Search

Background: High medicine prices contribute to increasing cost of healthcare worldwide. Many patients with limited resources in sub-Saharan Africa (SSA) are confronted with out-of-pocket charges, constraining their access to medicines. Diferent medicine pricing policies are implemented to improve afordability and availability; however, evidence on the experiences of implementations of these policies in SSA settings appears limited. Therefore, to bridge this knowledge gap, we reviewed published evidence and answered the question: what are the key determinants of implementation of medicines pricing policies in SSA countries? Methods: We identifed policies and examined implementation processes, key actors involved, contextual infuences on and impact of these policies. We searched fve databases and grey literature; screening was done in two stages fol‑ lowing clear inclusion criteria. A structured template guided the data extraction, and data analysis followed thematic narrative synthesis. The review followed best practices and reported using PRISMA guidelines. Results: Of the 5595 studies identifed, 31 met the inclusion criteria. The results showed thirteen pricing policies were implemented across SSA between 2003 and 2020. These were in four domains: targeted public subsides, regulatory frameworks and direct price control, generic medicine policies and purchasing policies. Main actors involved were government, wholesalers, manufacturers, retailers, professional bodies, community members and private and public health facilities. Key contextual barriers to implementation were limited awareness about policies, lack of regulatory capacity and lack of price transparency in external reference pricing process. Key facilitators were favourable policy environment on essential medicines, strong political will and international support. Evidence on efectiveness of these policies on reducing prices of, and improving access to, medicines was mixed. Reductions in prices were reported occasionally, and implementation of medicine pricing policy sometimes led to improved availability and afordability to essential medicines. Conclusions: Implementation of medicine pricing policies in SSA shows some mixed evidence of improved avail‑ ability and afordability to essential medicines. It is important to understand country-specifc experiences, diversity of policy actors and contextual barriers and facilitators to policy implementation. Our study suggests three policy implications, for SSA and potentially other low-resource settings: avoiding a ‘one-size-fts-all’ approach, engaging both private and public sector policy actors in policy implementation and continuously monitoring implementation and efects of policies. Systematic review registration: PROSPERO CRD42020178166 [ABSTRACT FROM AUTHOR]

This study was designed to test the hypothesis that fetal adrenal nitric oxide synthase (NOS) is elevated in response to long-term hypoxia (LTH). Pregnant ewes were maintained at high altitude (3820 m) for approximately the last 100 days of gestation. Between days 138 and 141 of gestation, adrenal glands were collected from LTH fetuses and age-matched normoxic controls. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western analysis were used to quantify NOS expression, and NOS distribution was examined by immunohistochemistry and double-staining immunofluorescence for endothelial NOS (eNOS) and 17α-hydroxylase (CYP17). Neuronal NOS (nNOS) was expressed at very low levels and with no differences between groups. Expression of eNOS was significantly greater in the LTH group compared with control. Neuronal NOS was distributed throughout the cortex while the greatest density of eNOS was observed in the zona fasciculata/reticularis area and eNOS co-localized with CYP17. We conclude that LTH enhances eNOS expression in the inner adrenal cortex which may play a role in regulation of cortisol biosynthesis in the LTH fetus. [ABSTRACT FROM AUTHOR]

An amendment to this paper has been published and can be accessed via a link at the top of the paper. [ABSTRACT FROM AUTHOR]

Evidence in several microorganisms indicates that Amt proteins are gas channels for NH3 and CH3NH2, and this has been confirmed structurally. Chlamydomonas reinhardtii has at least four AMT genes, the most reported for a microorganism. Under nitrogen-limiting conditions all AMT genes are transcribed and Chlamydomonas is sensitive to methylammonium toxicity. All 16 spontaneous methylammonium-resistant mutants that we analyzed had defects in accumulation of [14C] methylammonium. Genetic crosses indicated that 12 had lesions in a single locus, whereas two each had lesions in other loci. Lesions in different loci were correlated with different degrees of defect in [14C]methylammonium uptake. One mutant in the largest class had an insert in the AMT4 gene, and the insert cosegregated with methylammonium resistance in genetic crosses. The other 11 strains in this class also had amt4 lesions, which we characterized at the molecular level. Properties of the amt4 mutants were clearly different from those of rh1 RNAi lines. They indicated that the physiological substrates for Amt and Rh proteins, the only two members of their protein superfamily, are NH3 and CO3, respectively. [ABSTRACT FROM AUTHOR]

