized problem‐solving treatment approach is required.1Child undernutrition remains a public health problem in many low‐ and middle‐income countries (LMICs), despite some global improvement  create risk scores for different groups of risk factors, (2) assess the relative prevalence of these risk factors in wasted and stunted children compared with healthy children and (3) assess the extent to which the risk factors overlap in undernourished children.22.1This cross‐sectional study was conducted in seven out of 80 health facilities in Nairobi: Mbagathi District hospital, Kayole II sub‐county hospital, Ruben Medical Clinic, Makadara health centre, Mukuru kwa Njenga health centre, Soweto PhC clinic, which run child welfare clinics, outpatient therapeutic and supplementary feeding programmes. The health facilities were selected because of their proximity to slum areas, which are characterized by extreme poverty levels, poor access to basic hygiene and sanitation facilities as well as poor health outcomes  were recruited initially as well as any other child with severe stunting . Children were excluded if they either had medical complications such as oedema (n = 2), other medical conditions such as congenital heart disease (n = 1) or cleft lip and palate (n = 1). Healthy children were recruited between July and August 2016 in the child welfare clinics in the same centres and were included if they had no major medical conditions and had a WAZ > −2 SD. The healthy group was an ideal control because it would enable us to tease out what other factors potentially increase the risk of childhood undernutrition especially in cases where healthy and undernourished children are exposed to similar environmental conditions.Quota sampling was used to recruit caregiver child pairs aged 6–24 months based on their nutrition status . Undernourished children were further recruited based on the severity of their undernutrition and treatment status. Undernourished children were recruited between February and July 2015. At that time, children were included with an aim to recruit equal numbers of moderate and severely malnourished children based on their treatment status that is whether they had started treatment with ready to use foods  were also classified as wasted (WaSt) because their risk of mortality is equivalent to that of children who are severely wasted  principles applied to locally use complementary foods, grouped into eight categories Table  with sevOverall, meal frequency was assessed by asking caregivers to report types of food offered within each of five parts of the previous day. Foods were classified as either plated foods, finger foods or drinks. Plated foods were described as any cooked foods served on a plate. Finger foods included foods that a child could pick and self‐feed, such as pieces of fruit, biscuits and bread. Drinks included thin porridge, yoghurt and tea. Porridge was classified as a drink because in Kenya porridge has a liquid consistency and is low in energy  included three items avidity, food refusal and force‐feeding, assessed using a set of structured questions, some of which were derived from the Gateshead Millennium Study in the United Kingdom  to detect a prevalence of 15% for any risk factor in one group compared with 30% in another (relative risk = 2) which would require 150 subjects in each of the three subgroups.P < 0.05.Data analysis was done using Statistical Package for Social Sciences (SPSS) version 22. For each risk category , the total number of risks were counted per child. Chi‐squared analysis was used to test associations in categorical variables where Pearson's chi‐squared test was used for binary variables. The level of significance was set at 2.5Ethical approval for the study was obtained from the University of Glasgow Ethics review committee (200140057), University of Nairobi and Kenyatta National Hospital Ethics Review committee (P651/11/2014). Access to health facilities was granted by the Nairobi county and sub‐county health offices.3In total, 450 caregivers were approached for interviews, and 415 were interviewed, of whom 397 were included in the analysis Figure . Socio‐eOver half of healthy children had one or more socio‐economic risks, rising to almost three quarters for stunted children. WaSt children had slightly higher social risk than healthy, but this was not significant Table . All chiOnly a quarter of healthy children had one or more infant feeding risk, but this rose to 40% for children who were either WaSt or stunted and this result remained significant after adjusting for the child's age and socio‐economic risks Table .n = 90, were excluded from the analysis . All children were exposed to at least one individually modifiable risk factors, and three quarters were exposed to three or more, but WaSt children were 34% and stunted 32% more likely to be exposed to four or more; 1.2% healthy, 2.2% WaSt and 3.0% stunted children were exposed to all six modifiable risk factors.Overall, all children were exposed to a risk in at least one of the five risk groups Table , but WaSHygiene was the predominant risk factor seen where a child exposed to only one risk type, with dietary factors where there were two, whereas the other risk factors were commonly seen only when the child was exposed to multiple factors Figure . There w4This study aimed to identify the co‐occurrence and the number of modifiable risk factors for undernutrition, in order to better plan approaches to the care of individual undernourished children, as well as understand optimal prevention approaches. We found that nearly all children were exposed to dietary and hygiene risks regardless of their nutrition status. WaSt and stunted children were, however, more likely to have infant feeding risks and EFB risks and were more likely to be exposed to more than three risk factors.Quota sampling was used to ensure a large sample of undernourished children was recruited from selected health facilities in urban slums in Nairobi. The study was therefore not entirely representative of children in Nairobi slums. However, recruiting from multiple health facilities enabled sampling from different slum areas and a relatively more diverse sample of caregivers. Where we can compare our findings with population surveys, they are broadly similar  interventions when implemented alone or in combination with nutrition interventions have so far been shown to have only marginal effects on child growth and health (Humphrey et al., Low dietary diversity and infrequent meals were also ubiquitous. The measure of dietary diversity used, though based on WHO principles, had not been formally validated, but these findings were plausible, given other survey findings that indicate that a large proportion of children in Kenya do not receive diverse diets (Kenya National Bureau of Statistics, Current interventions in low‐income areas tend to rely on the provision of supplementary foods, which are expensive (Heckert et al., 5Almost all children in this study were exposed to factors associated with undernutrition, but those exposed to three or more risk factors were more likely to be undernourished. Most undernourished children were exposed to a variable number and combination of potentially modifiable risk factors, suggesting the need for individualized problem‐solving interventions.The authors declare that they have no conflicts of interest.ANM and CMW developed the overall research plan, ANM collected the data and performed statistical analysis with input from CMW and ALG. ANM and CMW wrote the first draft. ANM, CMW, ALG and EWK reviewed the subsequent drafts. ANM had primary responsibility for the final content. All authors have read and approved the final manuscript.Table S1: Socio demographic and hygiene characteristics of healthy, wasted and stunted childrenTable S2: Infant feeding, dietary factors and feeding practices by child nutrition statusClick here for additional data file.


