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Abstract Background and Aims While the number of female physicians has increased since the 1970s, there continues to be a lack of female surgeons compared to their male counterparts, with the gender gap more prominent in surgical subspecialties such as neurosurgery. While surgical subspecialities have accelerated initiatives to close the gap, potential disparities in research opportunities may position women at a disadvantage, particularly in neurosurgery, where academic publications are an indicator of residency match success. In this paper, we sought to investigate whether gender disparities exist in preresidency neurosurgery publications among current neurosurgery residents. Methods The present study selected residency programs from the top 25 neurology and neurosurgery hospitals in US News & World Report's 2022 Ranking. A database of neurosurgery residents and their publications was created using PubMed, neurosurgery residency program websites, and supplementary search. Articles published between the time of birth and December 31st of the year of graduation (medical degree) were used to determine publications before residency. Results Our research indicates that 25.7% (n = 135/526) of US neurosurgery residents at top 25 hospitals are women and 74.3% (n = 391/526) are men. Men (n = 391) had a median of 7 (interquartile range [IQR], 3–14.5; range, 0–129) publications before residency, and women (n = 135) had a median of 7 (IQR, 4–11.0; range, 0–74) publications before residency. There were no significant differences in the median number of publications between genders (p = 0.65). Conclusion In conclusion, our research indicates there is no gender disparity in preresidency publications among neurosurgery residents. To improve women's representation in the field, further study is needed to better understand gender inequality among neurosurgeons, particularly in the earlier stages of medical training.

ABSTRACTBackground Physical activity referral schemes have been used extensively as one pathway to support behaviour change in people with long term conditions. Best practice guidance, across countries, recommend that schemes use behaviour change practices. The effectiveness of these schemes is inconsistent, yet, little is known about the implementation of specific approaches, or what influences practitioner’s delivery. This article provides a narrative review of evidence exploring the implementation of behaviour change practices in physical activity referral schemes.Methods An electronic search of three databases (PubMed, Scopus, Google Scholar) was undertaken. A menu of iterative techniques was also applied from the CLUSTER approach to increase coverage.Results A total of 45 eligible articles was included covering diverse research designs. Enduring issues with the literature pertain to the insufficient emphasis on implementation, a conflation of behaviour change practice, and an inconsistency of scheme components. Against this backdrop, diverse factors within practitioner, attendee, partnership, work environment, and organisational domains influence the implementation of behaviour change practices.Conclusion The translation of behaviour change practices to applied physical activity settings must tend to the multilevel factors which have the potential to influence the quality of behaviour change implementation.

Sickle cell disease (SCD) is a collection of genetic lesions that manifest in the diminished effectiveness of hemoglobin. We collected and reviewed the recent and extant literature on SARS-CoV-2 (COVID-19) and SCD. We posit an answer to the question associated with any adaptive responses to COVID-19 in individuals with SCD. We collected papers from MEDLINE and all available published papers on COVID-19 and SCD. Unlike a formal meta-analysis, given the early phase of this review in the pandemic, we did not seek unpublished papers. We found an emerging literature where case studies dominated, and traditional large N epidemiological studies were absent. Patients with SCD share many comorbid illnesses with an increased risk of mortality associated with contracting COVID-19. There is sufficient empirical justification to accelerate research on the impact of a viral pathogen like COVID-19 on individuals with SCD. *************************************************************** List of all authors: Michaela Boggan,1,2,3 Christopher L. Edwards,1,2,3 Jordan Meek,1,2,3 Mary Wood,4 W. Jeff Bryson,5 John J. Sollers,1,2,3 Debra O. Parker,1,2,3 Camela S. Barker,2,5 Jessica Miller,2,6 Brianna Downey,2,5 Asha Lockett,2,5 Jazmin Rosales,1,2,3 Courtney Munroe, Jr.,2 Noa Wax,2,5 Sharena Scott,1,2,3 Bridget Pittman,1,2,3 Merell Turner,1,2,3 Hillary T. Dietahin,1,2,3 Eric Smith,1,2,3 Alexandria McDougald,1,2,3 Samantha Beavers,1,2,3 Lakaiya Meadows,1,2,3 Maya Walker,1,2,3 Andrea Richardson,1,2,3 John J. Sollers, IV,2,8 Grace D. Donahue,2,8 Goldie Byrd,7 Malik Muhammad,1,2 Alvin Kidd,9 Walter Charles,1,2 Jonathan Livingston,1,2,3 Shiv Sudhakar10 1North Carolina Central University; 2NCCU Psychoneuroendocrine and Rare Diseases Laboratory; 3NCCU Debra O. Parker Research Incubator; 4Duke University Medical Center; 5Fielding Graduate University; 6Bridges Point Sickle Cell Foundation; 7Wake Forest Medical Center; 8Thomas Moore University; 9Livingston College; 10California Northstate University, United States

Abstract Background Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited condition associated primarily with PKD1 and PKD2 genes. However, ADPKD patients in Latin America have had limited access to comprehensive care. The ProPKD score predicts the likelihood of kidney failure before the age of 60. This study aimed to describe the clinical and genetic characteristics of Chilean ADPKD patients and assess the ProPKD score. Methods We enrolled 40 ADPKD probands and 122 relatives from different centers. Genetic analysis of PKD1 and PKD2 genes was performed by combining direct and next-generation sequencing. Pathogenicity was determined using bioinformatic tools. ProPKD scores were calculated based on clinical and genetic data. Results ADPKD probands were diagnosed at a median age of 35 years. Pathogenic, likely pathogenic, or uncertain significance variants were identified in 38/40 pedigrees, with 89% involving PKD1 and 11% involving PKD2 variants. Among the identified variants, 62% were novel. Patients with PKD1 truncating variants had a more severe disease course, reaching kidney failure by a median age of 48.5 years. ProPKD scores were assessed in 72 individuals, stratifying them into high-, intermediate-, or low-risk categories and the median ages for kidney failure were 45, 49, and 52 years, respectively (log-rank p = 0.001). Conclusion This study provides valuable insights into the clinical and genetic profiles of ADPKD patients in Chile. ADPKD poses a significant public health concern, warranting improvements in diagnosis and treatment. The use of the ProPKD score to predict disease progression should be further explored to enhance patient care and management.

Dental office protocols to combat the SARS-CoV-2 (COVID-19) pandemic include mouth washing for an extended 60 s, thereby reducing detectable oral virus. However, it is unclear whether this protocol has any effects on the newly identified periodontal pathogen and obesity-related bacterium often found among pediatric patients, Selenomonas noxia. To determine if the mouthwash protocol has any measurable effect on S. noxia amongst pediatric patients, clinical pediatric saliva samples were obtained from pediatric patients during routine visits for clinical care and treatment. Using an approved protocol, two saliva samples were collected on the same visit before and after chlorhexidine mouthwash (Sample A, Sample B). The third sample (Sample C) was taken at the recall appointment—usually between two and eight weeks later. A total of n = 97 pre-mouthwash samples, and an equal number of matching post-mouthwash samples (n = 97) were collected, with a small number of matching recall samples (n = 36) that were subsequently collected and identified. The demographic composition of the study sample was analyzed using Chi square statistics. Sample DNA from the matching pre-, post-, and recall collections (Sample A, Sample B, and Sample C) was isolated and screened using qPCR and validated primers, which revealed that 11.1% (n = 4/36) from Sample A tested positive for S. noxia with 0% (n = 0/36) of Sample B testing positive and 13.9% (n = 5/36) of the recall (Sample C) testing positive. In addition, comparative analysis of the qPCR cycle threshold data revealed relatively lower expression (quantity) of S. noxia DNA among the recall samples, as determined by two-tailed t-tests (p=0.004). These data and results provide new evidence for the oral prevalence of S. noxia among pediatric patients, while also demonstrating that the COVID-19 protocol of mouth washing prior to clinical treatment for periods extending up to 60 s may be sufficient to reduce the levels of detectable S. noxia—at least temporarily. More research will be needed to determine whether these effects may be limited to the short- or may exhibit more lasting effects in the long-term.