We undertook a systematic review to synthesise the data on attitudes and behaviour towards the use of aspirin for cancer prevention, and healthcare providers' attitudes towards implementing aspirin in practice. Searches were carried out across 12 databases (e.g. MEDLINE, EMBASE). We used the Mixed Methods Appraisal Tool to evaluate study quality, and conducted a narrative synthesis of the data. The review was pre-registered (PROSPERO: CRD42018093453). Thirty-eight studies were identified. Uptake and adherence data were all from trials. Trials recruited healthy participants, those at higher risk of cancer, and those with cancer. Four studies reported moderate to high (40.9-77.7%) uptake to an aspirin trial among people who were eligible. Most trials (18/22) reported high day-to-day adherence (≥80%). Three trials observed no association between gender and adherence. One trial found no association between adherence and colorectal cancer risk. Three studies reported moderate to high (43.6-76.0%) hypothetical willingness to use aspirin. Two studies found that a high proportion of healthcare providers (72.0-76.0%) perceived aspirin to be a suitable cancer prevention option. No qualitative studies were identified. The likelihood that eligible users of aspirin would participate in a trial evaluating the use of aspirin for preventive therapy was moderate to high. Among participants in a trial, day-to-day adherence was high. Further research is needed to identify uptake and adherence rates in routine care, the factors affecting aspirin use, and the barriers to implementing aspirin into clinical care. [ABSTRACT FROM AUTHOR]

Following QuantCrit's tradition of highlighting the significance of race and racism in the U.S., we sought to investigate salient factors in the disproportionate representation of Black boys and in turn, Black men in STEM. We examined factors such as science dispositions and opportunities to learn as well as Black boys' specialized content knowledge using NAEP assessment data from both 2009 and 2015 for Black boys in fourth grade. The analysis revealed not only that schools have unprepared 4th-grade Black boys who lack appropriate levels of science proficiency but also indicated that most Black boys did not see science as their favorite class despite having confidence in their understanding of the subject matter. Thus, our study provided implications for future research, such as examining how science achievement and dispositions affect Black boys' decision-making in advanced science courses and careers. Our findings might provide an avenue for future studies on the relationship or lack thereof between science achievement and interest in STEM outcomes. [ABSTRACT FROM AUTHOR]

The aim of this study was to analyze umbilical hernia occurrences in patients who underwent laparoscopic or laparoendoscopic single-sight (LESS) cholecystectomy. Patients who underwent cholecystectomy by a single surgeon between 2015 and 2020 were surveyed. Data are presented as median (mean +/− standard deviation). Two hundred and fifty-three patients were sent the survey and 130 (51%) patients responded. The overall age was 57 (31 +/− 18) and the overall BMI was 30 (31 +/− 7). Twelve (9%) patients developed an umbilical hernia. Seventeen patients were active smokers and four (24%) developed an umbilical hernia. One hundred and thirteen patients were inactive smokers and eight (7%) developed an umbilical hernia. There was a statistical significance between umbilical hernia occurrence and smoking history (P <.05). Active smokers have a higher risk of developing an umbilical hernia following a minimally invasive cholecystectomy, regardless of operative approach. Elective cholecystectomy should be reconsidered for current smokers. [ABSTRACT FROM AUTHOR]

Frailty is a risk factor for adverse health outcomes. There is a paucity of literature on frailty progression defined by a cumulative deficit model among community dwelling older people. The objective of this review was to synthesise evidence on these changes in health and mortality among community-dwelling older people. Six databases (Medline, Embase, CINAHL, Cochrane, PsycInfo, Web of Science) and a clinical trials registry were searched in July 2021. The inclusion criteria were studies using a frailty index and providing information on transition between frailty states or to death in community-dwelling older people aged ≥ 50. Exclusion criteria were studies examining specific health conditions, conference abstracts and non-English studies. To standardise the follow-up period and facilitate comparison, we converted the transition probabilities to annual transition rates. Two reviewers independently screened 5078 studies and 61 studies were included for analysis. Of these, only three used the same frailty state cut-points to facilitate cross-cohort comparison. This review found that frailty tends to increase with time, people who are frail at baseline have greater likelihood to progress in frailty and die, and the main factor that accelerates frailty progression is age. Other risk factors for progression are having chronic disease, smoking, obesity, low-income or/and low-education levels. A frailty index is an accurate predictor of adverse outcomes and death. This systematic review demonstrated that worsening in frailty was a common frailty transition, and older people who are frail at baseline are more likely to die. A frailty index has significant power to predict adverse health outcomes. It is a useful tool for within-cohort comparison but there are challenges comparing different cohorts due to dependence of frailty progression on age and differences in how frailty index is defined and measured. • Older people who are frail at baseline have greater likelihood to progress in frailty and die. • Age tends to accelerate transitions to higher frailty and death. • The cumulative frailty index (FI) is a robust predictor of adverse health outcomes. • The FI is a useful tool for within cohort comparisons, but it is challenging to compare different cohorts. [ABSTRACT FROM AUTHOR]