To assess the availability of an institutional‐level respectful maternity care (RMC) index, its components, and associated factors.A cross‐sectional study design was applied to a 2016 census of 3804 health facilities in Ethiopia. The availability of an institutional‐level RMC index was computed as the availability of all nine items identified as important aspects of institutional‐level RMC during childbirth. Logistic regression analysis was used to identify factors associated with availability of the index.Three components of the institutional‐level RMC index were identified: “RMC policy,” “RMC experience,” and “facility for provision of RMC.” Overall, 28% of facilities  reported availability of the institutional‐level RMC index. Facility location urbanization (urban region), percentage of maternal and newborn health workers trained in basic emergency obstetric and newborn care, and availability of maternity waiting homes in health facilities were positively associated with availability of the institutional‐level RMC index.Only one in three facilities reported availability of the institutional‐level RMC index. The Ethiopian government should consider strengthening support mechanisms in different administrative regions , implementing the provision training for health workers that incorporates RMC components, and increasing the availability of maternity waiting homes. In Ethiopia, only one in three facilities reported availability of an institutional‐level respectful maternity care index. Factors associated with availability of the index were identified. It may also positively influence the utilization of maternity services. To our knowledge, potential components of institutional‐level RMC have not been systematically assessed before. Therefore, the primary aim of the present study was to describe an institutional‐level RMC index. Secondary aims were to (a) identify components of the institutional‐level RMC index during childbirth, (b) assess levels of the institutional‐level RMC index and components in hospitals and health centers in Ethiopia; and (c) determine institutional‐level factors associated with the reported institutional‐level RMC prerequisites.22.1The present study used a subset of the 2016 EmONC assessment data that focus on health facility level policies, norms, and practices that affect provision of RMC. The EmONC assessment utilized a cross‐sectional census of all health facilities in Ethiopia that provided childbirth services prior to the assessment.2.2The study included all private and public health facilities  across all nine regions and two city administrations in Ethiopia. All health facilities that had a mandate to provide childbirth services according to national accreditation agency criteria confirmed that births had taken place in the 12 months preceding the assessment and were functional during the data collection period.2.3The data collection tools were adapted to the Ethiopian context from the 2008 EmONC assessment tool and the 2014 Averting Maternal Death and Disability tools. The analyzed data were extracted from modules one and two (“facility identification” and “infrastructure and human resources”).The data collectors had at least a bachelor's degree in a health‐related field. All data collectors attended 10 days of training and worked in teams of three, with one group member serving as team leader. Field level data collection was conducted from approximately May 15 to December 15, 2016. Data were collected by interviewing health facility and maternity unit heads in a private area at the facility. The data collectors also observed the availability of facilities necessary for provision of RMC, such as curtains, waiting areas, and bathrooms.2.4To ensure accurate data quality, pre‐ and post‐tests were administered to data collectors to assess their learning and understanding of assessment guidelines and standards for data collection. Team leaders reviewed all completed questionnaires to ensure completeness. Regional and national coordinators visited and communicated with data collection teams to provide support and help when difficulties arose at individual facilities. Data were analyzed using Stata version 14 .2.5The “institutional‐level RMC index” was defined as the health facility's availability of physical infrastructure, equipment, policies, and norms that together enable women to experience RMC during childbirth services. It includes a physical infrastructure that encourages privacy and confidentiality, availability of waiting area for companions, availability of bathrooms, and facility‐related policies and norms to ensure a positive experience during labor and childbirth.In the first step, 11 items (questions) measured in a binary (yes/no) format were identified that highlight important aspects of institutional‐level RMC during childbirth: “women can choose a companion of their choice,” “women can choose birthing position,” “women can walk around during labor,” “availability of curtains for privacy,” “availability of waiting areas for women and companions,” “availability of functioning toilets for companions,” “availability of food for women,” “women have never shared beds before or after birth,” “women have never slept on the floor,” and “women have never given birth on the floor.”Two items  were excluded from the principal component analysis due to low factor loadings (<0.35), although one item was retained owing to technical relevance even though it did not fulfill statistical criteria. The nine remaining items that measured specific aspects of institutional RMC during childbirth were grouped into components Table . Three cThe component “policy” was calculated from three items  and labeled as available when all three items were reported as yes. The component “facility” was calculated from three items  and considered as available when all three conditions were observed or reported as yes. The component “experience” was calculated from three items  and considered to be available when all three items were reported as yes by the maternity unit lead. The variable institutional‐level RMC index was calculated as a composite score of all nine items. The institutional‐level RMC index was considered to be available only if all nine items were available.In the second step, multivariate logistic regression was used to identify factors associated with the availability of the institutional‐level RMC index during childbirth, which was the outcome variable. Covariates identified from other studies included managing authority, administrative region type, ratio of births to maternity beds, ratio of childbirth to maternity healthcare workers, proportion of MCH providers trained in BEmONC, and availability of MWHs in health facilities.P values to compensate for multiple testing.The variable “ratio of births per year to maternity beds” indicated the level of crowding at the facility, whereas”the ratio of childbirth to maternity healthcare workers” was applied as a measure of the workload of providers. Continuous explanatory variables  were categorized into four quartiles to facilitate data interpretation. Frequencies were calculated for a range of facility factors. The data are presented as odds ratio (OR) or adjusted odds ratio (aOR), combined with 99% confidence intervals (CIs) and 3Among 4385 private and public health facilities in Ethiopia, 11 were excluded from the assessment due to civil unrest in their catchment areas, 568 were excluded due to absence of service during the 12 months preceding the survey and 2 refused to participate in the assessment. Overall, 3804 facilities  were included in the analysis.n = 3074, 88.1%) were found in agrarian regions. Most hospitals  were in urban areas, whereas most health centers  were in rural areas. The majority of hospitals had the lowest delivery volume  and were the least crowded (≤31 births per MNH provider).The background characteristics of the health facilities are summarized in Table n = 969) of health centers fulfilled the institutional‐level RMC index. As compared with hospitals, health centers reported higher rates of RMC‐related policies  and facility‐level RMC experience . In terms of availability of the facility component necessary for the provision of RMC, hospitals reported better performance than health centers .Table P = 0.037), although the difference was not statistically significant , 1.74 , and 