Abstract Objectives To identify the social inclusion needs that were (i) most commonly identified and (ii) most and least commonly prioritised as support planning goals for mental health service users living in supported accommodation, using the online Social Inclusion Questionnaire User Experience (SInQUE). We qualitatively examined mental health supported accommodation staff and servicer users’ views on barriers to offering support with two less commonly prioritised areas: help finding a partner and feeling less lonely. Methods Anonymous SInQUE data were collected during a completed study in which we developed and tested the online SInQUE. Four focus groups were conducted with mental health supported accommodation staff (N = 2) and service users (N = 2). Results The most common social inclusion needs identified by service users (N = 31) were leisure activities, finding transport options, and feeling less lonely. Of the needs identified, those that service users and staff least frequently prioritised as support planning goals were having company at mealtimes, getting one’s own furniture, feeling less lonely, help with finances, and help finding a partner. In the focus groups, staff and service users identified barriers to helping with loneliness and finding a partner which related to staff and service users themselves, supported accommodation services, and wider societal factors.

Metastasis remains the leading cause of cancer deaths worldwide and lung cancer, known for its highly metastatic progression, remains among the most lethal of malignancies. Lung cancer metastasis can selectively spread to multiple different organs, however the genetic and molecular drivers for this process are still poorly understood. Understanding the heterogeneous genomic profile of lung cancer metastases is considered key in identifying therapeutic targets that prevent its spread. Research has identified the key source for metastasis being clusters of cells rather than individual cancer cells. These clusters, known as metastatic cancer cell clusters (MCCCs) have been shown to be 100-fold more tumorigenic than individual cancer cells. Unfortunately, access to these primary drivers of metastases remains difficult and has limited our understanding of their molecular and genomic profiles. Strong evidence in the literature suggests that differentially regulated biological pathways in MCCCs can provide new therapeutic drug targets to help combat cancer metastases. In order to expand research into MCCCs and their role in metastasis, we demonstrate a novel, proof of principle technology, to capture MCCCs directly from patients' whole blood. Our platform can be readily tuned for different solid tumor types by combining a biomimicry-based margination effect coupled with immunoaffinity to isolate MCCCs. Adopting a selective capture approach based on overexpressed CD44 in MCCCs provides a methodology that preferentially isolates them from whole blood. Furthermore, we demonstrate a high capture efficiency of more than 90% when spiking MCCC-like model cell clusters into whole blood. Characterization of the captured MCCCs from lung cancer patients by immunofluorescence staining and genomic analyses, suggests highly differential morphologies and genomic profiles. This study lays the foundation to identify potential drug targets thus unlocking a new area of anti-metastatic therapeutics.

IntroductionSubstance use is common among youth which can adversely affect youth health. Despite the legalization of cannabis in Canada and much of the United States, there is a lack of harm reduction cannabis education in schools. In addition, educators may not feel prepared to teach students about cannabis.MethodsA cross-sectional survey explored educator perceptions toward teaching harm reduction substance use education to students in grades 4-12. Data analysis included descriptive statistics to evaluate demographic variables, ANOVAs to identify subgroup differences, and inductive thematic analysis to establish themes from open-ended responses. From the sample of 170 educators, the majority were female (77%) and worked as classroom teachers (59%).ResultsNinety-two percent of educators felt harm reduction was an effective approach to substance use education, and 84% stated that they would feel comfortable teaching cannabis harm reduction education to students. While 68% of educators believed they would be able to recognize if a student was under the influence of cannabis, only 39% felt certain about how to respond to student cannabis use, and just 8% felt that their current teacher training allowed them to intervene and prevent cannabis-related harms. Most educators (89%) expressed interest in harm reduction training, particularly interactive training (70%) and instructor-led lessons (51%). Online curriculum resources were preferred by 57%. Responses differed by gender and age group, with females of any age and educators under 40 reporting greater support of harm reduction approaches and more interest in training.ConclusionEducators expressed considerable support for harm reduction substance use education, but many felt unprepared to address this topic with students. The findings identified a need for educator training on harm reduction substance use education, so that educators can help students make informed choices around substance use, thereby promoting youth health and safety.

Abstract Objective To analyse the transcriptional profiles of the pir multigene family of Plasmodium chabaudi chabaudi in male and female gametocytes isolated from the blood of infected mice. Results Infected red blood cells containing female and male P. chabaudi gametocytes transcribe a distinct set of genes encoded by the multigene family pir. The overall patterns are similar to what has been observed in the close relative P. berghei, but here we show that gametocyte-associated pir genes are distinct from those involved in chronic blood-stage infection and highlight a male-associated pir gene which should be the focus of future studies.

OBJECTIVES/GOALS: A new mandate for Clinical & Translational Science Award (CTSA) Programs is for pilot grant funding to support clinical and translational science (CTS) projects that study challenges in the translational research pipeline. This pivot requires new structures and supports to help investigators design and implement high-quality CTS projects. METHODS/STUDY POPULATION: The Michigan Institute for Clinical & Health Research (MICHR) at the University of Michigan (U-M) has launched two rounds of pilot funding since March 2023. Faculty and staff across U-M’s three campuses, community members, and those at collaborating institutions and hospitals were eligible to apply. New pre-award supports included a CTS project framework; a recorded webinar that educated about CTS and the funding opportunity; office hours to provide tailored project feedback; a letter of intent to screen for alignment with CTS; and reviewer training for academic and community reviewers. Funded projects operate like 'mini cooperative agreements”, with MICHR experts partnering with awardees to refine evaluation plans, prepare work products, advise on dissemination, and navigate emergent challenges. RESULTS/ANTICIPATED RESULTS: The first round of funding was launched in the absence of pre-award supports; ten applications we received from faculty proposing translational research rather than CTS. We quickly re-released the FOA, expanding eligibility to staff. We received nine applications, ultimately funding four staff and one faculty studying operational challenges in translation and helping them create robust evaluation plans. We piloted the pre-award supports in our second round, with 40 individuals viewing our webinar and 11 attending office hours. Those who watched the webinar before attending office hours better understood how to embed CTS questions within their programs of research. We recently received 19 letters of intent, addressing both operational and scientific challenges, with 16 eligible to submit applications. DISCUSSION/SIGNIFICANCE: Education and personalized feedback seem to elicit a higher yield of CTS projects. Staff are already adept at solving operational challenges, so the pre-award supports were most critical for faculty accustomed to writing traditional translational research proposals. Staff have most benefited from guidance in evaluation and dissemination.

Objectives To estimate the economic costs, health-related quality-of-life outcomes and cost-effectiveness of subthreshold micropulse laser (SML) versus standard laser (SL) for the treatment of diabetic macular oedema (DMO) with central retinal thickness (CRT) of

Abstract Parkinson’s disease (PD) is a highly heterogeneous disease both with respect to arising symptoms and its progression over time. This hampers the design of disease modifying trials for PD as treatments which would potentially show efficacy in specific patient subgroups could be considered ineffective in a heterogeneous trial cohort. Establishing clusters of PD patients based on their progression patterns could help to disentangle the exhibited heterogeneity, highlight clinical differences among patient subgroups, and identify the biological pathways and molecular players which underlie the evident differences. Further, stratification of patients into clusters with distinct progression patterns could help to recruit more homogeneous trial cohorts. In the present work, we applied an artificial intelligence-based algorithm to model and cluster longitudinal PD progression trajectories from the Parkinson's Progression Markers Initiative. Using a combination of six clinical outcome scores covering both motor and non-motor symptoms, we were able to identify specific clusters of PD that showed significantly different patterns of PD progression. The inclusion of genetic variants and biomarker data allowed us to associate the established progression clusters with distinct biological mechanisms, such as perturbations in vesicle transport or neuroprotection. Furthermore, we found that patients of identified progression clusters showed significant differences in their responsiveness to symptomatic treatment. Taken together, our work contributes to a better understanding of the heterogeneity encountered when examining and treating patients with PD, and points towards potential biological pathways and genes that could underlie those differences.