Background: There is a widespread belief that information technologies will improve diagnosis, treatment and care. Evidence about their effectiveness in health care is, however, mixed. It is not clear why this is the case, given the remarkable advances in hardware and software over the last 20 years. This review focuses on interoperable information technologies, which governments are currently advocating and funding. These link organisations across a health economy, with a view to enabling health and care professionals to coordinate their work with one another and to access patient data wherever it is stored. Given the mixed evidence about information technologies in general, and current policies and funding, there is a need to establish the value of investments in this class of system. The aim of this review is to establish how, why and in what circumstances interoperable systems affect patient safety. Methods: A realist synthesis will be undertaken, to understand how and why inter-organisational systems reduce patients' clinical risks, or fail to do so. The review will follow the steps in most published realist syntheses, including (1) clarifying the scope of the review and identifying candidate programme and mid-range theories to evaluate, (2) searching for evidence, (3) appraising primary studies in terms of their rigour and relevance and extracting evidence, (4) synthesising evidence, (5) identifying recommendations, based on assessment of the extent to which findings can be generalised to other settings. Discussion: The findings of this realist synthesis will shed light on how and why an important class of systems, that span organisations in a health economy, will contribute to changes in patients' clinical risks. We anticipate that the findings will be generalizable, in two ways. First, a refined mid-range theory will contribute to our understanding of the underlying mechanisms that, for a range of information technologies, lead to changes in clinical practices and hence patients' risks (or not). Second, many governments are funding and implementing cross-organisational IT networks. The findings can inform policies on their design and implementation. Systematic review registration: PROSPERO CRD42017073004 [ABSTRACT FROM AUTHOR]

Background and Hypothesis: The PLA2R antibody test is a valuable first-line diagnostic tool for primary membranous nephropathy (MN), helping to identify PLA2R-related MN and potentially eliminating the need for a kidney biopsy in some individuals. By reducing the reliance on biopsies, the test streamlines diagnosis and improves patient care. However, determining the optimal PLA2R measurement method and cut-off is critical to maximising the benefits of the test and minimising any harms., Methods: A systematic review and meta-analysis were performed to evaluate serum- and urine-based biomarkers for distinguishing between PLA2R-related MN and non-PLA2R MN. Searches were conducted in databases including Medline, Embase, Cochrane Library, Scopus, Web of Science, INAHTA, and ClinicalTrials.gov. The methodology followed Cochrane-recommended guidelines for systematic reviews and meta-analyses, and the QUADAS-2 tool was utilised to assess the overall risk of bias., Results: Ninety one studies met the eligibility criteria for inclusion in the review. Of these, 38 studies reporting the accuracy of the PLA2R-Ab test using the EUROIMMUN ELISA method and 27 using the EUROIMMUN IF method were suitable for meta-analysis.. The pooled sensitivity and specificity of EUROIMMUN ELISA at a cut-off value of 20 RU/ml were 0.64 (95% CI: 0.56, 0.72) and 94.7% (95% CI: 90.5 - 97.1%),  respectively. The pooled sensitivity and specificity of EUROIMMUN IF at a threshold of 1:10 was 0.69 (95% CI: 0.637 - 0.739) and 0.98 (95% CI: 0.931 - 0.994), respectively. Risk of bias was higher for studies evaluating the IF compared to ELISA test. We also explored whether the timing of the index test had an impact on the pooled diagnostic accuracy results; no significant differences were found., Conclusions: By evaluating the specificity and sensitivity of EUROIMMUN ELISA PLA2R-Ab and immunofluorescence (IF), we demonstrate that at ELISA levels ≥20 RU/mL, alongside thorough secondary screening, a kidney biopsy may be unnecessary. However, lower or negative levels still warrant a biopsy., (© The Author(s) 2025. Published by Oxford University Press on behalf of the ERA.)

Opinion Statement: Neuropathic cancer pain is experienced by 30-40% of patients with cancer. It significantly reduces quality of life and overall wellbeing for patients living with and beyond cancer. The underlying mechanisms of neuropathic pain in patients with cancer are complex and involve direct tumour involvement, nerve compression or infiltration, chemotherapy and/or radiotherapy-induced nerve damage, or post-surgical complications. It is crucial for healthcare professionals to assess and manage neuropathic cancer pain effectively. There is increasing recognition that standardisation of neuropathic pain assessment leads to tailored management and improved patient outcomes. Pain management strategies, including medication, interventional analgesia, physical and complementary therapy, can help alleviate neuropathic pain and improve the patient's comfort and quality of life., (© 2024. The Author(s).)

