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Abstract To investigate air pollution’s effect in the form of PM2.5 (particulate matter measuring less than 2.5 microns) on head and neck aerodigestive cancer incidence, an epidemiological cohort analysis was performed using data from the Surveillance Epidemiology and End Results national cancer database from the years 2002–2012. The relationship between US county mean PM2.5 levels and head and neck cancer (HNC) incidence rates were examined using a linear mixed model. Lagged effect of the pollutant’s effect on HNC incidence was analyzed. Our results showed a significant association between the incidence of HNC and certain subtypes with PM2.5 exposure after controlling for demographic characteristics, smoking and alcohol use. We observed the highest association at a 5-year lag period (β = 0.24, p value

Background: HER2-targeted therapies have revolutionised the treatment of HER2-positive breast cancer. However, de novo resistance or the emergence of acquired resistance is a persistent clinical problem. Here we report that neratinib, an irreversible pan-HER inhibitor, in combination with the multi-kinase inhibitor dasatinib, currently used to treat certain leukemias, has strong anti-proliferative effects against models of HER2-positive breast cancer that are innately resistant to trastuzumab or have acquired resistance to neratinib. Methods: Neratinib plus dasatinib was examined in a panel of 20 breast cancer cell lines, including HER2-positive, estrogen-receptor-positive, triple negative, and acquired HER2-targeted therapy resistant models. Drug effects on migration and apoptosis induction was evaluated and signaling alterations were determined by reverse phase protein array (RPPA). In vivo efficacy was examined using orthotopically-implanted HCC1954 cells. Results: Synergy was observed in cell lines innately resistant to trastuzumab, models with acquired resistance to neratinib, and in triple negative breast cancer cell lines. Further investigation showed that neratinib plus dasatinib induced apoptosis and inhibited cell migration to a greater degree than either drug alone. RPPA revealed that the combination caused suppression of key survival signaling through EGFR, Akt, and MAPK inhibition. In vivo, neratinib plus dasatinib was well tolerated and had a prolonged anti-tumor effect against HCC1954 xenografts. Conclusions: This study provides a strong pre-clinical rationale for the clinical investigation neratinib and dasatinib in HER2+ breast cancer.

This essay explores the – admittedly taboo – theme of eros as it relates to education. While eros is generally understood today in the restricted sense of sexual desire (hence the taboo), there are good reasons to expand the concept to include the full range of embodied human experiences of attraction or sensuous affinity. Such experiences are not merely physiological, but also infused with emotion and imagination, and they constitute an indelible aspect of presence. While traditional education aims more or less explicitly at suppressing the erotic dimension of presence, performative approaches – precisely because they are rooted in the body – in effect open this dimension and make it available as an area of experience, a source of knowledge, and a motivation for learning. But this introduces an element of unpredictability, even volatility; and given the complex and often unconscious movement of eros, we are never far from the zones of social taboo and therefore of ethical concern. Proponents of a performative teaching and learning culture must therefore give careful thought to the question of how to approach the erotic aspect of presence honestly, ethically, and in ways that not only promote learning but also foster self-esteem and respect.

Serratia marcescens is an environmental gram-negative bacterium that causes invasive disease in rare cases. During 2020–2022, an outbreak of 21 invasive Serratia infections occurred in a prison in California, USA. Most (95%) patients had a history of recent injection drug use (IDU). We performed whole-genome sequencing and found isolates from 8 patients and 2 pieces of IDU equipment were closely related. We also identified social interactions among patients. We recovered S. marcescens from multiple environmental samples throughout the prison, including personal containers storing Cell Block 64 (CB64), a quaternary ammonium disinfectant solution. CB64 preparation and storage conditions were suboptimal for S. marcescens disinfection. The outbreak was likely caused by contaminated CB64 and propagated by shared IDU equipment and social connections. Ensuring appropriate preparation, storage, and availability of disinfectants and enacting interventions to counteract disease spread through IDU can reduce risks for invasive Serratia infections in California prisons.

Multiple-hop tests are commonly used in both performance and rehabilitation settings to assess neuromuscular function. This study aimed to explore the relationship between hop performance and sprint ability. Specifically, it focused on three goals: (1) examining the connection between 3-Hop and 5-Hop distances and sprint performance and comparing the strength of relationship between hop kinetics and sprint times; (2) investigating two methods of calculating the 3-Hop and 5-Hop Reactive Strength Indexes (RSIhors) and their relationship to sprinting; and (3) assessing whether hop ratios or kinetic variables could distinguish sprinters of varying abilities. Forty-four male sportsmen participated, completing 3-Hop and 5-Hop tests and sprint times (5–45 m) over 54 inground force platforms. Ground reaction forces (GRFs) were collected during hop trials and horizontal and vertical hop propulsive and braking kinetics were determined. Results showed strong negative correlations between hop distances and sprint times (r = −0.700 to −0.796), while kinetic variables showed weaker relationships with sprint performance (r = −0.554 to 0.017). RSIhor, derived from hop distance, correlated more strongly with sprint performance than RSIhor from flight time. Hop ratios (5-Hop/3-Hop) did not differentiate fast from slow sprinters, and maximal vertical force and horizontal propulsive impulse were the best predictors of 10 m and 40 m sprint times. These findings suggest that hop distance and RSIhor are valuable tools for assessing sprint performance and reactive strength.