Abstract As the world transitions to net zero, energy storage is becoming increasingly important for applications such as electric vehicles, mini-grids, and utility-scale grid stability. The growing demand for storage will constrain raw battery materials, reduce the availability of new batteries, and increase the rate of battery retirement. As retired batteries are difficult to recycle into components, to avoid huge amounts of battery waste, reuse and repurposing options are needed. In this research, we explore the feasibility of using second-life batteries (which have been retired from their first intended life) and solar photovoltaics to provide affordable energy access to primary schools in Kenya. Based on interviews with 12 East African schools, realistic system sizes were determined with varying solar photovoltaic sizes (5–10 kW in 2.5 kW increments) and lithium-ion battery capacities (5–20 kWh in 5 kWh increments). Each combination was simulated under four scenarios as a sensitivity analysis of battery transportation costs (i.e., whether they are sourced locally or imported). A techno-economic analysis is undertaken to compare new and second-life batteries in the resulting 48 system scenarios in terms of cost and performance. We find that second-life batteries decrease the levelized cost of electricity by 5.6–35.3% in 97.2% of scenarios compared to similar systems with new batteries, and by 41.9–64.5% compared to the cost of the same energy service provided by the utility grid. The systems with the smallest levelized cost of electricity (i.e., 0.11 USD/kWh) use either 7.5 kW or 10 kW of solar with 20 kWh of storage. Across all cases, the payback period is decreased by 8.2–42.9% using second-life batteries compared to new batteries; the system with the smallest payback period (i.e., 2.9 years) uses 5 kW solar and 5 kWh storage. These results show second-life batteries to be viable and cost-competitive compared to new batteries for school electrification in Kenya, providing the same benefits while reducing waste.

Abstract This study evaluates the efficacy of current satellite observing systems to detect methane point sources from typical oil and gas production (O&G) facilities using a novel very high-resolution methane concentration dataset generated using a microscale model. Transport and dispersion of typical methane emissions from seven well pads were simulated and the column enhancements for pseudo satellite pixel sizes of 3, 1, and 0.05 km were examined every second of the 2-h simulations (7200 realizations). The detectability of plumes increased with a pixel resolution, but two orders of magnitude change in emission rates at the surface results only in about 0.4%, 1.6%, and 47.8% enhancement in the pseudo-satellite retrieved methane column at 3, 1, and 0.05 km, respectively. Average methane emission rates estimated by employing the integrated mass enhancement (IME) method to column enhancements at 0.05 km showed an underestimation of the mean emissions by 0.2–6.4%. We show that IME derived satellite-based inversions of methane emissions work well for large persistent emission sources (e.g., super emitters), however, the method is ill-suited to resolve short-term emission fluctuations (

In the 1980s, Carpentier and Cosgrove, reported the first series of aortic valve repair using Cabrol commissural annulopastia for annular reduction and leaflet wedge resection for prolapse correction. Later T. David and J. Schaefers describes valve-sparing techniques in aortic root surgery for aneurysms. The advantages of valve repair are multiple and also affect survival compared to prostheses. Studies with CT scan of the aortic root and in patients undergoing successful bicuspid valve repair using sub-commissural annuloplasty and Schaefers’ leaflet reconstruction, shown an elliptical configuration of the aortic ring. This has led to the development of a rigid internal ring for the aortic valve with the knowledge obtained with the principles of mitral valve repair. This manuscript describes the bases of the development, principles, implantation technique and current experience of the so-called “internal remodeling rings” for aortic valve repair. Resumen: En los años 80, Carpentier y Cosgrove reportaron las primeras series de reparación valvular aórtica usando la anuloplastia comisural de Cabrol y la resección en cuña de velos para corregir la dilatación anular y los prolapsos. Posteriormente, T. David y J. Schaefers describen las técnicas de preservación valvular en la cirugía de la raíz aórtica en caso de aneurismas. Las ventajas de la reparación valvular son múltiples y afectan tambien la supervivencia en comparativa con las prótesis. Estudios con angio-TAC de la raíz aórtica y en pacientes intervenidos con la anuloplastia subcomisural de Schaefers muestran una configuración elíptica del anillo aórtico. Esto ha llevado a desarrollar un anillo interno rígido para corregir la dilatación del anillo aórtico, con el aprendizaje obtenido con los principios de remodelado en la reparación de la válvula mitral. En el presente manuscrito se describen las bases del desarrollo, los principios, la técnica de implantación y la experiencia actual de los denominados «anillos de remodelado interno» para la reparación valvular aórtica.

Abstract Proteasome inhibitors bortezomib and carfilzomib are the backbones of treatments of multiple myeloma, which remains incurable despite many recent advances. With many patients relapsing despite high initial response rates to proteasome inhibitor-containing regimens, it is critical to understand the process of acquired resistance. In vitro generated resistant cell lines are important tools in this process. The majority of previously developed bortezomib-resistant cell lines bear mutations in the proteasome PSMB5 sites, the prime target of bortezomib and carfilzomib, which are rarely observed in patients. Here we present a novel bortezomib-resistant derivative of the KMS-12-BM multiple myeloma cell line, KMS-12-BM-BPR. Unlike previously published bortezomib-resistant cell lines, it was created using clinically relevant twice-weekly pulse treatments with bortezomib instead of continuous incubation. It does not contain mutations in the PSMB5 site and retains its sensitivity to carfilzomib. Reduced load on proteasome due to decreased protein synthesis appears to be the main cause of resistance. In addition, KMS-12-BM-BPR cells are more sensitive to Bcl-2 inhibitor venetoclax. Overall, this study demonstrates the feasibility of creating a proteasome inhibitor resistant myeloma cell lines by using clinically relevant pulse treatments and provides a novel model of acquired resistance.

BackgroundUpper extremity (UE) vascularized composite allotransplantation (VCA; hand transplantation) is a reconstructive treatment option for patients with UE loss. Approximately 37 UE VCAs have been performed in the United States to date; thus, little is known about long-term psychosocial outcomes and whether the benefits outweigh the risks. To make an informed treatment decision, patients must understand the procedure, risks, and potential benefits of UE VCA. However, few educational resources are publicly available providing unbiased, comprehensive information about UE VCA. ObjectiveThis paper described the development of a neutral, and accessible, educational website supporting informed decision-making about UE VCA as a treatment option for individuals with UE amputations. MethodsWebsite content development was informed by 9 focus groups conducted with individuals with UE amputations at 3 study sites. After initial website development, we conducted usability testing to identify ways to improve navigability, design, content, comprehension, and cultural sensitivity. Participants were administered the After-Scenario Questionnaire to assess user performance after completing navigational tasks, System Usability Scale to measure the perceived usability of the website, and Net Promoter Score to measure user satisfaction. Quantitative data were analyzed using descriptive statistics. Qualitative data were analyzed using rapid thematic analysis. ResultsA total of 44 individuals with UE amputations participated in focus groups (n=37, 84%) and usability testing (n=14, 32%). Most participants in the focus groups and usability testing were male (24/37, 65% and 11/14, 79%, respectively) and White (27/37, 73% and 9/14, 64%, respectively), had unilateral limb loss (22/37, 59% and 12/14, 86%, respectively), and had mean ages of 48 (SD 9.2) and 50 (SD 12.0) years, respectively. Focus group results are organized into accessibility, website design, website development, website tone and values, sitemap, terminology, images and videos, and tables and graphics. Usability testing revealed that participants had a positive impression of the website. The mean After-Scenario Questionnaire score of 1.3 to 2.3 across task scenarios indicated high satisfaction with website usability, the mean System Usability Scale score of 88.9 indicated user satisfaction with website usability, and the mean Net Promoter Score of 9.6 indicated that users were enthusiastic and would likely refer individuals to the website. ConclusionsThe findings suggest that our educational website, Within Reach, provides neutral, patient-centered information and may be a useful resource about UE VCA for individuals with UE amputations, their families, and health care professionals. Health care professionals may inform UE VCA candidates about Within Reach to supplement current VCA education processes. Within Reach serves as a resource about treatment options for patients preparing for scheduled or recovering from traumatic UE amputations. Future research should assess whether Within Reach improves knowledge about UE VCA and enhances informed decision-making about UE VCA as a treatment option.