Background: Many hospitals introduced procalcitonin (PCT) testing to help diagnose bacterial coinfection in individuals with COVID-19, and guide antibiotic decision-making during the COVID-19 pandemic in the UK., Objectives: Evaluating cost-effectiveness of using PCT to guide antibiotic decisions in individuals hospitalized with COVID-19, as part of a wider research programme., Methods: Retrospective individual-level data on patients hospitalized with COVID-19 were collected from 11 NHS acute hospital Trusts and Health Boards from England and Wales, which varied in their use of baseline PCT testing during the first COVID-19 pandemic wave. A matched analysis (part of a wider analysis reported elsewhere) created groups of patients whose PCT was/was not tested at baseline. A model was created with combined decision tree/Markov phases, parameterized with quality-of-life/unit cost estimates from the literature, and used to estimate costs and quality-adjusted life years (QALYs). Cost-effectiveness was judged at a £20 000/QALY threshold. Uncertainty was characterized using bootstrapping., Results: People who had baseline PCT testing had shorter general ward/ICU stays and spent less time on antibiotics, though with overlap between the groups' 95% CIs. Those with baseline PCT testing accrued more QALYs (8.76 versus 8.62) and lower costs (£9830 versus £10 700). The point estimate was baseline PCT testing being dominant over no baseline testing, though with uncertainty: the probability of cost-effectiveness was 0.579 with a 1 year horizon and 0.872 with a lifetime horizon., Conclusions: Using PCT to guide antibiotic therapy in individuals hospitalized with COVID-19 is more likely to be cost-effective than not, albeit with uncertainty., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Background: Information on the quality of life of people hospitalised with COVID-19 is important, both in assessing the burden of disease and the cost-effectiveness of treatments. However, there were potential barriers to collecting such evidence., Objective: To review the existing evidence on quality of life for people hospitalised with COVID-19, with a focus on the amount of evidence available and methods used., Design: A scoping review with systematic searches., Results: A total of 35 papers were selected for data extraction. The most common study type was economic evaluation ( N  = 13), followed by cross-sectional ( N  = 10). All economic evaluations used published utility values for other conditions to represent COVID-19 inpatients' quality of life. The most popular quality-of-life survey measure was the Pittsburgh Sleep Quality Index ( N  = 8). There were 12 studies that used a mental health-related survey and 12 that used a sleep-related survey. Five studies used EQ-5D, but only one collected responses from people in the acute phase of COVID-19. Studies reported a negative impact on quality of life for people hospitalised with COVID-19, although many studies did not include a formal comparison group., Limitations: Although it used systematic searches, this was not a full systematic review., Conclusion: Quality-of-life data were collected from people hospitalised with COVID-19 from relatively early in the pandemic. However, there was a lack of consensus as to what survey measures to use, and few studies used generic health measures. Economic evaluations for COVID-19 treatments did not use utilities collected from people with COVID-19. In future health crises, researchers should be vigilant for opportunities to collect quality-of-life data from hospitalised patients but should try to co-ordinate as well as ensuring generic health measures are used more., Funding: This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number NIHR132254.

Objectives: Food insecurity (FI) is defined as limited or uncertain access to sufficient food for a healthy and active lifestyle. Our objective was to explore how the coronavirus disease 2019 (COVID-19) pandemic affected the FI status of pediatric patients and their families through interviewing caregivers who screen positive for FI., Methods: Caregivers of all hospitalized patients at a tertiary children's hospital who screen positive for FI with a two-question screening tool were approached about enrolling in the study. Those who consented completed a presurvey and participated in a semistructured individual interview. Interviews were audio recorded, transcribed, and analyzed according to the guidelines of thematic analysis using NVivo 12., Results: Interviews were conducted with 15 caregivers between July 2021 and January 2022. Caregivers were 100% female and 80% Black, 13% White, and 7% Hispanic/Latinx, with a mean age of 33 years. Seventy-three percent did not experience FI until the COVID-19 pandemic. Themes include lost wages, mothers forced out of the workforce due to childcare limitations, inflation and shortages of goods, increased stress/anxiety for caregivers and children, the centrality of extended family support, and the necessity/inadequacy of federal food programs., Conclusions: The COVID-19 pandemic impacted unemployment and poverty and consequently exacerbated FI. Our findings point to the need to focus on proximal societal solutions, such as federal policies aimed at food assistance and childcare. Understanding the challenges related to FI that caregivers and patients experience can improve screening, support, and treatment of patients presenting for care and inform the design of necessary interventions for individuals and communities beyond COVID-19.