BackgroundFor the past several decades, the Ethiopian Ministry of Health has worked to decrease the maternal mortality ratio (MMR)—the number of pregnant women dying per 100,000 live births. However, with the most recently reported MMR of 267, Ethiopia still ranks high in the MMR globally and needs additional interventions to lower the MMR to achieve the sustainable development goal of 70. One factor contributing to the current MMR is the frequent stockouts of critical medications and supplies needed to treat obstetric emergencies. ObjectiveThis study describes the obstetric emergency supply chain (OESC) dynamics and information flow in Amhara, Ethiopia, as a crucial first step in closing stockouts and gaps in supply availability. MethodsApplying qualitative descriptive methodology, the research team performed 17 semistructured interviews with employees of the OESC at the federal, regional, and facility level to describe and gain an understanding of the system in the region, communication flow, and current barriers and facilitators to consistent emergency supply availability. The team performed inductive and deductive analysis and used the “Sociotechnical Model for Studying Health Information Technology in Complex Adaptive Healthcare Systems” to guide the deductive portion. ResultsThe interviews identified several locations within the OESC where barriers could be addressed to improve overall facility-level readiness, such as gaps in communication about supply needs and availability in health care facilities and regional supply hubs and a lack of data transparency at the facility level. Ordering supplies through the integrated pharmaceutical logistics system was a well-established process and a frequently noted strength. Furthermore, having inventory data in one place was a benefit to pharmacists and supply managers who would need to use the data to determine their historic consumption. The greatest concern related to the workflow and communication of the OESC was an inability to accurately forecast future supply needs. This is a critical issue because inaccurate forecasting can lead to undersupplying and stockouts or oversupplying and waste of medication due to expiration. ConclusionsAs a result of these interviews, we gained a nuanced understanding of the information needs for various levels of the health system to maintain a consistent supply of obstetric emergency resources and ultimately increase maternal survival. This study’s findings will inform future work to create customized strategies that increase supply availability in facilities and the region overall, specifically the development of electronic dashboards to increase data availability at the regional and facility levels. Without comprehensive and timely data about the OESC, facilities will continue to remain in the dark about their true readiness to manage basic obstetric emergencies, and the central Ethiopian Pharmaceutical Supply Service and regional hubs will not have the necessary information to provide essential emergency supplies prospectively before stockouts and maternal deaths occur.

New treatments are urgently required for triple-negative breast cancer (TNBC). As TP53 is mutated in approximately 80% of TNBC, it is theoretically an attractive target for new drugs for this disease. Arsenic trioxide (ATO), which is used to treat promyelocytic leukaemia, was recently shown to reactivate mutant p53 and restore wild-type functionality. The aim of this study was to evaluate ATO as a potential new treatment for TNBC. Using a panel of 20 cell lines, we found that TNBC cell lines were more sensitive to ATO than non-TNBC cell lines (P = 0.045). Consistent with its ability to reactivate mutant p53, ATO was a more potent inhibitor of proliferation in cell lines with mutant TP53 than the wildtype TP53 (P = 0.027). Direct evidence of mutant p53 reactivation was the induction of multiple wild-type p53 canonical target genes such as CDKN1A, SLC7A11, BBC3, PMAIP1, SESN2, SRXN1 and TXNRD1. Our findings support the activation of mutant p53 by ATO and, furthermore, the possible repurposing of ATO to treat TP53-mutated TNBC.