Rheumatic diseases cover a wide spectrum of conditions, including primary and secondary degenerative joint diseases and autoimmune inflammatory rheumatic diseases. The risks of cardiovascular disease and osteoporosis and resultant fractures in aging female rheumatic disease populations, especially those with autoimmune rheumatic diseases, are increased. Changes in the immune system in aging populations need to be considered especially among patients with autoimmune rheumatic diseases. Immunosenescence is closely aligned to reduced adaptive immunity and increased non-specific innate immunity leading to chronic inflammation of inflammaging. The effective use of disease-modifying antirheumatic drugs to control autoimmune rheumatic diseases may also mitigate factors leading to cardiovascular disease and osteoporosis. Rheumatic diseases, which largely manifest as arthritis, predispose patients to premature joint degeneration and poor bone health and therefore have a higher risk of developing end-stage arthritis requiring joint arthroplasties sooner or more often than other patients without rheumatic disease.

Abstract Background: Contactless photoplethysmography (PPG) potentially affords the ability to obtain vital signs in pediatric populations without disturbing the child. Most validity studies have been conducted in laboratory settings or with healthy adult volunteers. This review aims to evaluate the current literature on contactless vital signs monitoring in pediatric populations and within a clinical setting. Methods: OVID, Webofscience, Cochrane library, and clinicaltrials.org were systematically searched by two authors for research studies which used contactless PPG to assess vital signs in children and within a clinical setting. Results: Fifteen studies were included with a total of 170 individuals. Ten studies were included in a meta-analysis for neonatal heart rate (HR), which demonstrated a pooled mean bias of −0.25 (95% limits of agreement (LOA), −1.83 to 1.32). Four studies assessed respiratory rate (RR) in neonates, and meta-analysis demonstrated a pooled mean bias of 0.65 (95% LOA, −3.08 to 4.37). All studies were small, and there were variations in the methods used and risk of bias. Conclusion: Contactless PPG is a promising tool for vital signs monitoring in children and accurately measures neonatal HR and RR. Further research is needed to assess children of different age groups, the effects of skin type variation, and the addition of other vital signs.

Contactless photoplethysmography (cPPG) is a method of physiological monitoring. It differs from conventional monitoring methods (e.g., saturation probe) by ensuring no contact with the subject by use of a camera. The majority of research on cPPG is conducted in a laboratory setting or in healthy populations. This review aims to evaluate the current literature on monitoring using cPPG in adults within a clinical setting. Adhering to the Preferred Items for Systematic Reviews and Meta-analysis (PRISMA, 2020) guidelines, OVID, Webofscience, Cochrane library, and clinicaltrials.org were systematically searched by two researchers. Research articles using cPPG for monitoring purposes in adults within a clinical setting were selected. Twelve studies with a total of 654 individuals were included. Heart rate (HR) was the most investigated vital sign (n = 8) followed by respiratory rate ((n = 2), Sp02 (n = 2), and HR variability (n = 2). Four studies were included in a meta-analysis of HR compared to ECG data which demonstrated a mean bias of –0.13 (95% CI, –1.22–0.96). This study demonstrates cPPG can be a useful tool in the remote monitoring of patients and has demonstrated accuracy for HR. However, further research is needed into the clinical applications of this method.

Animals raised in environments that prevent natural foraging opportunities may have difficulty adapting to novelty, such as feeding and management changes. Our objective was to evaluate how early provision and presentation of forage in dairy calves affected response to novel TMR (total mixed ration; grain and alfalfa) at weaning. Holstein heifer calves were housed individually in a covered outdoor hutch with an attached uncovered wire-fenced pen on sand bedding. Calves were fed a diet of starter grain and milk replacer (5.7-8.4L/d step-up) via a bottle (Control, n = 9) or given additional access to mountaingrass hay presented either in a bucket (Bucket, n = 9), or PVC pipe feeder (Pipe, n = 9). Treatments were applied from birth through 50 d of age, when step-down weaning began. All calves had 3 buckets and a pipe feeder provided in their uncovered pen area. On d 50, each calf was briefly blocked inside their hutch. TMR was put in the 3rd bucket that previously contained hay (Bucket) or was empty (Control, Pipe). The calf was released from the hutch and video-recorded for 30 min. Neophobia towards TMR was affected by prior experience with presentation: Bucket calves began eating TMR faster than Pipe and Control (P≤0.012) and showed the fewest number of startle responses (P = 0.004). Intake was similar across groups (P = 0.978), suggesting this apparent neophobia was transient, but Control calves took longer to eat than Bucket (P

Abstract COVID‐19 has been linked to dysautonomia in the current literature, as has uncontrolled diabetes. Here, we present a case report of severe dysautonomia following a COVID‐19 infection in a patient with pre‐existing poorly controlled type‐1 diabetes. This patient exhibited symptoms consistent with both postural orthostatic tachycardia syndrome (POTS), as well as orthostatic hypotension. His symptoms became so severe that he was unable to come to a standing position without experiencing syncope. Extensive workup was completed to identify an alternative cause of his dysautonomia with inconclusive results. Dysautonomia can have devastating consequences in regard to physical, social, and psychological health. Counseling individuals with poorly controlled diabetes about the importance of maintaining tight blood glucose control and avoiding COVID‐19 infection should be primary interventions when treating patients with this DM1. Early detection and management of diabetes mellitus, COVID‐19, and of possible resultant dysautonomia through medical interventions, as well as lifestyle changes, are extremely important measures to avoid development of dangerous and potentially life‐threatening consequences.

Abstract This study investigates thoroughly whether acute exposure to outdoor PM2.5 concentration, P, modifies the rate of change in the daily number of COVID-19 infections (R) across 18 high infection provincial capitals in China, including Wuhan. A best-fit multiple linear regression model was constructed to model the relationship between P and R, from 1 January to 20 March 2020, after accounting for meteorology, net move-in mobility (NM), time trend (T), co-morbidity (CM), and the time-lag effects. Regression analysis shows that P (β = 0.4309, p

Background Increasing awareness of milder presentations of cystic fibrosis (CF) and greater interest in non-CF bronchiectasis are likely to lead to more CF screening by respiratory clinicians. As a result, adults who may not strictly fulfil CF diagnostic criteria yet display evidence of abnormal CF transmembrane conductance regulator (CFTR) function are being identified. The degree of agreement on diagnosis and care needs in these cases between CF clinicians remains unknown, and has implications for patient care, including access to CFTR modulator therapies. Methods We surveyed adult CF physicians in Canada, the USA, the UK and Ireland, and presented them with anonymised vignettes of adult patients referred for assessment of possible CF. Diagnostic inter-rater agreement over diagnosis, ease of classifying cases and appropriate follow-up was assessed using Krippendorff's reliability coefficient (α). Results Agreement over diagnosis (α=0.282), ease of classification (α= −0.01) and recommended follow-up (α=0.054) was weak. Clinician experience (>10 and 5–10 years versus

Abstract Neurodegenerative diseases are characterized by chronic neuroinflammation and may perpetuate ongoing fibrotic reactions within the central nervous system. Unfortunately, there is no therapeutic available that treats neurodegenerative inflammation and its sequelae. Here we utilize cromolyn, a mast cell inhibitor with anti-inflammatory capabilities, and its fluorinated analogue F-cromolyn to study fibrosis-related protein regulation and secretion downstream of neuroinflammation and their ability to promote microglial phagocytosis and neurite outgrowth. In this report, RNA-seq analysis shows that administration of the pro-inflammatory cytokine TNF-α to HMC3 human microglia results in a robust upregulation of fibrosis-associated genes. Subsequent treatment with cromolyn and F-cromolyn resulted in reduced secretion of collagen XVIII, fibronectin, and tenascin-c. Additionally, we show that cromolyn and F-cromolyn reduce pro-inflammatory proteins PLP1, PELP1, HSP90, IL-2, GRO-α, Eotaxin, and VEGF-Α, while promoting secretion of anti-inflammatory IL-4 in HMC3 microglia. Furthermore, cromolyn and F-cromolyn augment neurite outgrowth in PC12 neuronal cells in concert with nerve growth factor. Treatment also differentially altered secretion of neurogenesis-related proteins TTL, PROX1, Rab35, and CSDE1 in HMC3 microglia. Finally, iPSC-derived human microglia more readily phagocytose Aβ42 with cromolyn and F-cromolyn relative to controls. We propose the cromolyn platform targets multiple proteins upstream of PI3K/Akt/mTOR, NF-κB, and GSK-3β signaling pathways to affect cytokine, chemokine, and fibrosis-related protein expression.