Background: A major driver of antimicrobial resistance (AMR) is the inappropriate use of antimicrobials. At the community level, people are often engaged in behaviors that drive AMR within human, animal, and environmental (One Health) impacts. This scoping review consolidates research to determine (a) the community's knowledge, attitudes, and practices around AMR; (b) existing community-based interventions; and (c) barriers and enablers to addressing AMR in Nepal., Methods: This scoping review follows the Joanna Briggs Institute scoping review methodology. Literature indexed in PubMed, Scopus, CINAHL, Global Index Medicus, HINARI-SUMMON, Embase (Ovid), Global Health (Ovid), CAB Abstracts (Ovid), Web of Science, and Google Scholar between January 2000 and January 2023 were reviewed for inclusion. Articles were included in the review if they considered the issues of AMR at the community level in Nepal; this excluded clinical and laboratory-based studies. A total of 47 studies met these criteria, were extracted, and analyzed to consolidate the key themes., Results: A total of 31 (66%) articles exclusively included human health; five (11%) concentrated only on animal health; no studies solely focused on environmental aspects of AMR; and the remaining studies jointly presented human, animal, and environmental aspects. Findings revealed inadequate knowledge accompanied by inappropriate practice in both the human and animal health sectors. Four community interventions improved knowledge and practices on the appropriate use of antimicrobials among community people. However, various social and economic factors were found as barriers to the appropriate use of antimicrobials in the community., Conclusion: Community engagement and One Health approaches could be key tools to improve awareness of AMR and promote behavioral change related to AM use in communities, as current studies have revealed inadequate knowledge alongside inappropriate practices shared in both human and animal health sectors., Systematic Review Registration: DOI: 10.17605/OSF.IO/FV326., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Parajuli, Mitchell, King, Arjyal, Latham, King and Baral.)

Background: Pericytes are multifunctional contractile cells that reside on capillaries. Pericytes are critical regulators of cerebral blood flow and blood-brain barrier function, and pericyte dysfunction may contribute to the pathophysiology of human neurological diseases including Alzheimers disease, multiple sclerosis, and stroke. Induced pluripotent stem cell (iPSC)-derived pericytes (iPericytes) are a promising tool for vascular research. However, it is unclear how iPericytes functionally compare to primary human brain vascular pericytes (HBVPs)., Methods: We differentiated iPSCs into iPericytes of either the mesoderm or neural crest lineage using established protocols. We compared iPericyte and HBVP morphologies, quantified gene expression by qPCR and bulk RNA sequencing, and visualised pericyte protein markers by immunocytochemistry. To determine whether the gene expression of neural crest iPericytes, mesoderm iPericytes or HBVPs correlated with their functional characteristics in vitro, we quantified EdU incorporation following exposure to the key pericyte mitogen, platelet derived growth factor (PDGF)-BB and, contraction and relaxation in response to the vasoconstrictor endothelin-1 or vasodilator adenosine, respectively., Results: iPericytes were morphologically similar to HBVPs and expressed canonical pericyte markers. However, iPericytes had 1864 differentially expressed genes compared to HBVPs, while there were 797 genes differentially expressed between neural crest and mesoderm iPericytes. Consistent with the ability of HBVPs to respond to PDGF-BB signalling, PDGF-BB enhanced and a PDGF receptor-beta inhibitor impaired iPericyte proliferation. Administration of endothelin-1 led to iPericyte contraction and adenosine led to iPericyte relaxation, of a magnitude similar to the response evoked in HBVPs. We determined that neural crest iPericytes were less susceptible to PDGFR beta inhibition, but responded most robustly to vasoconstrictive mediators., Conclusions: iPericytes express pericyte-associated genes and proteins and, exhibit an appropriate physiological response upon exposure to a key endogenous mitogen or vasoactive mediators. Therefore, the generation of functional iPericytes would be suitable for use in future investigations exploring pericyte function or dysfunction in neurological diseases., (© 2024. The Author(s).)

Aims: School-based physical therapists (SBPTs) rapidly transitioned to telehealth during the pandemic. This study explored the perceptions of, and strategies utilized by, SBPTs delivering therapy via telehealth., Methods: Using a grounded theory qualitative design, semi-structured interviews were completed with 13 SBPTs. Interviews were transcribed and theme coded until saturation was achieved., Results: The following themes emerged: supports and education, challenges, strategies promoting success, and the outcomes of telehealth. SBPTs overcame challenges including those associated with technology, communication, space, equipment, and examination. Coaching techniques, incorporation into the daily routine, and the sharing of demonstrations promoted success. Telehealth service delivery was perceived to improve communication with educational teams and families, improve efficiency and productivity, increase access to students, promote an appreciation of the family and home context, and enhance family engagement. SBPTs believe incorporating elements of telehealth in conjunction with in-person delivery is ideal., Conclusions: While the COVID-19 pandemic forced a rapid transition to telehealth for SBPTs, lessons learned could have a long-lasting positive impact on school-based services. The benefits of telehealth should be considered in the delivery of school-based physical therapy services.