Background Barth syndrome is a rare, life-threatening X-linked recessive mitochondrial disorder of lipid metabolism primarily affecting males. Previous research suggests that bezafibrate may ameliorate cellular lipid abnormalities and reduce cardiac dysfunction in an animal model. Objectives Estimate the effect of bezafibrate on clinical, biochemical, and quality-of-life outcomes. Investigate whether within-participant clinical changes parallel in vitro changes in cardiolipin ratio/profile and mitochondrial morphology when each participant’s cells are cultured with bezafibrate. Investigate as for objective 2, culturing each participant’s cells with resveratrol. Describe the most feasible methods and standardised outcome measures to optimise the conduct of future trials and evaluations in Barth syndrome. Describe features of the research infrastructure which optimised recruitment, retention and communication with families and people with Barth syndrome. Describe the perceptions of participants and their families about the research and any important potential barriers to participation. Design Randomised, placebo-controlled, crossover trial of bezafibrate versus placebo. Setting NHS hospital providing UK-wide Barth Syndrome Service. Participants Males aged ≥ 6 years with a confirmed diagnosis of Barth syndrome with stable cardiac status, able to swallow tablets of bezafibrate/placebo. Exclusions were: hypersensitivity or allergy to bezafibrate or any component of bezafibrate; hepatic, liver or renal dysfunction; gallbladder disease; or recent deterioration in general health. Interventions Fifteen weeks of bezafibrate in one period and placebo in a second period, or vice versa (randomly allocated), with at least a 1-month washout between periods. Main outcome measures The primary outcome was peak VO2; secondary outcomes were cardiac function rest and exercise echocardiography and magnetic resonance imaging, cardiolipin ratio, quality of life, dynamic skeletal muscle P-magnetic resonance spectroscopy, mitochondrial studies and neutrophil counts, and adverse events. Outcomes were measured at baseline and the end of each period. Results Eleven males were studied; all attended all three assessments. There was no difference in peak VO2 between periods (0.66 ml/kg/min lower with bezafibrate than placebo, 95% confidence interval 2.34 to 1.03; p = 0.43). There was a trend towards a higher left ventricular ejection fraction with bezafibrate when measured by echocardiography but not magnetic resonance imaging, and better echocardiography-derived rest longitudinal and circumferential strain with bezafibrate. There was no difference in quality of life or cardiolipin ratio between periods. Skeletal muscle 31P magnetic resonance spectroscopy was performed cross-sectionally and showed a trend to higher Tau and lower Qmax indices in the bazafibrate group. Two participants had serious, expected adverse reactions when taking bezafibrate; otherwise, bezafibrate was well tolerated. Limitations The sample size was very small; the bezafibrate dose may have been too low or 15 weeks too short to observe an effect; measurements of mitochondrial content and membrane potential were highly variable; P-magnetic resonance spectroscopy was available only at the final assessment. Conclusions This study did not show significant improvement in the primary and secondary outcomes with bezafibrate treatment. Future work Elamipretide, studied in a small crossover trial in the USA, is another potential intervention which may be worth evaluating in an international study. Trial registration This trial is registered as ISRCTN58006579. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 12/205/56) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 13. See the NIHR Funding and Awards website for further award information. Plain language summary Barth syndrome is a rare genetic syndrome with mutations in the tafazzin gene causing long-term effects in several organ systems, leading to significant lifelong comorbidities and a reduced quality of life. Barth syndrome shows an X-linked inheritance, hence it is almost exclusively present in males. Tafazzin gene mutations impair overall cell energy metabolism, and affected individuals show compromise of the immune system with a high risk for life-threatening infections, as well as cardiac dysfunction and cardiomyopathy, muscle and general fatigue, and generally reduced mobility also leading to psychological challenges and dysfunction. Currently, specific medical therapies are limited to symptomatic treatment, and drug therapies targeting the causative mitochondrial energy disturbance are urgently needed. This randomised controlled trial explored the use of oral bezafibrate, a licensed drug that can improve cell energy metabolism. Eleven male patients received either bezafibrate or a placebo for 4 months. Exercise capacity by cardiopulmonary exercise testing on a cycle ergometer, as the primary outcome measurement, as well as cardiac function by echocardiography and magnetic resonance imaging, and cellular anatomy and function by in vitro assays and microscopy, were measured before and after this 4-month period. Bezafibrate did not significantly improve exercise capacity, cardiac function or the cellular metabolism, although several cardiac function parameters showed slight improvements with bezafibrate treatment. No significant adverse effects were recorded. The limitations of the trial were its low participant number and the relatively short duration of the drug treatment phase. The trial did prove that complex randomised controlled drug trials are feasible in people with rare diseases. Adherence was good, with parents reporting few difficulties with pill swallowing. The qualitative interviews also found that the study was acceptable to participants and the burden of participating not too onerous. We hope the research can provide a template for future studies. Scientific summary Introduction Barth syndrome is a very rare, life-threatening, X-linked recessive genetic disease almost exclusively affecting young males, caused by abnormal lipids in mitochondria. The tafazzin gene (TAZ) encodes tafazzin, a phospholipid acyltransferase. Tafazzin transfers unsaturated fatty acids with acyl chains from phospholipids to monolysocardiolipin (MLCL) and regulates remodelling and maturation of cardiolipin, a phospholipid located exclusively in the inner mitochondrial membrane. Mature tetralinoleoyl-cardiolipin (L4-CL) is essential in the mitochondrial membrane for maintaining mitochondrial membrane potential, structural integrity of electron transport chain complexes and mitochondrial cristae architecture. Cardiolipin is a major constituent of inner mitochondrial membranes, and the major effects of the aberrant gene are on muscular tissues. Cardiac and skeletal manifestations of Barth syndrome are thought to result from impaired formation of respiratory chain super-complexes. TAZ mutations decrease L4-CL and increase intermediate species of MLCL, resulting in a marked increase in the MLCL : L4-CL ratio, which provides a highly sensitive and specific biochemical test for Barth syndrome. Barth syndrome is characterised by many gene mutations and profound phenotypic variability between affected patients within families and those in different families. The disease carries many risks and problems for its sufferers, as well as major healthcare costs. Almost one-third (30%) of living UK patients have undergone cardiac transplantation. Several patients who have died due to cardiac rejection or post-transplant lymphoproliferative disease had previously undergone cardiac transplantation. Other patients who have died deteriorated too fast to undergo transplantation or died of complications while awaiting transplantation. Neutropenia