Objective Antenatal care (ANC) is crucial to protecting the health of pregnant women and their unborn children; however, the uptake of ANC among pregnant women in low and middle-income countries (LMICs) is suboptimal. One popular strategy to increase the uptake of health services, including ANC visits, are conditional cash transfer (CCT) programmes. CCT programmes require beneficiaries to comply with certain conditionalities in order to receive a financial sum. A systematic review was carried out to determine whether CCT programmes have a positive impact on ANC uptake in LMIC populations.Methods Electronic databases CENTRAL, MEDLINE, Embase, Maternity and Infant Care and Global Health were searched from database inception to 21 January 2022. Reference checking and grey literature searches were also applied. Eligible study designs were randomised controlled trials, controlled before-after studies and interrupted time series analysis. Risk of bias assessments were undertaken for each study by applying the Risk of Bias 2 tool and the Risk of Bias in Non-randomised Studies of Interventions tool.Results Out of 1534 screened articles, 18 publications were included for analysis. Eight studies reported statistically non-significant results on all reported outcomes. Seven studies demonstrated statistically significant positive effects ranging from 5.5% to 45% increase in ANC service uptake. A further three studies reported small but statistically significant impact of CCT on the use of ANC services in both positive (2.5% increase) and negative (3.7% decrease) directions. Subanalysis of results disaggregated by socioeconomic status (SES) indicated that ANC attendance may be more markedly improved by CCT programmes in low SES populations; however, results were inconclusive.Conclusion Our evidence synthesis presented here demonstrated a highly heterogeneous evidence base pertaining to the impact of CCTs on ANC attendance. More high-powered studies are required to elucidate the true impact of CCT programmes on ANC uptake, with particular focus on the barriers and enablers of such programmes in achieving intended outcomes.

One in three grade 7 to 12 students in Canada report trying vaping or e-cigarettes. Despite consequences like nicotine addiction, impaired brain development, increased respiratory symptoms, and association with an increased risk of COVID-19 diagnosis, 48% of youth believe occasional vaping has little to no risk. There is a clear need for youth to learn about vaping consequences. We developed and piloted a novel free interactive educational program on vaping risks which has been used by over 800 grade 7 to 9 students. In post-program surveys, students reported a subjective increase in knowledge about the health consequences of vaping.

Objectives To understand how essential workers with confirmed infections responded to information on COVID-19.Design Qualitative analysis of semistructured interviews conducted in collaboration with the national contact tracing management programme in Ireland.Setting Semistructured interviews conducted via telephone and Zoom Meetings.Participants 18 people in Ireland with laboratory confirmed SARS-CoV-2 infections using real-time PCR testing of oropharyngeal and nasopharyngeal swabs. All individuals were identified as part of workplace outbreaks defined as ≥2 individuals with epidemiologically linked infections.Results A total of four high-order themes were identified: (1) accessing essential information early, (2) responses to emerging ‘infodemic’, (3) barriers to ongoing engagement and (4) communication strategies. Thirteen lower order or subthemes were identified and agreed on by the researchers.Conclusions Our findings provide insights into how people infected with COVID-19 sought and processed related health information throughout the pandemic. We describe strategies used to navigate excessive and incomplete information and how perceptions of information providers evolve overtime. These results can inform future communication strategies on COVID-19.

Abstract Proteasome inhibitors bortezomib and carfilzomib are approved for the treatment of multiple myeloma and mantle cell lymphoma and have demonstrated clinical efficacy for the treatment of acute lymphoblastic leukemia (ALL). The t(4;11)(q21;q23) chromosomal translocation that leads to the expression of MLL–AF4 fusion protein and confers a poor prognosis, is the major cause of infant ALL. This translocation sensitizes tumor cells to proteasome inhibitors, but toxicities of bortezomib and carfilzomib may limit their use in pediatric patients. Many of these toxicities are caused by on-target inhibition of proteasomes in non-lymphoid tissues (e.g., heart muscle, gut, testicles). We found that MLL–AF4 cells express high levels of lymphoid tissue-specific immunoproteasomes and are sensitive to pharmacologically relevant concentrations of specific immunoproteasome inhibitor ONX-0914, even in the presence of stromal cells. Inhibition of multiple active sites of the immunoproteasomes was required to achieve cytotoxicity against ALL. ONX-0914, an inhibitor of LMP7 (ß5i) and LMP2 (ß1i) sites of the immunoproteasome, and LU-102, inhibitor of proteasome ß2 sites, exhibited synergistic cytotoxicity. Treatment with ONX-0914 significantly delayed the growth of orthotopic ALL xenograft tumors in mice. T-cell ALL lines were also sensitive to pharmacologically relevant concentrations of ONX-0914. This study provides a strong rationale for testing clinical stage immunoproteasome inhibitors KZ-616 and M3258 in ALL.

Abstract This study ascertained the accumulation of polyprenol from four Irish conifer species Picea sitchensis, Cedrus atlantica ‘Glauca’, Pinus sylvestris and Taxus baccata and one flowering tree Cotoneaster hybrida using supercritical fluid extraction with carbon dioxide (SFE-CO2) and solvent extraction. The effects of SFE-CO2 parameters such as temperature (ranged from 40 to 70 $$^\circ{\rm C}$$ ∘ C ), pressure (ranged from 100 to 350 bars) and dynamic time (from 70 min to 7 h) were analysed on the extraction efficiency of polyprenol. Qualitative and quantitative analysis of polyprenol was examined using high-performance liquid chromatography. Results showed that P. sylvestris accumulated the highest polyprenol yield of 14.00 ± $$0.4$$ 0.4 mg g−1 DW when extracted with hexane:acetone (1:1 v/v). However, with SFE-CO2 conditions of 200 bars, 70 $$^\circ{\rm C}$$ ∘ C , 7 h, with absolute ethanol as a cosolvent with a flow rate of 0.05 ml min−1, P. sitchensis accumulated the highest polyprenol yield of 6.35 ± $$0.4$$ 0.4 mg g−1DW. This study emphasised the potential application of SFE-CO2 in the extraction of polyprenol as an environmentally friendly method to be used in pharmaceutical and food industries.

Abstract Cromolyn is a known mast cell stabilizer and is approved for treatment of asthma and for other allergic indications. Cromolyn, in a new redesigned dry powder formulation, is being tested in a pivotal clinical trial in combination with low dose ibuprofen to treat early Alzheimer’s Disease (AD) subjects. To better understand the mechanistic effect cromolyn has in slowing down or halting the neuroinflammatory response associated with AD progression, we tested the effect of cromolyn to dampen the inflammatory response in the human HMC3 microglia cell line. The direct effect of cromolyn on HMC3 microglia is on cytokines and chemokines production following their activation by the inflammatory cytokine TNF-α. Cromolyn and a new fluorinated analog dramatically reduced the secretion of a wide spectrum of inflammatory mediators, which included cytokines such as IL-1β, IL-6, IL-8 and IFN-γ, and chemokines such as CXCL10, CCL2, CCL3 and CCL4. These results bolster our understanding of how our cromolyn platform modulates toxic microglia behavior as a dynamic future treatment option for neurodegenerative disorders.