1.84 , respectively. Lastly, facilities with freestanding MWHs were 41% more likely to fulfill the institutional‐level RMC index as compared with those with no MWHs .Facilities in the higher  quartiles of providers trained in BEmONC were more likely to fulfill the institutional‐level RMC index: aOR, 1.75 , and facilities with freestanding MWHs were significantly associated with higher availability of the institutional‐level RMC index. In line with previous research, the institutional‐level RMC index was found to comprise three components: policy, facilities, and experience. The components policy and facilities were also included as health systems conditions and constraints in a 2015 systematic review of mistreatment during childbirth.The finding that facilities in urban regions performed better on availability of the institutional‐level RMC index might be due to the better provision of resources in urban areas.The finding that facilities with a higher proportion of MNH providers trained in BEmONC (quartiles 2–4) had higher availability of the institutional‐level RMC index might be attributed to both the fact that RMC is included in the national BEmONC training package,The finding that facilities with freestanding MWHs were associated with availability of the institutional‐level RMC index might be related to strong community links and management of facilities. Construction of MWHs involves the involvement of both health facility management and the local community; thus, the provision of a MWH is an important indicator of a health facility's management commitment to improving maternity care access to women from distant areas. Establishing good community ties, managing health facilities better, and investing in maternity healthcare workers all show a higher awareness of women's needs and more willingness to improve care in order to attain RMC. The Ethiopian MOH standardized the implementation of MWHs in 2015 and supported its expansion across the country to improve access to childbirth service for women in rural areas.The present study has both strengths and limitations. An important strength is that it examined institutional‐level factors affecting the availability of RMC by assessing all facilities in the country. Its limitations encompass the fact that the number of items included to measure the overall RMC condition were selected from a small set of questions, as opposed to a longer list covering all theoretic aspects of institutional‐level RMC conditions. It should be acknowledged, however, that the limited items included to represent RMC were selected from published studies after conducting an expert review,In conclusion, the present study found that the institutional‐level RMC index in health facilities comprised three components: policy, facilities, and experience. Urban administrative region, proportion of healthcare providers trained in EmONC, and availability of MWHs were associated with availability of the institutional‐level RMC index. Two in three health facilities did not have the institutional‐level RMC index in place. In line with its effort to provide a compassionate, respectful, and caring service, the study suggests that the Ethiopian government needs to consider strengthening support mechanisms in different administrative regions , implement the provision of healthcare training that incorporates components of RMC, and increase the availability of MWHs. We recommend that the government should develop and implement RMC policies at the health facility level. The government also needs to support health facilities with the necessary resources to ensure availability of the necessary infrastructure and supplies for the provision of RMC.The authors have no conflicts of interest.EDS contributed to study conceptualization, data analysis, original draft preparation, and manuscript editing. RB contributed to study conceptualization, original draft preparation, and manuscript editing. YMK, TVA, and JS contributed to the conceptualization, writing, review and editing of the manuscript. TT contributed to study design, and manuscript review and editing. AG contributed to manuscript review and editing. All authors read and approved the final manuscript.Table S1‐S2Click here for additional data file.


The Journal of Clinical Hypertension, the study by Dr. Fan and colleagues aimed to explore longitudinal blood pressure (BP) trajectory patterns and determine their prognostic role in stroke outcomes.In the current issue of The results of this study provide useful insights to advance our understanding of the intriguing relationship between BP variations after stroke and clinical outcomes. Advances in stroke treatment have reduced the overall mortality rate, whereas the number of survivors with complications and disability has increased.1Most studies on the effects of BP during acute and subacute stroke phases on clinical outcome have used one time‐point BP values and only a few studies have focused on BP trajectory patterns.The effects of BP changes on outcome in acute ischemic stroke and the impact of baseline values and history of hypertension have been explored in 791 patients registered in the Acute Stroke Registry and Analysis of Lausanne.Among 316 patients included in the Blood Pressure and Clinical Outcome in TIA or Ischemic Stroke Study who presented with ischemic stroke and admission SBP ≥160 mm Hg, the analysis of BP values during the first 7 days after onset identified three SBP trajectories: sustained high SBP (T1), moderate decrease (T2), and rapid decrease in SBP (T3).The Scandinavian Candesartan Acute Stroke Trial was a multicenter, randomized controlled, double‐blind trial of candesartan in acute stroke, which recruited 2029 patients presenting within 30 h of acute stroke and with SBP ≥140 mm Hg.Five SBP trajectories of high, high‐to‐moderate‐low, moderate‐high, moderate‐low, and low were defined in 4036 patients with acute ischemic stroke and elevated BP from the China Antihypertensive Trial in Acute Ischemic Stroke trial who had their BP measured from day 1 until hospital discharge or death.The influence of BP trajectory on subsequent clinical events up to 1 year after stroke was explored in 8376 patients with cerebral infarct admitted within 24 h of symptom onset and included in a prospective multicenter registry.Interestingly, the magnitude of BP reduction was a predictor of in‐hospital outcomes also in patients with hemorrhagic stroke. In a cohort of 757 patients with spontaneous intracerebral hemorrhage, unsupervised functional principal components analysis revealed that mean SBP over 24 h and SBP reduction within the first 6 h from stroke accounted for 76.8% of the variation in SBP trajectories.2Although the management of BP in acute stroke has been investigated in several trials, optimal BP levels have not been well‐established yet, and uncertainty remains about whether, when, and how BP should be lowered.During the acute phase of stroke, cerebral blood flow follows the systemic arterial pressure due to impairment of autoregulatory mechanisms, where both extremely high and low BP values have been associated with poor outcomes. High BP may increase the risk of hemorrhagic transformation of infarcted area, favor hematoma expansion by promoting ongoing bleeding and re‐bleeding and enhance brain formation. Of note, the rise in BP may also favor recanalization and represent a protective response to guarantee perfusion in the presence of dysfunctional cerebral autoregulation and raised intracranial pressure.Importantly, BP dynamics may serve as an important modifiable and prognostic factor. The relationship between BP and outcome is not simply linear, and BP changes during the acute stroke phase can play a role in the development of complications.Additional research is still warranted to explore the relevance of BP trajectories in different stroke populations, assess the reciprocal interaction of causes and effects of BP variations, and investigate the utility of trajectory patterns in identifying the best candidates for BP‐lowering therapy. Indeed, it is likely that a variety of patient‐specific factors such as age, stroke type, recanalization treatment, infarct volume, status of collaterals, cardiovascular comorbidities, and prior antihypertensive therapy may influence the range of optimal BP values and vulnerability to the detrimental effects of BP changes.None.