is another life-threatening issue. Two-thirds of UK patients are treated with granulocyte colony-stimulating factor by subcutaneous injection. Managing neutropenia in this disease is challenging, since patients have highly variable neutrophil counts, which prevents administration of a consistent daily dose and requires repeated blood counts and physician oversight. Exercise intolerance, lethargy and fatigue are universal, interfering with daily life, schoolwork and play and often necessitating use of a wheelchair. Patients cannot perform strenuous or demanding jobs. Many have major feeding problems from infancy through to adult life; for example, requiring feeding via gastrostomies. There can be rapid deterioration during periods of stable health despite expert medical care. Ventricular arrhythmia (tachycardia or fibrillation) affects 10% of adolescents and can cause sudden cardiac death at any time. There are no specific treatments for Barth syndrome. There is no evidence that standard medications for cardiomyopathy ameliorate long-term poor outcomes. Treatment is multidisciplinary and currently limited to treating intercurrent bacterial infections, bone marrow support, physiotherapy, nutritional support, management of heart failure and arrhythmia, and consideration for heart transplantation. Experiments using lymphoblasts from patients with Barth syndrome show that either bezafibrate or resveratrol can partially normalise the deranged cardiolipin ratio. This may be important, since some patients with Barth syndrome who lack neutropenia and tend to have good exercise tolerance have cardiolipin ratios intermediate between those of typical patients and normal individuals. Bezafibrate also improved left ventricular function and showed other benefits at supraphysiological doses in a TAZ knockdown mouse model. This trial was motivated by the need for disease-specific therapy to prevent morbidity, mortality, psychological distress, and disruption of quality of life (QoL) in affected patients and their families. An effective therapy also has the potential to generate savings for the NHS. Bezafibrate is a lipid-lowering drug used in adults and children, with a good safety record in long-term use. These characteristics made it a candidate for investigation. Bezafibrate has been reported to significantly ameliorate a mitochondrial myopathy in adults and shown promising results in several animal/human cellular models of mitochondrial disease. Several of the laboratory assays and clinical investigations proposed in this study were also considered potentially important beyond the scope of this specific study, to assess associations between genotype and phenotype and for future evaluations of therapies in Barth syndrome. Objectives Estimate the effect on clinical, biochemical and QoL outcome measures of bezafibrate compared to placebo. Investigate whether clinical improvements parallel in vitro changes in cardiolipin ratio and mitochondrial morphology in each participant’s cells when cultured with bezafibrate. Investigate whether clinical improvements and culture findings with bezafibrate parallel in vitro changes in each participant’s cells when exposed to resveratrol in laboratory culture. Describe the most feasible methods and standardised outcome measures for future trials. Describe features of the research infrastructure which optimised recruitment, retention and communication with participants and families. Describe participants’ and their families’ perceptions of research and important potential barriers to participation. Methods Study design and participants CARDIOlipin MANipulation trial (CARDIOMAN) was a double-blind, placebo-controlled crossover randomised trial. Treatment was given in two 15-week periods with a minimum of 1 month’s washout period between these when no treatment was given. Twenty-six males and one female with the disease were alive in the UK when the trial was designed. Males aged ≥ 6 years in the UK diagnosed with Barth syndrome were eligible. Exclusion criteria were: hypersensitivity to bezafibrate or component of the investigational medicinal product (IMP), photoallergic or phototoxic reaction to fibrate, unstable cardiac condition, cardiac chamber shortening fraction < 25% or significant decrease in shortening fraction in the preceding year, atrial or ventricular arrhythmia not stabilised by treatment, inability to swallow the IMP, hepatic dysfunction, renal impairment (creatinine clearance < 90 ml/min), gallbladder disease, recent unspecified significant deterioration in general health, prisoners and adults lacking capacity to provide informed consent. Randomisation and masking Participants were randomised to receive either bezafibrate then placebo, or the reverse order. Allocations were generated in advance by the Bristol Trials Centre and provided to the trial pharmacy which dispensed the IMP. All investigators, members of the research team (apart from pharmacy) and participants remained blind to treatment allocation. Intervention and procedures The intervention IMP was bezafibrate taken orally as 100-mg tablets. Children aged 6–9 years started on 100 mg once daily for the first 4 weeks and, if well tolerated, increased to 100 mg twice daily for the remaining 11 weeks. Children aged 10–17 years started on 200 mg once daily for the first 4 weeks and, if well tolerated, increased to 200 mg twice daily for the remaining 11 weeks. Adults (≥ 18 years) took 200 mg twice daily throughout. The comparator IMP was placebo taken orally as visually identical tablets and manufactured to be as similar as possible in taste and smell to the intervention. The IMP was prescribed at the start of the first period and again at the end of the first period for the second period. Outcomes All in vivo outcomes except magnetic resonance spectroscopy (MRS) were assessed three times: at baseline and in the final week of each treatment phase. The primary outcome measure was peak oxygen consumption on bicycle ergometry [peak volume of oxygen (VO2)]. Secondary outcomes were: MLCL/L4-CL ratio and cardiolipin profile in blood cells; phosphocreatine (PCr)/adenosine 5’ triphosphate (ATP) ratio in cardiac muscle on 31P MRS; skeletal muscle oxidative function/on 31P MRS; QoL [age-appropriate Pediatric Quality of Life Inventory (PedsQLTM) questionnaires]; absolute neutrophil count; amino acid expression (serum arginine and cysteine); cardiac function [left and right ventricular function: left ventricular ejection fraction (LVEF%), right ventricular ejection fraction (RVEF%); and 2-D longitudinal and circumferential strain at rest, peak exercise and after recovery]; mitochondrial size and number in lymphocytes; mitochondrial area in lymphocytes and as a proportion of cytoplasm area; mitochondrial function and cristae organisation in lymphocytes/neutrophils; arrhythmia profile from 12-lead electrocardiogram at rest and during exercise. Qualitative research methods explored participants’ and families’ experiences of the different interventions. Adverse events Serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from participants from the time of consent until 1 month after the final period. Participants’ general practitioners were asked to inform the research team of suspected AEs. Participants were asked questions about SAEs/AEs at each research clinic visit and in monthly phone calls, including during the washout period. SAEs were reviewed by the Chief Investigator, who decided whether the SAE was related to bezafibrate. Statistical analysis A total of 20 males aged ≥ 6 years were potentially eligible. The sample size was dictated by the number of eligible boys willing to take part. The primary analysis estimated the difference in mean peak VO2 between placebo and bezafibrate periods (two-tailed 5% significance