Abstract The human airway epithelium lining the bronchial tree contains basal cells that proliferate, differentiate, and communicate with other components of their microenvironment. One method that cells use for intercellular communication involves the secretion of exosomes and other extracellular vesicles (EVs). We isolated exosome-enriched EVs that were produced from an immortalized human airway basal cell line (BCi-NS1.1) and found that their secretion is increased by exposure to cigarette smoke extract, suggesting that this stress stimulates release of EVs which could affect signaling to other cells. We have previously shown that primary human airway basal cells secrete vascular endothelial growth factor A (VEGFA) which can activate MAPK signaling cascades in endothelial cells via VEGF receptor–2 (VEGFR2). Here, we show that exposure of endothelial cells to exosome-enriched airway basal cell EVs promotes the survival of these cells and that this effect also involves VEGFR2 activation and is, at least in part, mediated by VEGFA present in the EVs. These observations demonstrate that EVs are involved in the intercellular signaling between airway basal cells and the endothelium which we previously reported. The downstream signaling pathways involved may be distinct and specific to the EVs, however, as increased phosphorylation of Akt, STAT3, p44/42 MAPK, and p38 MAPK was not seen following exposure of endothelial cells to airway basal cell EVs.

Abstract Background Time out of clinical training can impact medical trainees’ skills, competence and confidence. Periods of Out of Programme for Research (OOPR) are often much longer than other approved mechanisms for time of out training. The aim of this survey study was to explore the challenges of returning to clinical training following OOPR, and determine potential solutions. Methods All current integrated academic training (IAT) doctors at the University of Leeds (United Kingdom) and previous IAT trainees undertaking OOPR in the local region (West Yorkshire, United Kingdom)(n = 53) were invited to complete a multidisciplinary survey. Results The survey was completed by 33 participants (62% response rate). The most relevant challenges identified were completing the thesis whilst transitioning back to clinical work, the rapid transition between full-time research and clinical practice, a diminished confidence in clinical abilities and isolation from colleagues. Potential solutions included dedicated funds allocated for the renewal of lapsed skills, adequate notice of the clinical rotation to which trainees return, informing clinical supervisors about the OOPR trainee returning to practice and a mandatory return to standard clinical days. Conclusions Addressing these issues has the potential to improve the trainee experience and encourage future trainees to take time out of training for research activities.

Objectives To report the reduction in new neovascular age-related macular degeneration (nAMD) referrals during the COVID-19 pandemic and estimate the impact of delayed treatment on visual outcomes at 1 year.Design Retrospective clinical audit and simulation model.Setting Multiple UK National Health Service (NHS) ophthalmology centres.Participants Data on the reduction in new nAMD referrals were obtained from four NHS Trusts comparing April 2020 with April 2019. To estimate the potential impact on 1-year visual outcomes, a stratified bootstrap simulation model was developed drawing on an electronic medical records dataset of 20 825 nAMD eyes from 27 NHS Trusts.Main outcome measures Simulated mean visual acuity and proportions of eyes with vision ≤6/60, ≤6/24 and ≥6/12 at 1 year under four hypothetical scenarios: 0-month, 3-month, 6-month and 9-month treatment delays. Estimated additional number of eyes with vision ≤6/60 at 1 year nationally.Results The number of nAMD referrals dropped on average by 72% (range 65%–87%). Simulated 1-year visual outcomes for 1000 nAMD eyes with a 3-month treatment delay suggested an increase in the proportion of eyes with vision ≤6/60 from 15.5% (13.2%–17.9%) to 23.3% (20.7%–25.9%), and a decrease in the proportion of eyes with vision ≥6/12 (driving vision) from 35.1% (32.1%–38.1%) to 26.4% (23.8%–29.2%). Outcomes worsened incrementally with longer modelled delays. Assuming nAMD referrals are reduced to this level for 1 month nationally, these simulated results suggest an additional 186–365 eyes with vision ≤6/60 at 1 year.Conclusions We report a large decrease in nAMD referrals during the COVID-19 lockdown and provide an important public health message regarding the risk of delayed treatment. As a conservative estimate, a treatment delay of 3 months could lead to a >50% relative increase in the number of eyes with vision ≤6/60 and 25% relative decrease in the number of eyes with driving vision at 1 year.

Introduction Improving the lives of children and adolescents with parental mental illness (CAPRI) remains an urgent political and public health concern for the UK and European Union. Recurrent parental mental illness is believed to lead to fractures in the family, academic and social lives of these children, yet interventions are poorly targeted and non-specific. Part of an interdisciplinary programme of work (the CAPRI Programme; grant number: 682741), CAPRI-Voc aims to achieve two goals: first, to test the feasibility of our longitudinal imaging paradigm in mother–infant pairs where the mother has a diagnosis of severe mental illness. Second, to compare development of vocal processing in these infants with infants in the general population.Methods and analysis Recruitment of 100 infants of mothers with mental illness, alongside 50 infants of healthy mothers. Both cohorts of infants will undergo functional near infrared spectroscopy (fNIRS) brain imaging at three time points: 9, 12 and 18 months to explore differences between cohorts in their neural responses to vocal stimuli in our language paradigm. Mothers will complete an interview and psychological questionnaires. We shall also complete an infant developmental battery and mother–child interaction play session. Data on recruitment, retention and dropout will be recorded.Ethics and dissemination It will be made clear that fNIRS is a safe, non-invasive technology widely used in infant clinical and psychological research. We shall reassure mothers that no definitive causal link exists between maternal mental illness and language development in infants, and that individual data will only exist as part of the wider dataset. As the study includes both children and vulnerable adults, all research staff will complete National Health Service (NHS) Safeguarding level 3 training. Dissemination will be via direct feedback to stakeholders, patient and advisory groups, and through presentations at conferences, journal publications and university/NHS trust communications. The study was approved through North West–Greater Manchester West Research Ethics Committee (17/NW/0074) and Health Research Authority (212715).

DNA damage response mechanisms have meiotic roles that ensure successful gamete formation. While completion of meiotic double-strand break (DSB) repair requires the canonical RAD9A-RAD1-HUS1 (9A-1-1) complex, mammalian meiocytes also express RAD9A and HUS1 paralogs, RAD9B and HUS1B, predicted to form alternative 9-1-1 complexes. The RAD1 subunit is shared by all predicted 9-1-1 complexes and localizes to meiotic chromosomes even in the absence of HUS1 and RAD9A. Here, we report that testis-specific disruption of RAD1 in mice resulted in impaired DSB repair, germ cell depletion, and infertility. Unlike Hus1 or Rad9a disruption, Rad1 loss in meiocytes also caused severe defects in homolog synapsis, impaired phosphorylation of ATR targets such as H2AX, CHK1, and HORMAD2, and compromised meiotic sex chromosome inactivation. Together, these results establish critical roles for both canonical and alternative 9-1-1 complexes in meiotic ATR activation and successful prophase I completion.

We developed a method for altering terrain unevenness on a treadmill to study gait kinematics. Terrain consisted of rigid polyurethane disks (12.7 cm diameter, 1.3-3.8 cm tall) which attached to the treadmill belt using hook-and-loop fasteners. Here, we tested four terrain unevenness conditions: Flat, Low, Medium, and High. The main objective was to test the hypothesis that increasing the unevenness of the terrain would result in greater gait kinematic variability. Seventeen younger adults (age 20-40 years), 25 higher-functioning older adults (age 65+ years), and 29 lower-functioning older adults (age 65+ years, Short Physical Performance Battery score < 10) participated. We customized the treadmill speed to each participant's walking ability, keeping the speed constant across all four terrain conditions. Participants completed two 3-minute walking trials per condition. Using an inertial measurement unit placed over the sacrum and pressure sensors in the shoes, we calculated the stride-to-stride variability in step duration and sacral excursion (coefficient of variation; standard deviation expressed as percentage of the mean). Participants also self-reported their perceived stability for each condition. Terrain was a significant predictor of step duration variability, which roughly doubled from Flat to High terrain for all participant groups: younger adults (Flat 4.0%, High 8.2%), higher-functioning older adults (Flat 5.0%, High 8.9%), lower-functioning older adults (Flat 7.0%, High 14.1%). Similarly, all groups exhibited significant increases in sacral excursion variability for the Medium and High uneven terrain conditions, compared to Flat. Participants were also significantly more likely to report feeling less stable walking over all three uneven terrain conditions compared to Flat. These findings support the hypothesis that altering terrain unevenness on a treadmill will increase gait kinematic variability and reduce perceived stability in younger and older adults.