SD). Using linear mixed‐effects models, we investigated whether communities in PAs had lower climatic debt and different patterns of community change than communities outside PAs. For CTI and CTISD combined, communities inside PAs had more species, higher colonization, lower extirpation, and lower climatic debt (16%) than communities outside PAs. Thus, our results suggest that PAs facilitate 2 independent processes that shape community dynamics and maintain biodiversity. The community adjustment was, however, not sufficiently fast to keep pace with the large temperature increases in the central and northeastern western Palearctic. Our results underline the potential of combining CTI and CTISD metrics to improve understanding of the colonization‐extirpation patterns driven by climate warming.Climate warming is driving changes in species distributions and community composition. Many species have a so‐called climatic debt, that is, shifts in range lag behind shifts in temperature isoclines. Inside protected areas (PAs), community changes in response to climate warming can be facilitated by greater colonization rates by warm‐dwelling species, but also mitigated by lowering extirpation rates of cold‐dwelling species. An evaluation of the relative importance of colonization‐extirpation processes is important to inform conservation strategies that aim for both climate debt reduction and species conservation. We assessed the colonization‐extirpation dynamics involved in community changes in response to climate inside and outside PAs. To do so, we used 25 years of occurrence data of nonbreeding waterbirds in the western Palearctic . We used a community temperature index (CTI) framework based on species thermal affinities to investigate species turnover induced by temperature increase. We determined whether thermal community adjustment was associated with colonization by warm‐dwelling species or extirpation of cold‐dwelling species by modeling change in standard deviation of the CTI (CTI Article impact statement: Protected areas are needed to facilitate waterbird distribution change in response to climate warming in the western Palearctic. Global warming is one of the major causes of biological changes among the growing number and variety of anthropogenic pressures on the natural world   across 39 countries 7071 sites). We examined community dynamics within the CTI framework and the related community thermal standard deviation (CTI sites. Wwww.wetlands.org) . The data used for the analyses included 97 species of nonvagrant waterbirds that overwinter in the western Palearctic (Supporting Information) and are listed in the African‐Eurasian Migratory Waterbird Agreement (http://www.unep-aewa.org).We used IWC data from almost all of the western Palearctic (39 countries with sufficient data according to criteria below [Supporting Information]) from 1993 to 2017. The IWC monitors nonbreeding waterbirds  with a single count each year in January by ornithologists, either professionals or citizen scientists. The count is coordinated by Wetlands International (e Delany  for the www.eea.Europa.eu) (Supporting Information). We included all levels of International Union for Conservation of Nature (IUCN) PA management category (I–VI), following the definition given by UNEP‐WCMC, IUCN and NGS (2021). A site was considered a PA when its coordinates fell within the polygon of a PA designated before 2017, meaning that we investigated the effect of the area where the PA was established rather than the effect of PA designation. If polygon data were absent (12% of the cases), a circular area was delineated based on the PA size reported in the World Database on Protected Areas (100% concordance of site‐protection status was found by delineating a circular area on the subset of PAs with polygons). The sites inside (n = 3374) and outside (n = 3697) PAs had a similar number of counts and spatial distribution (Supporting Information).Site protection is reported for 3374 sites from the World Database on Protected Areas , the Natura 2000 database, and the Common Database on Designated Areas  experienced by the species across the nonbreeding (overwintering) distribution during the monitoring period  were computed as the species thermal affinity across each species’ nonbreeding distribution following Gaget et al.  (adaptedhe World ). SubspeSD) were computed following Devictor et al.  (Gaussian error distribution). The explanatory terms were year (continuous variable from 1993 to 2017), site protection status (inside or outside), and the interaction of year × protection status. Site identity was added as a random effect on the intercept in the CTI and CTISD models. Spatial autocorrelation was taken into account by including the site geographical coordinates as an exponential spatial correlation structure in the model , and ε is the residual variance for each observation under a Gaussian distribution and an exponential spatial correlation. To visually assess whether it was appropriate to model interannual changes as a linear effect, we generated and plotted mean annual values (95% CI) by using the same model, but changing year to a categorical variable. We conducted complementary analyses to assess the robustness of the results to species’ identity and abundance with a resampling approach. Resampling followed Devictor et al.  based on occurrence and abundance data (Supporting Information).where r et al. , in whicWe looked for evidence of climatic debt accumulated by the waterbird communities by assessing the difference between the linear trends of temperature and CTI, following Devictor et al. . First, In addition, we assessed the temporal trend of cold‐ and warm‐dwelling species inside versus outside PAs to illustrate the absolute changes of thermal‐dwelling composition in the communities. We used 2 simplified thermal‐dwelling categories to classify species as cold dwelling or warm dwelling based on their STI in relation to the CTI of each individual site: cooler or warmer STI than the mean CTI across the site's whole time series, respectively. Then, the number of cold‐ and warm‐dwelling species was summed per survey. The temporal changes in number of cold‐ and warm‐dwelling species were assessed using in a GLMM (Poisson error distribution) with fixed effects of year, thermal‐dwelling category (cold or warm), site PA status (inside or outside), and their 3‐way interaction. Site identity was added as a random factor. Spatial autocorrelation was taken into account by including the site geographical coordinates as an exponential spatial correlation structure in the model. The GLMM wasi,j,kN is the number of species summed per survey in year i at site j for the thermal‐dwelling category k, μ is the intercept, PA is the site protection status of site j, D is the thermal‐dwelling category (cold or warm), site is the random intercept per site that follows a Gaussian distribution (mean of 0 and variance σ²), and ε is the residual variance for each observation under a Gaussian distribution and an exponential spatial correlation.where SD trends were correlated with the proportion of PA surface with a moving‐window approach. First, we performed one GLMM per cell  per response variable  to investigate changes in cells over time. We used site identity as a random effect and included the site geographical coordinates as an exponential spatial correlation structure. Second, we investigated the relationship between the proportion of PA surface per cell and the CTI spatial shift, CTISD, or climatic debt trends (estimated from the above models). The proportion of PA surface was assessed per cell as the sum of the studied site inland PA surfaces divided by the total inland surface per cell . One linear model was used per response variable . Fixed effects were the proportion of PA surface per cell and the temperature spatial shift, plus their interaction. To investigate the relationship between coverage of the studied PAs and their location in the western Palearctic, we also assessed with a linear model whether proportion of PA surface increased with latitude, longitude, and their interaction. Spatiotemporal changes in temperature, CTI, and climatic debt were expressed in units of kilometers per year and in degrees Celsius per year for the CTISD. Each cell included both protected and unprotected sites and at least 15 sites  to avoid cells with a small number of sites at the edge of the study area.We investigated whether the CTI, climatic debt, and CTIAll statistical analyses were performed with R 3.4.3 (R Core Team p < 0.001) without a significant difference between