Pericytes play several important functions in the neurovascular unit including contractile control of capillaries, maintenance of the BBB, regulation of angiogenesis, and neuroinflammation. There exists a continuum of pericyte subtypes along the vascular tree which exhibit both morphological and transcriptomic differences. While different functions have been associated with the pericyte subtypes in vivo, numerous recent publications have used a primary human brain vascular pericytes (HBVP) cell line where this pericyte heterogeneity has not been considered. Here, we used primary HBVP cultures, high-definition imaging, cell motility tracking, and immunocytochemistry to characterise morphology, protein expression, and contractile behaviour to determine whether heterogeneity of pericytes also exists in cultures. We identified five distinct morphological subtypes that were defined using both qualitative criteria and quantitative shape analysis. The proportion of each subtype present within the culture changed as passage number increased, but pericytes did not change morphological subtype over short time periods. The rate and extent of cellular and membrane motility differed across the subtypes. Immunocytochemistry revealed differential expression of alpha-smooth muscle actin (αSMA) across subtypes. αSMA is essential for cell contractility, and consequently, only subtypes with high αSMA expression contracted in response to physiological vasoconstrictors endothelin-1 (ET1) and noradrenaline (NA). We conclude that there are distinct morphological subtypes in HBVP culture, which display different behaviours. This has significance for the use of HBVP when modelling pericyte physiology in vitro where relevance to in vivo pericyte subtypes along the vascular tree must be considered., (© 2023. The Author(s).)

Stroke therapy has largely focused on preventing damage and encouraging repair outside the ischemic core, as the core is considered irreparable. Recently, several studies have suggested endogenous responses within the core are important for limiting the spread of damage and enhancing recovery, but the role of blood flow and capillary pericytes in this process is unknown. Using the Rose Bengal photothrombotic model of stroke, we illustrate blood vessels are present in the ischemic core and peri-lesional regions 2 weeks post stroke in male mice. A FITC-albumin gel cast of the vasculature revealed perfusion of these vessels, suggesting cerebral blood flow (CBF) may be partially present, without vascular leakage. The length of these vessels is significantly reduced compared to uninjured regions, but the average width is greater, suggesting they are either larger vessels that survived the initial injury, smaller vessels that have expanded in size (i.e., arteriogenesis), or that neovascularization begins with larger vessels. Concurrently, we observed an increase in platelet-derived growth factor receptor beta (PDGFRβ, a marker of pericytes) expression within the ischemic core in two distinct patterns, one which resembles pericyte-derived fibrotic scarring at the edge of the core, and one which is vessel associated and may represent blood vessel recovery. We find little evidence for dividing cells on these intralesional blood vessels 2 weeks post stroke. Our study provides evidence flow is present in PDGFRβ-positive vessels in the ischemic core 2 weeks post stroke. We hypothesize intralesional CBF is important for limiting injury and for encouraging endogenous repair following cerebral ischemia., (© 2022 The Authors. Journal of Neuroscience Research published by Wiley Periodicals LLC.)

Purpose: Side-effects of adjuvant endocrine therapy (AET) are common in breast cancer survivors, and can affect adherence to treatment. We synthesised the evidence for strategies to self-manage these side-effects., Methods: We searched for systematic reviews and clinical guidelines on self-management strategies for AET side-effects (arthralgia, fatigue, hot flashes, gastrointestinal discomfort, nausea, vulvovaginal symptoms, and sleep disturbance). We searched oncology organisation's websites and eight databases (Inception-November 2020). Screening, data extraction and quality assessment were completed independently in duplicate., Prospero: 2019CRD4201914001., Results: We identified 33 systematic reviews and 18 clinical guidelines. 21% of reviews were high quality, and the average quality score for guidelines was 44%. Evidence for most strategies was absent or weak. There was consensus from a low-quality review and multiple guidelines to recommend moisturisers, gels and lubricants for vulvovaginal symptoms. Evidence was weak for physical activity for self-managing most symptoms, although two high-quality reviews indicated yoga and aerobic exercise could reduce fatigue. Primary research was often biased by weak and underpowered study designs. Eleven reviews did not report information on adverse events., Conclusions: Most self-management strategies for breast cancer survivors experiencing side-effects from AET lack evidence. Primary research is needed using high-quality well-powered designs focusing on implementable strategies., Implications for Cancer Survivors: Patients and clinicians should be aware that although the risk of harm is low for these self-management strategies, the likelihood of benefit is often unclear. Women should consider moisturisers, gels or lubricants for self-managing vulvovaginal symptoms, and yoga or aerobic exercise for alleviating fatigue., (© 2021. The Author(s).)