Rapid identification of potentially life-threatening blood stream infections (BSI) improves clinical outcomes, yet conventional blood culture (BC) identification methods require ~24-72 hours of liquid culture, plus 24-48 hours to generate single colonies on solid media suitable for identification by mass spectrometry (MS). Newer rapid centrifugation techniques, such as the Bruker MBT-Sepsityper® IVD, replace culturing on solid media and expedite the diagnosis of BCs but frequently demonstrate reduced sensitivity for identifying clinically significant Gram-positive bacterial or fungal infections. This study introduces a protocol that utilises the broad-range binding properties of an engineered version of mannose-binding lectin linked to the Fc portion of immunoglobulin (FcMBL) to capture and enrich pathogens combined with matrix-assisted laser desorption-ionisation time-of-flight (MALDI-TOF) MS for enhanced infection identification in BCs. The FcMBL method identified 94.1% (64 of 68) of clinical BCs processed, with a high sensitivity for both Gram-negative and Gram-positive bacteria (94.7 and 93.2%, respectively). The FcMBL method identified more patient positive BCs than the Sepsityper® (25 of 25 vs 17 of 25), notably with 100% (3/3) sensitivity for clinical candidemia, compared to only 33% (1/3) for the Sepsityper®. Additionally, during inoculation experiments, the FcMBL method demonstrated a greater sensitivity, identifying 100% (24/24) of candida to genus level and 9/24 (37.5%) top species level compared to 70.8% (17/24) to genus and 6/24 to species (25%) using the Sepsityper®. This study demonstrates that capture and enrichment of samples using magnetic FcMBL-conjugated beads is superior to rapid centrifugation methods for identification of BCs by MALDI-TOF MS. Deploying the FcMBL method therefore offers potential clinical benefits in sensitivity and reduced turnaround times for BC diagnosis compared to the standard Sepsityper® kit, especially for fungal diagnosis.

Abstract Cranial internal hemipelvectomy can be successful for excision of ilial CSA with minimal complications. Iliectomy with adjuvant radiation therapy was well tolerated in a dog with grade II ilial CSA. The dog survived 1,271 days postoperatively and supposedly succumbed to a disease process unrelated to the CSA.

Introduction The Megha Health Insurance Scheme (MHIS) was launched in 2013 in the North-East Indian state of Meghalaya to reduce household out-of-pocket expenditure on health and provide access to high-quality essential healthcare. Despite substantial expansion of the MHIS since the scheme’s inception, there is a lack of comprehensive documentation and evaluation of the scheme’s performance against its Universal Health Care (UHC) objectives. Methods We analysed six years of enrolment and claims data (2013–2018) covering three phases of the scheme to understand the pattern of enrolment, utilisation and care provision under the MHIS during this period. De-identified data files included information on age, sex, district of residence, the district of provider hospital, type of hospital, date of admission, status at discharge, claimed category of care, package codes, and amount claimed. Descriptive statistics were generated to investigate key trends in enrolment, service utilisation, and Government health spending under the MHIS. Results Approximately 55% of the eligible population are currently enrolled in MHIS. Enrolment increased consistently from phase I through III and remained broadly stable across districts, gender, age group and occupation categories, with a small decline in males 19–60 years. Claims were disproportionately skewed towards private provision; 57% of all claims accrued to the 18 empanelled private hospitals and 39% to the 159 public sector facilities. The package ‘General Ward Unspecified’ was responsible for the highest volume of claims and highest financial dispensation across all three phases of the scheme. This likely indicates substantial administrative error and is potentially masking both true burden of disease and accurate financial provision for care under the MHIS. Anti-rabies injections for dog/cat bite contributed to 11% of total claims under MHIS III, and 1.6% of all claims under MHIS II. This warrants investigation to better understand the burden of animal bites on the Meghalayan population and inform the implementation of cost-effective strategies to reduce this burden. Conclusions This paper describes the first analysis of health insurance enrolment and claims data in the state of Meghalaya. The analysis has generated an important evidence base to inform future MHIS enrolment and care provision policies as the scheme expands to provide Universal Health Coverage to the state’s entire population.

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in people with cystic fibrosis (pwCF) can lead to severe outcomes. Methods In this observational study, the European Cystic Fibrosis Society Patient Registry collected data on pwCF and SARS-CoV-2 infection to estimate incidence, describe clinical presentation and investigate factors associated with severe outcomes using multivariable analysis. Results Up to December 31, 2020, 26 countries reported information on 828 pwCF and SARS-CoV-2 infection. Incidence was 17.2 per 1000 pwCF (95% CI: 16.0–18.4). Median age was 24 years, 48.4% were male and 9.4% had lung transplants. SARS-CoV-2 incidence was higher in lung-transplanted (28.6; 95% CI: 22.7–35.5) versus non-lung-transplanted pwCF (16.6; 95% CI: 15.4–17.8) (p≤0.001). SARS-CoV-2 infection caused symptomatic illness in 75.7%. Factors associated with symptomatic SARS-CoV-2 infection were age >40 years, at least one F508del mutation and pancreatic insufficiency. Overall, 23.7% of pwCF were admitted to hospital, 2.5% of those to intensive care, and regretfully 11 (1.4%) died. Hospitalisation, oxygen therapy, intensive care, respiratory support and death were 2- to 6-fold more frequent in lung-transplanted versus non-lung-transplanted pwCF. Factors associated with hospitalisation and oxygen therapy were lung transplantation, cystic fibrosis-related diabetes (CFRD), moderate or severe lung disease and azithromycin use (often considered a surrogate marker for Pseudomonas aeruginosa infection and poorer lung function). Conclusion SARS-CoV-2 infection yielded high morbidity and hospitalisation in pwCF. PwCF with forced expiratory volume in 1 s

Background OligoG is a low molecular-weight alginate oligosaccharide that improves the viscoelastic properties of cystic fibrosis (CF) mucus and disrupts biofilms, thereby potentiating the activity of antimicrobial agents. The efficacy of inhaled OligoG was evaluated in adult patients with CF. Methods A randomised, double-blind, placebo-controlled multicentre crossover study was used to demonstrate safety and efficacy of inhaled dry powder OligoG. Subjects were randomly allocated to receive OligoG 1050 mg per day (10 capsules three times daily) or matching placebo for 28 days, with 28-day washout periods following each treatment period. The primary end-point was absolute change in percentage predicted forced expiratory volume in 1 s (FEV1) at the end of 28-day treatment. The intention-to-treat (ITT) population (n=65) was defined as randomised to treatment with at least one administration of study medication and post-dosing evaluation. Results In this study, 90 adult subjects were screened and 65 were randomised. Statistically significant improvement in FEV1 was not observed in the ITT population. Adverse events included nasopharyngitis, cough and pulmonary exacerbation. The number and proportions of patients with adverse events and serious adverse events were similar between OligoG and placebo group. Conclusions Inhalation of OligoG-dry powder over 28 days was safe in adult CF subjects. Statistically significant improvement of FEV1 was not reached. The planned analyses did not indicate a significant treatment benefit with OligoG compared to placebo. Post hoc exploratory analyses showed subgroup results that indicate that further studies of OligoG in this patient population are justified.