inside and outside PA (p = 0.2)  Table . The CTI2) Table . The CTIAs Table . Therefop < 0.001) and −0.31° C for the CTI . The temperature increase was equivalent to a latitudinal shift of 11.4 km/year (285 km in 25 years). The temporal CTI trend was equivalent to a shift 43% larger inside PAs than outside (about 3.5 km/year inside PAs [87 km over 25 years] and 2.0 km/year outside [50 km over 25 years]). Consequently, the climatic debt was about 7.9 km/year inside PAs and 9.4 km/year outside .Temporal changes in CTI lagged behind changes in temperature. The temperature latitudinal gradient was about −0.38° C/decimal degree  and increased faster than that of cold‐dwelling species  (Supporting Information). Inside PAs, the number of warm‐dwelling species also increased faster than that of cold‐dwelling species ; but the interaction of proportion of PA surface and temperature spatial shift was not significant (Table p ≤ 0.001) , but it was not significantly affected by the proportion of PA surface  and increased with the latitude . The interaction was negative and significant .The CTI spatial shift increased as inland proportion of PA surface increased per cell and temperature spatial shift increased (nt Table . Consequ1) Table . The temce Table . The proOur study represents one of the first empirical and international assessments addressing differences in community changes in response to climate warming in PAs on a continental scale. We found that a fast increase in CTI inside PAs compared with outside PAs was driven mainly by colonization from warm‐dwelling species, which is consistent with other studies on birds and other taxonomic groups  increased over time, and we found a general increase in CTI of both cold‐ and warm‐dwelling species over time. Our findings suggest that inside PAs, species with high thermal affinity colonized the community, but at the same time, species with low thermal affinity were less likely to be extirpated, which likely increased their extinction debt. The PAs can act as refuges by improving species resilience against climate warming (Santangeli & Lehikoinen 2017), likely by ensuring ecological requirements needed for species persistence despite the proximity to their thermal niche edge. Consequently, despite smaller climatic debts inside PAs because of the large colonization by warm‐dwelling species, both persistence and colonization by cold‐dwelling species likely increased the climatic debt estimated for the whole community.Species richness of nonbreeding waterbirds increased over the study area, particularly inside PAs, in line with recent general positive trends of western Palearctic waterbird populations . With these simple indicators, we identified that the community adjustment to temperature was mainly due to high colonization by the warm‐dwelling and reduced extirpation of cold‐dwelling species inside PAs, whereas outside PAs, the extirpation of the most cold‐dwelling species was nearly equivalent to the colonization by warm‐dwelling species  in both protected and unprotected areas Delany . HoweverNonbreeding waterbirds have high capacity to respond to climate warming with a distribution change  should be directed to the corresponding author.Click here for additional data file.


Patients who default from HIV care are usually poorly adherent to antiretroviral treatment which results in suboptimal viral suppression. The study assessed the outcomes of retention in care and viral suppression by expansion of an intervention using two patient tracers to track patients lost to follow up at a large HIV clinic in Trinidad.Two Social Workers were trained as patient tracers and hired for 15 months (April 2017–June 2018) to call patients who were lost to follow up for 30 days or more during the period July 2016–May 2018 at the HIV clinic Medical Research Foundation of Trinidad and Tobago.3  and if they were retained in care at 12 months . Persons initiated on ART for 4–6 years , 7–9 years , > 10 years  patients were no longer in active care—89 patients dead, 65 migrated, 55 hospitalized, 33 transferred to another treatment clinic and 19 incarcerated. Of the remaining 2212 patients eligible for tracing, 1869 (84.5%) patients were returned to care, 1278 (68.6%) were virally unsuppressed  and 1727 (92.4%) were re-initiated on ART. Twelve months after their return, 1341 (71.7%) of 1869 patients were retained in care and 1154 (86.1%) of these were virally suppressed. Multivariate analysis using logistic regression showed that persons were more likely to be virally suppressed if they were employed , if they had baseline CD4 counts < 200 cells/mmPatient Tracing is a feasible intervention to identify and resolve the status of patients who are loss to follow up and targeted interventions such as differentiated care models may be important to improve retention in care. The use of anti-retroviral therapy (ART) which effectively suppresses the HIV viral load of patients results in reduced HIV transmission, reduced CD4+ T cell depletion and improved reconstitution of the immune system thereby transforming HIV into a chronic, manageable disease –4. Thus The twin island republic of Trinidad and Tobago are the southernmost islands of the Caribbean and comprise a single nation with a population of approximately 1.36 million (2019 mid-year estimate). The first cases of AIDS were reported in 1983 among gay/bisexual men  and by 1The Medical Research Foundation of Trinidad and Tobago (MRFTT), the largest HIV clinic in Trinidad and Tobago and the Southern Caribbean, recently conducted a 6-month pilot which assessed the feasibility of a patient tracing programme for HIV that re-engaged in care those patients who missed their clinic appointments and the data from this study was previously reported . In thisThe data and outcomes of this pilot study assisted in allocation of programme resources for targeted interventions to reduce lost to follow up and increase patient retention in HIV care through a tailored package of HIV services to better serve the needs patients enrolled in HIV care  to incluWith these differentiated care services available for patients attending the clinic, the purpose of this study was to evaluate the outcomes of an expanded intervention using patient tracers to find patients lost to follow up from the Medical Research Foundation HIV clinic, and monitor their retention and viral suppression 12 months after their return to care.This was a retrospective study to track patients who missed their scheduled clinic visit for over 1 month and were deemed lost to follow up at the HIV clinic, Medical Research Foundation of Trinidad and Tobago (MRFTT). As of June 30, 2018, a total of 6486 patients were reported to be enrolled active in care at the HIV clinic. The patient tracing methods at the MRFTT are described elsewhere [Any patient attending the HIV clinic who missed their clinic visit for 30 days or more (lost to follow up) during the period July 2016–May 2018.Any patient attending the HIV clinic who missed their clinic visit for less than 30 days (missed appointments) during the period July 2016–May 2018.Any patient attending the HIV clinic who did not miss clinic visits during the period July 2016–May 2018.The source population was the patients attending the HIV clinic, MRFTT during the period July 2016-May 2018. Generally, one patient tracer would follow up with one particular patient so that a relationship could be established and trust built up. “Treat all” started in September 2017 at the MRFTT and all patients who returned to care were offered or restarted on ART and followed up bi-weekly, then monthly, then 3 monthly and finally every 6 months once they were stable on ART and their HIV viral loads were suppressed.All study protocols and procedures were reviewed and approved the University of the West Indies, Campus Research Ethics Committee, St. Augustine, Trinidad. De-identified patient data were extracted for analysis and this was cleaned and organised into an excel spreadsheet database which was imported into the Statistical Package for Social Sciences (SPSS version 25). The data were compiled to a flowchart to examine all the patients who returned to the clinic including those patients who were lost to follow up. The sociodemographic characteristics of the patients were examined by descriptive analyses and the outcomes were stratified by selected descriptive features. The analysis consisted of a Pearson's chi-square test in order to determine if a statistically significant relationship existed between selected descriptive features and the 12-month outcomes of retention in care and