level). A sample size of 12 participants allowed the trial to detect a difference of 0.90 (within subject) standard deviations with 80% power. The statistical analysis plan (SAP) prespecified that all analyses should be conducted according to the intention-to-treat (ITT) principle. The ITT population comprised all participants and periods, according to the randomised allocations. The safety population comprised all randomised participants, according to the treatment received in each period, who received at least one dose of IMP. All statistical tests were two-sided and used a 5% significance level, except for interactions that used a 10% significance level. Treatment effects were estimated with 95% confidence intervals (CIs). No formal adjustment was made for multiple testing. The treatment effect for the primary outcome was analysed using mixed linear regression models, adjusting for period (fixed effect; exploring interactions where necessary) and participants (random effects). Model assumptions were tested using standard methods, and the carry-over effect was estimated by including treatment order. Treatment effects for continuously scaled secondary outcomes (prespecified in the SAP) were estimated and tested using the same methods. Results There was no statistically significant difference between bezafibrate and placebo in peak VO2, which was 0.66 ml/kg/min lower (95% CI −2.34 to 1.03; p = 0.43) with bezafibrate. There was a borderline statistically significant increase in LVEF% using echocardiography (3.72%, 95% CI −0.26% to 7.69%; p = 0.065) but no evidence of a difference when using magnetic resonance imaging (MRI) (0.15%, 95% CI −3.21% to 3.51%; p = 0.926). There was also no difference for RVEF% between bezafibrate and placebo (0.32, 95% CI −2.32 to 2.96; p = 0.801). Longitudinal and circumferential strain at rest were better (lower) with bezafibrate than with placebo; differences were –1.67 (95% CI −3.11 to −0.22; p = 0.026) and −2.72 (95% CI −5.03 to −0.40; p = 0.024) respectively. There was no difference in diastolic ratio at rest between bezafibrate and placebo, and no differences in strain or diastolic ratio at peak exercise or after 2 minutes’ recovery. All participants had sinus rhythm at rest and during exercise for all three time points. Magnetic resonance spectroscopy was only performed after the second period for 10 participants. PCr/ATP ratio in cardiac muscle was not collected. Cross-sectionally (five vs. five participants), MRS appeared to increase Tau and reduce Qmax parameters with bezafibrate compared to placebo. Monolysocardiolipin/L4-CL ratio did not differ between bezafibrate and placebo but deteriorated in the second period (20% higher, 95% CI 3% to 40%; p = 0.024). Neutrophil count also showed no difference between bezafibrate and placebo but increased in the second period (2.26, 95% CI 0.08 to 4.45; p = 0.043). Plasma cysteine increased with bezafibrate (32% higher, 95% CI 8% to 62%; p = 0.001) but plasma arginine did not (25% higher, 95% CI −10% to 72%; p = 0.180). Mitochondrial outcomes on blood samples did not show marked differences and were not formally compared. Quality-of-life scores were transformed to a 0–100 scale (higher being better). Bezafibrate had no effect on core (−3.41, 95% CI −8.67 to 1.86; p = 0.192) or fatigue (1.71, 95% CI −6.28 to 9.71; p = 0.659) QoL scores. Emerging themes identified in qualitative interviews were classified as overarching, related to lived experience with Barth syndrome, and trial participation and conduct. Participants and families were pleased to take part in the trial, viewing participation as ‘giving back’ to the medical community. No participant withdrew, and the trial was not perceived to be too onerous for families. Participating in the research gave both individuals and families a sense of responsibility for their condition, partly driven by appreciation for the Barth Syndrome Service and staff expertise. Monolysocardiolipin/L4-CL ratio in vitro was estimated from samples of cells incubated with control, bezafibrate or resveratrol. Each drug reduced the MLCL/L4-CL ratio, largely by increasing intermediate cardiolipin species, and more so with resveratrol than with bezafibrate. Ratios were nevertheless profoundly abnormal in comparison to patients with intermediate Barth phenotypes. Discussion Main findings: study results There was no clinically important or statistically significant improvement in peak VO2 with bezafibrate compared to placebo. There were inconsistent findings for LVEF% by method of measurement; echocardiography showed a borderline improvement that cardiac MRI did not demonstrate. Longitudinal and circumferential strain measurements were better at rest with bezafibrate, but not at peak exercise. There were no clinically important or statistically significant improvements in core or fatigue QoL domains. Plasma cysteine was significantly improved with bezafibrate treatment. Plasma arginine also increased but not significantly. Neutrophil count was unaffected and there was no significant change in cardiolipin ratio in participants’ blood with bezafibrate. There were no significant period effects except for MLCL/L4-CL ratio and neutrophil count, both increased in the second period. In vitro incubation of Epstein–Barr virus-transformed patient lymphoblasts with either bezafibrate or resveratrol resulted in improved MLCL/L4-CL ratios, an effect that was more profound with resveratrol. Treatment with this drug also resulted in a more obvious increase in intermediate MLCL species. Strengths and limitations Strengths of the trial are: randomisation and placebo blinding; crossover design; excellent retention; completeness of the data, good adherence and IMP tolerance. There were several limitations. The sample size (outside our control) was very small, and interpretation of effects for many secondary outcomes was challenging. Longer treatment duration or a higher bezafibrate dose might have produced better outcomes. Bezafibrate may have induced adverse reactions in some participants, inadvertently causing unblinding. The group of participants randomised to receive bezafibrate first was older than the group randomised to the opposite order, which may explain period effects. The electron microscopic and mitochondrial assessments proved problematic and were not completed in vitro. Measurements of mitochondrial content and membrane potential were highly variable. Amino acid levels were not assayed after fasting. Echocardiography images during exercise testing were often suboptimal. Lessons for the future Magnetic resonance spectroscopy in children is still exploratory, and protocols need to be better validated, but it is considered very promising as a potential objective functional outcome. Cardiolipin profile is not a good outcome for research, although it is appropriate for diagnosis because the Barth cardiolipin profile is so extremely different from a normal profile. Electron microscopy measurements of mitochondria should not be considered as outcomes in future trials. Peak VO2 should be the preferred current primary outcome because it is resistant to bias compared to other functional outcomes. Conclusion The trial did not show a significant treatment effect for the primary outcome, peak VO2. Some secondary outcomes such as systolic function measured by echocardiography and amino acid levels provided some evidence of benefit. The trial provided insights about trial methods and conduct in the context of a very rare paediatric disease that should inform future studies. Trial registration This trial is registered as ISRCTN58006579. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 12/205/56) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 13. See the NIHR Funding and Awards website for further award information.