Adjusting dosing regimens based on measurements of carbapenem levels may improve carbapenem exposure in patients. This systematic review aims to describe the effect carbapenem therapeutic drug monitoring (TDM) has on health outcomes, including the emergence of antimicrobial resistance (AMR). Four databases were searched for studies that reported health outcomes following adjustment to dosing regimens, according to measurements of carbapenem concentration. Bias in the studies was assessed with risk of bias analysis tools. Study characteristics and outcomes were tabulated and a narrative synthesis was performed. In total, 2 randomised controlled trials (RCTs), 17 non-randomised studies, and 19 clinical case studies were included. Significant variation in TDM practice was seen; consequently, a meta-analysis was unsuitable. Few studies assessed impacts on AMR. No significant improvement on health outcomes and no detrimental effects of carbapenem TDM were observed. Five cohort studies showed significant associations between achieving target concentrations and clinical success, including suppression of resistance. Studies in this review showed no obvious improvement in clinical outcomes when TDM is implemented. Optimisation and standardisation of carbapenem TDM practice are needed to improve intervention success and enable study synthesis. Further suitably powered studies of standardised TDM are required to assess the impact of TMD on clinical outcomes and AMR.

Capillary pericytes have numerous functions important for tissue maintenance. Changes in pericyte function are implicated in diseases such as cancer, where pericyte-mediated angiogenesis contributes to the blood supply that tumors use to survive. Some anti-cancer agents, like imatinib, target platelet-derived growth factor receptor-beta (PDGFRβ). Healthy pericytes rely on PDGFRβ phosphorylation for their survival. Therefore, we hypothesised that pharmacological agents that block PDGFRβ phosphorylation could be used to kill pericytes. We treated human brain vascular pericytes, which express PDGFRβ, with three receptor tyrosine kinase inhibitors: imatinib, sunitinib and orantinib. Imatinib and sunitinib, but not orantinib, inhibited PDGFRβ phosphorylation in pericytes. Imatinib and sunitinib also reduced viability, prevented proliferation, and induced death, while orantinib only blocked pericyte proliferation. Overall, we found that receptor tyrosine kinase inhibitors that block PDGFRβ phosphorylation cause healthy pericytes to die in vitro. While useful in cancer to limit tumor growth, these agents could impair healthy brain pericyte survival and impact brain function., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Dosing regimens guided by therapeutic drug monitoring (TDM) may be able to improve penicillin exposure in patients, which could result in improved patient health outcomes., Objectives: This systematic review aims to describe the impact penicillin TDM has on health outcomes, including antimicrobial resistance (AMR)., Methods: Studies measuring penicillins in patient samples that adjusted regimens according to the result, and reported health outcomes were selected. Study bias was assessed according to study type. Included study characteristics were tabulated and described by narrative synthesis., Results: Three randomized controlled trials (RCTs), 16 cohort studies, and 9 case studies were included. No RCTs showed statistically significant improvements in health outcomes. Five cohort studies showed improvement in at least one health outcome associated with target attainment. However, there was a high risk of bias in all studies for health outcomes. One study assessed the impact of penicillin TDM on AMR and found that improved target attainment was associated with suppression of resistance. No studies found a detrimental effect of penicillin TDM., Conclusions: There is little evidence to suggest that TDM improves health outcomes, however neither health outcomes nor impact on AMR were adequately addressed. Variations in TDM implementation meant that a meta-analysis was not suitable. Penicillin TDM needs standardization, however there is currently no clear evidence of optimal conditions. Suitably powered studies are required to resolve the ambiguity surrounding the impact of TDM on clinical outcomes, including AMR. Further, standardized protocols and concentration targets need to be identified for TDM to be implemented successfully., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Background: Preservatives are used widely in cosmetic, household, and industrial products to prevent microbial growth and spoiling of the products. There has been a recent epidemic of contact allergy to methylisothiazolinone (MI)., Objectives: To establish emerging trends in preservative contact allergy as MI is replaced., Methods: We performed a retrospective study on consecutively patch-tested patients at our center from January 2011 to December 2019., Results: A total of 7846 consecutively patch-tested patients were included who were patch tested between January 2011 and December 2019. The prevalence of allergy to MI fell from a peak of 9.39% in 2013 to 1.98% in 2019. MI/methylchloroisothiazolinone (MCI) followed a similar trend, with a peak prevalence of 7.85% in 2014 and falling to 1.39% in 2018. The prevalence of contact allergy to benzisothiazolinone (BIT) has increased steadily increased in 2014 from 0.26% (confidence interval [CI] 0.03-0.93) to 3.42% (CI 2.43-4.66) in 2019., Conclusions: Our data show a significant increase in the prevalence of contact allergy to BIT over the last 6 years, probably as a consequence of increased use in household products. It is essential to continue to look for emerging trends in contact allergy to enable prompt preventative measures to be taken., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Physician associates (PAs) are a relatively new medical professional group working as part of the multidisciplinary team to deliver patient care. This article aims to look at how PAs can work effectively in teams, highlighting the benefits and current working practices of PAs across the NHS and address the concerns and challenges raised., Competing Interests: Jeannie Watkins is a founder and director of the recruitment organisation PAs Transforming Healthcare (PATH)., (© 2019 © 2019 THE AUTHORS. Published by Elsevier Limited on behalf of the Royal College of Physicians.)