viral suppression. Multivariate analysis using logistic regression was then carried out on the variables that had a statistically significant association with the outcomes to identify the influence of these variables on the 12-month outcomes of retention in care and viral suppression. Both the start-up and implementation costs of the interventions were assessed.Retention in care was defined as a patient in care and having at least two documented clinic visits (physician visit or/pharmacy medication pick-up or laboratory tests) separated by ≥ 90 days during a calendar year. Viral suppression was defined as a viral load of less than 200 copies/ml.Figure Table Figure 3 (p = 0.033) and those who had initiated ART for longer periods of time (p < 0.001). Statistically significant associations for viral load suppression at 12 months were seen for those who were employed (p = 0.001), those who ever used drugs such as marijuana/crack/cocaine (p = 0.007) those with baseline CD4 counts < 200 cells/mm3 (p = 0.005), those who had initiated ART for longer periods of time (p < 0.001) and those who were retained in care at 12 months (p < 0.001).Table Multivariate analysis using logistic regression Table  showed p3  and if they were retained in care at 12 months .Multivariate analysis using logistic regression Table  showed pThe pilot phase of the programme took place over the 6-month period April-September 2017 and of the 866 patients were eligible for patient tracing, 589 (68%) were successfully contacted and returned to care  as compaBoth the start-up and implementation costs of the intervention were assessed Table . The mai3, so some patients defaulted from clinic as they claimed no treatment was offered to them as their CD4 cell count was “stable”. During the phone calls, the patient tracers explained to the patients the benefits of ART and assured them that once they returned to clinic, ART would be initiated/reinitiated.During the 15 month extended programme, two patient tracers working 5 days per week were able to determine the status of 1910 (86.3%) of 2212 patients who were lost to follow up and were eligible for patient tracing. The intervention resulted in returning 1869 (84.5%) of 2212 patients to care as compared to 589 of 866 (68%) patients successfully contacted and returned to care in the 6-month pilot programme (p < 0.001). Thus the effect of the intervention improved over time as more patients were successfully returned to care which may be attributed to the enhanced efficiency of the patient tracing programme as the patient tracers became more proficient at calling patients who missed their clinic appointments and getting them back into care; due to cultivated relationships between the patient tracers and staff from other treatment sites so that patient transfers among sites were more readily ascertained and the MRFTT started a prison programme in January 2018 so that incarcerated patients could be readily identified. In addition, “treat all’ was introduced in September 2017, before this ART was indicated for patients at MRFTT whose CD4 counts fell below 350 cells/mmPatient tracing programmes have been shown to be effective in determining the status of patients who missed their clinic appointments , however3 [3  however the results were not statistically significant for retention in care at 12 months. There are mixed results in patients with CD4 < 200 cells/mm3 and subsequent viral suppression as a systematic review by Lailulo et al. [3  in resource limited areas perhaps due to HIV related opportunistic infections, increased pill burdens and the potential to develop increased drug toxicity in patients with advanced disease on multiple medications [Patients who miss their clinic appointments often have unsuppressed and transmissible viral loads and are generally not included in the ascertainment of the HIV Treatment Cascade of the HIV clinic . Of the 3  which ma3 , 28. In o et al.  done to ications .The International Labour Organization (ILO) conducted a systematic review of 23 studies involving 6674 PLHIV assessing adherence rates and found that persons who were employed at the time of the study were more likely to have achieved optimal ART adherence  than those who were unemployed . It was In the study by Rosen and Ketlhapile in South Africa, 20 of 97 patients (21%) who missed clinic visits were returned to care by patient tracing at a cost of $432 USD per patient, which was quite expensive and unsustainable . Table 4To improve the efficiency of the patient tracing intervention, it is recommended that Trinidad and Tobago (with a population of approximately 1.36 million inhabitants) invest in a National Health Management Information System (HMIS) to link and track HIV cases/patients who transfer to other treatment facilities/clinics which would result in enhanced tracking and monitoring of patients across sites. The inability to track patients who have transferred to other treatment facilities obfuscates inferences about retention in care. Improved reporting of deaths and linking the national death registry to a HIV case surveillance HMIS can also be effective in validating the status of patients not active in care and lost to follow up  as well As in the pilot programme, the three most common barriers to re engagement in care are, (1) patients not remembering their appointments, (2) patients not getting time off from work to attend their clinic appointments, and (3) patients’ fear of being seen attending the HIV clinic . To addrThe ability of the patient tracers to identify and counsel patients and successfully reintegrate them into HIV care further highlights the effectiveness of the Patient Tracing intervention. Patient tracers as trained social workers provided counselling to both treatment experienced and naïve patients assisting them to overcome the barriers to ART reinitiation and/or initiation which is critical component of treat all strategy at the MRFTT. The study found that the number of years since ART initiation increased the likelihood of patients being retained in care after the 12-month period compared to patients who never initiated ART. Patients who were on ART had a higher likelihood of retention in care compared to those not initiated on ART. The results of the analysis demonstrated a higher likelihood for patient retention in care as time since ART initiation increased—hence underscoring the relationship between early ART initiation and retention in care after missed clinic visits. Of the 1869 patients returned to care, 1727 (92.4%) were re-initiated/started on ART, and after 12 months, 1341 (77.6%) of these were retained in care and 1154 (86.1%) of these were virally suppressed. Given these outcomes, the Patient Tracing Programme was critical in reducing treatment interruptions which if left unattended may lead to high levels of viremia with attendant risks of increasing HIV transmission, the potential for drug resistance, the development of opportunistic infections , subsequOne of the limitations of the study is the difficulty in tracking patients’ VL over time, given the cross-sectional approach used. This approach may underestimate the VL burden given the changing nature of VL suppression over time . AnotherAnother limitation of the study is the use of a retrospective study design given that only sociodemographic and clinical characteristics data collected as part of routine program reporting were included in the analysis and therefore limiting the comparability of results across similar studies. Also, the data used in the analysis were reported either at baseline or last observed at the time of data extraction. This may also present a bias given that patients may have fallen in and out of care over the period of the analysis–hence making it difficult to measure continuous retention in HIV care.Patient Tracing is a feasible and effective intervention to identify and resolve the status of patients who miss clinic appointments, re-engage and retain them in care. In this study, patient tracers as social workers provided enhanced psychosocial support assisting patients to overcome the barriers to ART initiation and/or re-initiation, retention in continuous care, and to achieve and maintain viral suppression. To enhance patient tracing outcomes, targeted interventions are needed to ensure early ART initiation and differentiated care interventions to address client specific barriers as these may improve retention in care and viral suppression. A longitudinal study design will provide additional opportunities to track the long-term effect of differentiated care interventions over time.