Hamstring strain injuries are one of the most common non-contact injuries in sport. Hamstring strength and asymmetry are two key modifiable risk factors for hamstring strain injuries; therefore, it seems important to find reliable tests for assessing hamstring strength. The purpose of this study was to determine the within- and between-session reliability of a portable fixed dynamometer for measuring hamstring strength using three different protocols. Fourteen male participants completed three hamstring isometric protocols across three testing occasions separated by seven days. Peak force, mean force and impulse all had good to excellent within- and between-session reliability for the standing hamstring, supine 90:90 and standing 90:20 assessment (CV = 2.6–11.7%, ICC = 0.74–0.99), while peak rate of force development had moderate to excellent relative consistency (ICC = 0.64–0.90) and unacceptable absolute consistency (CV = 17.1–36.6%). The 90:20 assessment produced significantly higher values (33.4–47.3%) compared to the standing and 90:90 assessments for peak force, mean force and impulse. It appears that a portable fixed dynamometer can reliably measure a range of force–time metrics during three different hamstring assessments; however, the results of the tests cannot be used interchangeably and practitioners comparing hamstring force capability between individuals/research studies need to be cognizant of this and proceed with caution.

Abstract We investigate the underlying assumptions and limits of applicability of several documented models for outbreaks of airborne disease inside buildings by showing how they may each be regarded as special cases of a system of equations which combines quanta conservation and compartmental epidemiological modelling. We investigate the behaviour of this system analytically, gaining insight to its behaviour at large time. We then investigate the characteristic timescales of an indoor outbreak, showing how the dilution rate of the space, and the quanta generation rate, incubation rate and removal rate associated with the illness may be used to predict the evolution of an outbreak over time, and may also be used to predict the relative performances of other indoor airborne outbreak models. The model is compared to a more commonly used model, in which it is assumed the environmental concentration of infectious aerosols adheres to a quasi-steady-state, so that the the dimensionless quanta concentration is equal to the the infectious fraction. The model presented here is shown to approach this limit exponentially to within an interval defined by the incubation and removal rates. This may be used to predict the maximum extent to which a case will deviate from the quasi steady state condition.