Abstract Introduction: Access to qualified biostatisticians to provide input on research design and statistical considerations is critical for high-quality clinical and translational research. At diverse health science institutions, like the University of Michigan (U-M), biostatistical collaborators are scattered across the campus. This model can isolate applied statisticians, analysts, and epidemiologists from each other, which may negatively affect their career development and job satisfaction, and inhibits access to optimal biostatistical support for researchers. Furthermore, in the era of modern, complex translational research, it is imperative to elevate biostatistical expertise by offering innovative training. Methods: The Michigan Institute for Clinical and Health Research established an Applied Biostatistical Sciences (ABS) network that is a campus-wide community of staff and faculty statisticians, epidemiologists, data scientists, and researchers, with the intention of supporting both researchers and biostatisticians, while promoting high-quality clinical and translational research. Results: Since its inception in early 2018, the ABS Network has grown to several hundred faculty and staff members across a range of health and research disciplines. The ABS Network offers free trainings on innovative methods and tools in the biostatistical field, a web-based portal with resources and training lectures, and connections to U-M faculty and/or staff members for consultation and collaboration. Conclusions: Although challenging, if approached strategically, the creation of a collaboration network of biostatisticians can be accomplished. Furthermore, the process can be adopted and implemented for establishing collaboration with any network of professionals with common interests across different disciplines and professional fields regardless of size.

ObjectiveBacterial Infections remains a leading cause of death in the Paediatric Intensive Care Unit (PICU). In this era of rising antimicrobial resistance, new tools are needed to guide antimicrobial use. The aim of this study was to investigate the accuracy of procalcitonin (PCT), neutrophil gelatinase-associated lipocalin (NGAL), resistin, activated partial thromboplastin time (aPTT) waveform and C-reactive protein (CRP) for the diagnosis of serious bacterial infection (SBI) in children on admission to PICU and their use as prognostic indicators.SettingA regional PICU in the United Kingdom.PatientsConsecutive PICU admissions between October 2010 and June 2012.MeasurementsBlood samples were collected daily for biomarker measurement. The primary outcome measure was performance of study biomarkers for diagnosis of SBI on admission to PICU based on clinical, radiological and microbiological criteria. Secondary outcomes included durations of PICU stay and invasive ventilation and 28-day mortality. Patients were followed up to day 28 post-admission.Main resultsA total of 657 patients were included in the study. 92 patients (14%) fulfilled criteria for SBI. 28-day mortality was 2.6% (17/657), but 8.7% (8/92) for patients with SBI. The combination of PCT, resistin, plasma NGAL and CRP resulted in the greatest net reclassification improvement compared to CRP alone (0.69, pConclusionCombinations of biomarkers, including PCT, may improve accurate and timely identification of SBI on admission to PICU.

Background: The consumption of controlled substances in North Carolina and the nation has created a health crisis with epidemic levels of medication diversion, abuse, overdose and death. Primary care providers are the principal prescribers of controlled substances and at greatest risk of encountering patients that abuse medications. Guidelines recommend patient agreements with monitoring requirements when prescribing opioids and stimulants. Studies have focused on opioids and excluded stimulants. Adherence to recommended monitoring requirements has not been fully evaluated. Methodology: This was a quality improvement project using the Plan-Do-Check-Act procedure. The following outcome measures were evaluated: signed agreement on file, prescription monitoring program (pmp) checks, urine screens, and prescriptions written without a mandatory visit. Implementation: Who: patients aged 19 and over prescribed a long-term Schedule II medication for the chronic conditions of pain and/or attention deficit hyperactivity disorder. What: implemented a patient agreement and measured fidelity to components of the agreement. When: seven months pre- to seven months post-implementation. Where: in an adult primary care practice with approximately 2,500 patients. How: an agreement was implemented with monthly feedback provided. Results: Post-implementation, 94% of patients meeting criteria had a signed agreement in their medical record. Adherence to urine screening improved from 5.3% to 71.1%. Guideline adherence to pmp checks improved from 11.3% to 99.0%. Guideline deviation for prescriptions written without a visit improved from 20.6% to 0%. All improvements were statistically significant (P < .001). Conclusion: A Schedule II controlled substance patient agreement was successfully implemented in a primary care practice reducing risk for both the patient and provider.

Objective To validate whether a wearable remote vital signs monitor could accurately measure heart rate (HR), respiratory rate (RR) and temperature in a postsurgical patient population at high risk of complications.Design Manually recorded vital signs data were paired with vital signs data derived from the remote monitor set in patients participating in the Trial of Remote versus Continuous INtermittent monitoring (TRaCINg) study: a trial of continuous remote vital signs monitoring.Setting St James’s University Hospital, UK.Participants 51 patients who had undergone major elective general surgery.Interventions The intervention was the SensiumVitals monitoring system. This is a wireless patch worn on the patient’s chest that measures HR, RR and temperature continuously. The reference standard was nurse-measured manually recorded vital signs.Primary and secondary outcome measures The primary outcomes were the 95% limits of agreement between manually recorded and wearable patch vital sign recordings of HR, RR and temperature. The secondary outcomes were the percentage completeness of vital sign patch data for each vital sign.Results 1135 nurse observations were available for analysis. There was no clinically meaningful bias in HR (1.85 bpm), but precision was poor (95% limits of agreement −23.92 to 20.22 bpm). Agreement was poor for RR (bias 2.93 breaths per minute, 95% limits of agreement −8.19 to 14.05 breaths per minute) and temperature (bias 0.82°C, 95% limits of agreement −1.13°C to 2.78°C). Vital sign patch data completeness was 72.8% for temperature, 59.2% for HR and 34.1% for RR. Distributions of RR in manually recorded measurements were clinically implausible.Conclusions The continuous monitoring system did not reliably provide HR consistent with nurse measurements. The accuracy of RR and temperature was outside of acceptable limits. Limitations of the system could potentially be overcome through better signal processing. While acknowledging the time pressures placed on nursing staff, inaccuracies in the manually recorded data present an opportunity to increase awareness about the importance of manual observations, particularly with regard to methods of manual HR and RR measurements.

Ecological relationships between bacteria are important when considering variation in bacterial communities in humans, with such variation playing an important role in both health and disease. Using high-throughput sequence data of the 16S rRNA marker-gene, we analysed the prevalence of taxa in the airways of a number of health- and disease-associated cohorts and determined the main drivers of community variance and bacterial co-occurrence. A number of facultative and obligately anaerobic bacterial taxa are commonly associated with the upper airways, forming the main “core” microbiota, e.g. Streptococcus spp., Veillonella spp., Prevotella spp., Granulicatella spp. and Fusobacterium spp. Opportunistic pathogenic bacteria associated with chronic airways disease, such as Pseudomonas spp. (Pseudomonas aeruginosa), Burkholderia spp. (Burkholderia cepacia complex) and Haemophilus spp. (Haemophilus influenzae) demonstrated poor correlation with other members of their respective communities (ρ0.005), indicating probable independent acquisition and colonisation. Furthermore, our findings suggest that intra-genus variation between health and disease may affect community assemblies. Improved understanding of how bacteria assemble in time and space during health and disease will enable the future development of tailored treatment according to the patient's own signature microbiota, potentially providing benefit to patients suffering from airway diseases characterised by chronic infection.

There have been several recent developments in surgical treatments for male and female incontinence. This article reviews the current options for treatments of urge and stress incontinence in men and women. Treatments for urge incontinence discussed include intradetrusor onabotulinum toxin A, sacral neuromodulation and percutaneous tibial nerve stimulation. For stress incontinence, suburethral mesh, bulking agents, autologous slings, colposuspension, male slings and artificial urinary sphincters are assessed.

The utilization of person-centered care is highlighted as essential for health promotion, yet implementation has been inconsistent and multiple issues remain. There is a dearth of applied research exploring the facets of successful implementation. In this paper, a person-centered wellbeing program spanning various groups is discussed, outlining the central principles that have allowed for successful outcomes. Ten years of pragmatic pre–post service evaluation have shown consistent improvement in measures of functional capacity and wellbeing. The method for this paper is a reflective exploration of the theory and practices that can explain the continual improvement the clinics have achieved over 10 years. Core principles relate to connecting with people, connecting through groups, and connecting with self. The operationalization and theoretical explanation of these principles is outlined. The discussion of these principles posits essential factors to prioritize to advance the implementation of person-centered care in health promotion for long-term conditions.