Developing a novel therapeutic product for the treatment of type 2 diabetes (T2D) is a long, resource‐intensive process. Novel biomarkers could potentially aid clinical trial design by shortening clinical trials or enabling better prediction of at‐risk populations and/or disease progression. Novel clinical trial designs could lead to reduced costs of development and less burden to patients, due to shorter trial duration, and/or less burdensome assessments. This is a review of the potential use of biomarkers in novel clinical trial design. It also describes the IMI2 RHAPSODY consortium. Developing a novel therapeutic product for the treatment of T2D is a long, resource‐intensive process. However, it is important that its risks and benefits are evaluated in the context of relevant populations and conditions of use, so that adequate prescribing information can be provided to physicians, healthcare professionals and patients.https://imi‐rhapsody.eu/project). Its aim is to define a molecular taxonomy of T2D that could support patient segmentation, inform clinical trial design, and the establishment of regulatory paths for the adoption of novel strategies for diabetes prevention and treatment.RHAPSODY is an IMI2 public‐private consortium . Though a well‐recognized end‐point of long‐term blood glucose control, HbA1c provides limited information on other important end‐points of this multifaceted disease and may not predict the full burden of disease on the patient.1Currently, there are few data sets available on the prospective use of genetic and/or biomarkers for patient selection in clinical trials for T2D. As each patient is unique with different personal goals, medical history and expectations, only a general evaluation of the efficacy of a therapeutic agent over a range of types of patients can be made. It would be extremely useful to be able to select patients based upon potential biomarkers for disease progression or disease status. Biomarkers identified within RHAPSODY could potentially allow for such selection.Enrolling clinical trial populations based on biomarker profiles may facilitate improved clinical trial efficiency and conduct.Biomarkers can also be used to target populations that are more likely to respond.2Clinical trials use end‐points of disease progression to evaluate efficacy and safety. Sometimes these end‐points take many years to develop. Having a biomarker that is a surrogate for disease end‐points could potentially save time in determining if a treatment is effective.A biomarker of disease progression would allow assessment of specific disease outcomes. For example, cardiovascular outcome trials are large and run for many years. However, the size (10 000s patients) and length of clinical trials (5 years +) needed to evaluate therapies using observational methods are prohibitive to the development of therapeutics. For novel therapeutic agents for T2D, the evaluation of any effects of new agents on cardiovascular outcomes is also required by regulators. If there were biomarkers of cardiovascular disease progression within prediabetes and T2D, this could mean improved CV safety and reduced cost, with shorter, smaller clinical trials. Similarly for therapies developed for the treatment of diabetic kidney disease, currently regulators mandate the need for ‘hard outcome’ event‐driven studies, which are consequently extensive in terms of study duration and cost. The identification of novel biomarkers for use with other clinically meaningful surrogate end‐points could allow for a more rapid efficacy assessment in the future. However, shortening the timeframe of a therapeutic trial based solely upon biomarker behaviour may reduce opportunities to observe unintended, longer‐term, off‐target effects.3The impact of a therapeutic, as experienced by the patient, is an important consideration. Regulators are increasingly involving patients in the review of new medicines, asking them to provide input on which measures are clinically meaningful to their daily lives, and their perception of benefits and risks. Furthermore, payers are requiring evidence that medicines are adding value to the patient's quality of life.co‐design). Though this is in its infancy, greater efforts are being made to maximize patient involvement in this area by industry.Patients are also being involved in many aspects of drug development, including aiding in the design of trials (The use of continuous glucose‐monitoring (CGM) technologies to monitor time‐in‐range and patient‐reported outcome measures (PROMs) could also be utilized to assess impact on sleep patterns, anxiety, diabetes distress or resilience. A stepped or adaptive trial design approach, use of real‐world evidence, actively recruiting ethnic minorities and limiting the  exclusion of comorbid patients would further help with future study‐population stratification, while creating a more holistic understanding of the efficacy of the trials and their impact on patients.Table


Synapses are fundamental structures of neural circuits that transmit information between neurons. Thus, the process of neural circuit formation via proper synaptic connections shapes the basis of brain functions and animal behavior. Synapses continuously undergo repeated formation and elimination throughout the lifetime of an organism, reflecting the dynamics of neural circuit function. The structural transformation of synapses has been described mainly in relation to neural activity‐dependent strengthening and weakening of synaptic functions, that is, functional plasticity of synapses. An increasing number of studies have unveiled the roles of microglia, brain‐resident immune cells that survey the brain parenchyma with highly motile processes, in synapse formation and elimination as well as in regulating synaptic function. Over the past 15 years, the molecular mechanisms underlying microglia‐dependent regulation of synaptic plasticity have been thoroughly studied, and researchers have reported that the disruption of microglia‐dependent regulation causes synaptic dysfunction that leads to brain diseases. In this review, we will broadly introduce studies that report the roles of microglia in synaptic plasticity and the possible underlying molecular mechanisms. DAP12 is expressed in microglia in the brain, where it forms a complex with triggering receptor expressed on myeloid cells 2 (TREM2), whose downstream signals negatively regulate microglial functions, such as phagocytosis and inflammatory cytokine production. Because DAP12 expression in hippocampal microglia was observed from Embryonic Day 17 to Postnatal Day 3, the authors predicted that DAP12 is involved in the formation of excitatory synapses. In acute hippocampal slices and primary hippocampal neuronal cultures from DAP12KI mice, the AMPAR/NMDAR ratio in CA1 pyramidal cells was increased, which suggests that DAP12 is involved in the synaptic maturation process. In addition, in their previous report  function  in synaptosomes and the frequency of NMDAR‐ and AMPAR‐dependent mEPSCs decreased. These results suggest that microglia are involved in the formation of functional synapses during learning. Next, the authors focused on a previous study . The authors further found that PSD95 and spine density at 15 days of age in CX3CR1 KO mice were increased compared to those in wild‐type mice. Consistent with these results, the excitatory postsynaptic current (EPSC) frequency and amplitude of pyramidal cells were increased in CX3CR1 KO mice, suggesting that microglia are involved in synapse elimination during development through CX3CL1‐CX3CR1 signaling. When pentylenetetrazole (PTZ) treatment induced epileptic seizures, seizure latency was reduced in CX3CR1 KO mice at 17–18 days of age, suggesting that increased synaptic density contributed to the excitability of neural circuits. By contrast, this reduction in latency was not observed in adult mice, suggesting that CX3CR1 KO delays the formation of neural circuits via synapse elimination.In a paper published around the same time , SchaferSince