Abstract This work evaluates glacial dust as a source of sediment, and associated iron (Fe), to the Fe‐limited Gulf of Alaska (GoA). A reanalysis of GoA sediment data, using rare earth elements and thorium as provenance tracers, suggests a flux to the ocean surface of Copper River (AK) glacial dust, and associated Fe, that is comparable to the flux of dust from Asia, at least 1,000 km from the narrow mountain valley glacial dust source area. This work suggests dust from Asia may not be the largest source of Fe to the GoA. Dust models fail to accurately simulate this glacial dust transport because their coarse resolution underestimates wind speeds, and the dust flux. This work suggests that glacial dust fluxes may have been important in the geologic past (e.g., the last glacial maximum) from locations where there was more extensive coverage by glaciers than at present.

Abstract Alzheimer's disease is a complex and progressive condition that affects essential neurological functions such as memory and reasoning. In the brain, neuronal loss, synaptic dysfunction, proteinopathy, neurofibrillary tangles, and neuroinflammation are the hallmarks of Alzheimer's disease pathophysiology. In addition, recent evidence has highlighted that microbes, whether commensal or pathogenic, also have the ability to interact with their host and to regulate its immune system, therefore participating in the exchanges that lead to peripheral inflammation and neuropathology. Because of this intimate relationship, bacteria, viruses, fungi, and protozoa have been implicated in the development of Alzheimer's disease. Here, we bring together current and most recent evidence of the role of microbes in Alzheimer's disease, raising burning questions that need to be addressed to guide therapeutic approaches and potential prophylactic strategies.

Background: Immune checkpoint inhibitors (ICIs) have significantly improved outcomes in various cancers. ICI treatment is associated with the incidence of immune-related adverse events (irAEs) which can affect any organ. Data on irAEs occurrence in relation to sex- differentiation and their association with gender-specific factors are limited. Aims: The primary objective of the G-DEFINER study is to compare the irAEs incidence in female and male patients who undergo ICI treatment. Secondary objectives are: to compare the irAEs incidence in pre- and postmenopausal female patients; to compare the irAEs incidence in female and male patients according to different clinical and gender-related factors (lifestyle, psychosocial, and behavioral factors). Exploratory objectives of the study are to compare and contrast hormonal, gene-expression, SNPs, cytokines, and gut microbiota profiles in relation to irAEs incidence in female and male patients. Methods and Results: The patients are recruited from Fondazione IRCCS Istituto Nazionale dei Tumori, Italy, St Vincent’s University Hospital, Ireland, Oslo University Hospital, Norway, and Karolinska Insitutet/Karolinska University Hospital, Sweden. The inclusion of patients was delayed due to the Covid pandemic, leading to a total of 250 patients recruited versus a planned number of 400 patients. Clinical and translational data will be analyzed. Interpretation: The expected outcomes are to improve the management of cancer patients treated with ICIs, leading to more personalized clinical approaches that consider potential toxicity profiles. The real world nature of the trial makes it highly applicable for timely irAEs diagnosis.

Abstract HER2-positive (HER2+) breast cancer accounts for 20–25% of all breast cancers. Predictive biomarkers of neoadjuvant therapy response are needed to better identify patients with early stage disease who may benefit from tailored treatments in the adjuvant setting. As part of the TCHL phase-II clinical trial (ICORG10–05/NCT01485926) whole exome DNA sequencing was carried out on normal-tumour pairs collected from 22 patients. Here we report predictive modelling of neoadjuvant therapy response using clinicopathological and genomic features of pre-treatment tumour biopsies identified age, estrogen receptor (ER) status and level of immune cell infiltration may together be important for predicting response. Clonal evolution analysis of longitudinally collected tumour samples show subclonal diversity and dynamics are evident with potential therapy resistant subclones detected. The sources of greater pre-treatment immunogenicity associated with a pathological complete response is largely unexplored in HER2+ tumours. However, here we point to the possibility of APOBEC associated mutagenesis, specifically in the ER-neg/HER2+ subtype as a potential mediator of this immunogenic phenotype.

Mudrocks are fine-grained clay-rich rocks that comprise different lithotypes forming more than 60% of all sedimentary rocks, and thus, they occur frequently in engineering projects either as natural ground or as made ground. These rocks may display a range of engineering behaviours controlled mostly by their composition and structural features. Due to rapid breakdown and susceptibility to volume changes, they may cause problems both during and after construction. Research into the susceptibility of mudrocks to breakdown aims to predict problematic behaviour and provide guidance for avoiding or mitigating these effects. Low-durability materials that disintegrate during sampling and testing can be especially difficult to assess. The paper reviews laboratory techniques for mudrock characterization as well as describes geological and engineering geological classification schemes generally used to describe and classify these materials. The value of some of the tests and determinations in the evaluation of a series of mudrock data taken from the literature is presented.