Healthcare systems worldwide are investing in networked health IT systems that link healthcare providers across multiple organisations. Much of the policy arguments in favour of such investment rely on the assumption that networked health IT will lead to improved patient safety. As part of the first stage of a realist review to determine how and in what contexts networked, inter-organisational health IT does lead to improved patient safety, we elicited stakeholders' theories from the literature that reveal possible answers to this question. A key mechanism appears to be that the information provided supports improved decision making. Greatest benefits are likely to be found in relation to medication information, in scenarios where the patient is less able to provide accurate information about their medications themselves. However, access and use of this information depends on ease of access, clinicians' perception of the likelihood that the desired information will be available, and clinicians' trust in the information.

Environmental enrichment (EE) has been consistently reported to enhance cognitive function in mouse models of neuropathology. Microglia, implicated in Alzheimer's disease pathology, may mediate this effect. The aim of the present study was to investigate the effect of EE on cognitive function and microglia in mouse models of aging and amyloidosis. Male wild-type (Wt) and APP/PS1 mice were randomly assigned to standard housing (SH) or EE from 12 to 18 months of age. Spatial memory testing was performed using the Y and Barnes maze. Immunohistochemical analysis of Aβ load, Iba1 and CD-68-labeled (phagocytic-type) microglia was examined between conditions. EE from 12 months of age was associated with improved short-term memory performance in APP/PS1 mice, despite no reductions to Aβ load. APP/PS1 mice in SH had significantly increased microglia occupying the neocortex and hippocampus (p = 0.02; p = 0.004, respectively) relative to Wt animals. Microglia labeling was not statistically different between EE-exposed APP/PS1 compared to Wt mice, indicating that EE may attenuate the increased microglial load in aging APP/PS1 mice. APP/PS1 mice from EE had significantly (p = 0.01) higher colocalization of Iba1 and CD-68 labeling, indicative of increased phagocytic microglia compared to mice from SH. The findings of the present study suggest that EE after substantial brain amyloidosis, has the potential to preserve domains of cognitive function, while having no effect on Aβ deposition. The current study demonstrates that EE may attenuate microglia in aging APP/PS1 mice, and may promote alterations in cellular phenotype., (Copyright © 2019 IBRO. Published by Elsevier Ltd. All rights reserved.)

Objectives: The number of UK service personnel who have a diagnosis of PTSD is unclear, but there has been a recent increase in referrals to services for PTSD symptomology. It is imperative to understand the impact this may have on the children of affected service families. This review of literature aimed to explore and provide insight into the experiences of services children whose parent has a diagnosis of PTSD., Design: A comprehensive review of the literature., Data Sources: Online databases CINAHL, MEDLINE, psychARTICLES, The Psychology and Behavioural Sciences Collection and PILOTS were searched., Review Methods: The studies were chosen in keeping with a specified inclusion and exclusion criteria. The literature was critically analysed and key themes identified through the strategy of thematic analysis., Results: Five studies met the inclusion criteria. Three key themes were identified from the five articles; secondary traumatisation; impact on the child's mental health; and impact on the child's adult relationships., Conclusion: The findings highlighted the prevalence of secondary traumatisation and a potential negative impact on the child's mental health and relationships. However, literature used in the review was conducted in countries outside of the UK, therefore the comparison of results may be compromised. This review identifies the paucity of research on this topic and highlights the need for UK based research to be carried out in this area., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The function of the Rhesus (Rh) complex in the human red cell membrane has been unknown for six decades. Based on the organismal, organ, and tissue distribution of Rh proteins, and on our evidence that their only known paralogues, the ammonium and methylammonium transport proteins (also called methylammonium permeases), are gas channels for NH(3), we recently speculated that Rh proteins are biological gas channels for CO(2). Like NH(3), CO(2) differs from other gases in being readily hydrated. We have now tested our speculation by studying expression of the RH1 gene in the photosynthetic microbe Chlamydomonas reinhardtii. Expression of RH1 was high for cells grown in air supplemented with 3% CO(2) or shifted from air to high CO(2) (3%) for 3 h. Conversely, RH1 expression was low for cells grown in air (0.035% CO(2)) or shifted from high CO(2) to air for 3 h. These results make viable the hypothesis that Rh1 and Rh proteins generally are gas channels for CO(2).