these studies, there have been an increasing number of reports of synaptic phagocytosis by microglia. In 2013, Ji et al. examined phagocytosis of synaptic elements by microglia using organotypic slice cultures or primary neuronal cultures prepared from the rodent hippocampus  of presynaptic structures (boutons). The authors claimed in their discussion that microglia did not phagocytose dendritic spines and claimed that synapse phagocytosis by microglia is a presynapse‐specific event, at least under physiological conditions. However, it must be noted that the shape of microglia in tissue culture can differ significantly from that in vivo in terms of cell body size, the complexity of processes , and the expression of steady‐state lysosomes , which is exposed on the surface of apoptotic cells and makes them detectable by phagocytes, regulates synapse elimination during development  and brain stem, in addition to the hippocampus and LGN, during development . In mice, there is a predominant reaction in the eyes on the opposite side of the visual cortex. However, when one eye is closed during the critical period, the neural circuit is reconstructed so that the open eye becomes dominant. When monocular occlusion was induced in mice during the critical period to induce structural plasticity of synapses due to ocular dominance, the amount of GluR1 phagocytosis by microglia was increased in the region opposite to that showing ocular dominance. On the other hand, in P2Y12 KO mice, structural plasticity of synapses due to eye dominance did not occur, and the increase in GluR1 phagocytosis by microglia was suppressed. These results suggest that microglia may regulate the structural plasticity of synapses by recognizing and phagocytosing synapses whose activity is decreased owing to ocular dominance via P2Y12. In 2017, Lowery et al. examined the involvement of microglial CX3CR1 in the activity‐dependent structural plasticity of synapses in the visual cortex. In 28‐day‐old mice, KO of CX3CR1 did not affect microglial density or motility. In addition, in vivo two‐photon imaging showed no change in the contact time or frequency between microglia and spines. Furthermore, CX3CR1 KO did not show any change in ocular dominance, suggesting that the regulation of structural plasticity of synapses by CX3CR1 varies depending on the developmental stage or brain region.More recently, in 2020, Wang et al. reported that microglia may be involved in memory loss   production in microglia. It was shown that these ROS induce the disappearance of dendritic spines and cause a decline in active avoidance learning performance. However, it remains unclear whether this spine loss was caused by microglial phagocytosis.In 2016, Hong et al. found that the accumulation of C1q at postsynapses was increased in J20 mice and mice treated with Aβ oligomers  is a major constituent protein of ubiquitin‐positive inclusions found in neurons and glial cells in the brains of ALS and frontotemporal lobar degeneration (FTLD) patients. TDP‐43 is a ubiquitously expressed nuclear protein and is known to be involved in transcription and splicing. In 2017, it was shown that KO of TDP‐43 in AD model mice promoted microglia‐dependent phagocytosis of not only Aβ but also synaptic proteins , caloe (heat), tumor (swelling), and doloe (pain) ‐infected model mice was impaired, suggesting synaptic dysfunction , CD68 expression in striatal microglia was increased  patients and experimental autoimmune encephalomyelitis (EAE) model mice  administration to the striatum, Aono et al. reported microglial activation, such as cell body hypertrophy, increased CD68 expression and decreased densities of synapsin‐I and PSD95 in the substantia nigra reticulum (SNr)  and elevated CD68 expression. On the other hand, SE decreased the expression level of the CD200 receptor, whose ligand is a suppressor of microglial pro‐inflammatory response. From these results, it is possible that pro‐inflammatory microglia may promote synapse elimination after epilepsy. It has also been suggested that the complement pathway is activated in the brains of patients with epilepsy  induced by kainic acid ‐fed mice, dendritic spine density and synaptic proteins were decreased in CA1 pyramidal neurons  is an adhesion molecule that is expressed specifically in excitatory neurons in the telencephalon and is distributed in dendrites and immature spines to regulate the formation and structural plasticity of synapses. It was shown that ICAM‐5 was released from neurons in an activity‐dependent manner (Tian et al., ATP is essential for synaptic activity, and approximately 70% of ATP in neurons is consumed by synapses (Harris et al., Neuronal activity promotes the release of exosomes from neurons. In 2015, Bahrini et al. found that PC12 cell‐derived exosomes increased the phagocytosis of PC12 cell processes by MG6 microglia in their coculture system (Bahrini et al., 5In this review, we describe how microglia regulate synaptic plasticity and the structural and functional changes in the brain that result from disrupted microglia–synapse interactions. Although the involvement of various molecules in synaptic plasticity has been revealed, many questions remain to be answered. For example, are the molecular mechanisms identified in previous studies shared by multiple brain regions? Large‐scale gene expression analysis has shown that neurons and microglia have different properties depending on the brain region, and there may be a brain region‐specific mechanism of synaptic plasticity regulation that has not yet been clarified. To further elucidate the interaction between microglia and neurons, particularly synapses, it is necessary to study the involvement of other cell types and the extracellular matrix around synapses. For this purpose, a well‐regulated in vitro system is needed in which cellular structures and mRNA properties reflecting in vivo conditions are reproduced and high‐resolution live imaging and molecular manipulation are possible.The mechanisms by which microglia phagocytose synapses still need to be further clarified. Recent studies implied that microglia can phagocytose synapses from living neurons, but direct evidence from live imaging and knowledge of the underlying mechanisms are insufficient. It remains unclear whether there is a preference for microglia to eliminate either presynapses or postsynapses, which could be different between healthy and diseased brains or between brain regions. Furthermore, what are the mechanisms by which microglia determine which synapse to phagocytose among adjacent synapses? First, is it critical for the function of a whole neural circuit to determine which among the synapses in close proximity are phagocytosed? To answer this question, we need to examine whether and how neural activity differs between phagocytosed synapses and protected synapses in adjacent locations.If these questions are answered and the mechanisms of synaptic plasticity by microglia are understood, manipulation of the identified molecules may lead to the treatment of diseases caused by synaptic degeneration. Moreover, if abnormalities of the microglia‐dependent synaptic plasticity can be normalized in advance, it will be possible to prevent disease onset. In recent years, iPSC‐derived microglia that have properties close to those of human microglia have been developed. These tools will be useful for drug discovery research targeting microglia.Finally, microglia are mesoderm cells and have a different origin from neurons and astrocytes, which are ectoderm cells, leading us to hypothesize that interactions between microglia and other brain cells can be very specific. Why did the brain, which is mainly composed of ectoderm cells, entrust cells of mesoderm origin with the plasticity of synapses, the most essential structures for neurotransmission? Further elucidation of the existence and role of microglia‐specific genes may lead to the discovery of novel mechanisms underlying synaptic plasticity.The authors declare no conflicts of interests.