Abstract Background Monitoring the behavior of wild animals in situ can improve our understanding of how their behavior is related to their habitat and affected by disturbances and changes in their environment. Moose (Alces alces) are keystone species in their boreal habitats, where they are facing environmental changes and disturbances from human activities. How these potential stressors can impact individuals and populations is unclear, in part due to our limited knowledge of the physiology and behavior of moose and how individuals can compensate for stress and disturbances they experience. We collected data from collar-mounted fine-scale tri-axial accelerometers deployed on captive moose in combination with detailed behavioral observations to train a random forest supervised classification algorithm to classify moose accelerometer data into discrete behaviors. To investigate the generalizability of our model to collared new individuals, we quantified the variation in classification performance among individuals. Results Our machine learning model successfully classified 3-s accelerometer data intervals from 12 Alaskan moose (A. a. gigas) and two European moose (A. a. alces) into seven behaviors comprising 97.6% of the 395 h of behavioral observations conducted in summer, fall and spring. Classification performance varied among behaviors and individuals and was generally dependent on sample size. Classification performance was highest for the most common behaviors lying with the head elevated, ruminating and foraging (precision and recall across all individuals between 0.74 and 0.90) comprising 79% of our data, and lower and more variable among individuals for the four less common behaviors lying with head down or tucked, standing, walking and running (precision and recall across all individuals between 0.28 and 0.79) comprising 21% of our data. Conclusions We demonstrate the use of animal-borne accelerometer data to distinguish among seven main behaviors of captive moose and discuss generalizability of the results to individuals in the wild. Our results can support future efforts to investigate the detailed behavior of collared wild moose, for example in the context of disturbance responses, time budgets and behavior-specific habitat selection.

Abstract The reduced prevalence of insulin resistance and type 2 diabetes in countries with endemic parasitic worm infections suggests a protective role for worms against metabolic disorders, however clinical evidence has been non-existent. This 2-year randomised, double-blinded clinical trial in Australia of hookworm infection in 40 male and female adults at risk of type 2 diabetes assessed the safety and potential metabolic benefits of treatment with either 20 (n = 14) or 40 (n = 13) Necator americanus larvae (L3) or Placebo (n = 13) (Registration ACTRN12617000818336). Primary outcome was safety defined by adverse events and completion rate. Homoeostatic model assessment of insulin resistance, fasting blood glucose and body mass were key secondary outcomes. Adverse events were more frequent in hookworm-treated participants, where 44% experienced expected gastrointestinal symptoms, but completion rates were comparable to Placebo. Fasting glucose and insulin resistance were lowered in both hookworm-treated groups at 1 year, and body mass was reduced after L3-20 treatment at 2 years. This study suggests hookworm infection is safe in people at risk of type 2 diabetes and associated with improved insulin resistance, warranting further exploration of the benefits of hookworms on metabolic health.

# Background Isokinetic dynamometers are widely used when assessing neuromuscular function including knee extension kinetics. However, these dynamometers are often prohibitively expensive and are not portable. Thus strain-gauge technology has grown in popularity. # Purpose The purpose of this study was to compare kinetic data captured via an isokinetic dynamometer against an affordable and portable strain-gauge with a treatment plinth during maximal isometric knee extensions. # Study Design Cross-sectional study. # Methods Healthy participants (8 males and 6 females; age 30.2±7.1 years) volunteered and performed knee extensions at a 90° knee angle on a dynamometer and a treatment plinth with a portable strain-gauge. Peak force (PF), peak rate of force development (PRFD), rate of force development (RFD~2080~) and impulse (IMP~2080~) from 20-80% of onset to peak force were assessed using both strain-gauge and isokinetic dynamometer. Between-device differences were evaluated by the Wilcoxon signed-rank test, Cohen's *d* effect sizes (ES), Pearson's correlation coefficients (*r*), and Bland-Altman plots. # Results No significant or meaningful differences were identified between isokinetic and strain-gauge devices (all *p*≥0.268, ES≤0.35). However, slightly greater (2.5-9.5%) outputs were observed with the isokinetic dynamometer. Very large significant between-device correlations were found for PF (*r*=0.77, *p*=0.001) and PRFD (*r*=0.73, *p*=0.003), while small and moderate non-significant between-device correlations were found for RFD~2080~ (*r*=0.48, *p*=0.079) and IMP~2080~ (*r*=0.59, *p*=0.060). Bland-Altman plots did not reveal apparent biases from high to low performers. # Conclusions These results indicate that the strain-gauge device can produce valid maximal and rapid force expression measurements. Similar results, such as those quantified via an isokinetic device, can be obtained without extreme rigour and constraint. The study's findings support using the practically relevant treatment plinth and strain-gauge combination as a suitable alternative to the isokinetic dynamometry for measuring PF and PRFD. Therefore, more rehabilitation and sports performance practitioners can confidently assess knee extension kinetics. # Level of Evidence 3

Background The gut microbiota has been extensively implicated in health and disease. The functional outputs of the gut microbiota, such as microbial metabolites, are considered particularly important in this regard. Significant associations exist between alterations in the relative abundance of specific microbial taxa and mental health disorders. Dietary fiber has the potential to alter gut microbiota composition and function, modifying bacterial enzymatic function and the production of metabolites. As many taxa of microorganisms have enzymes capable of producing or degrading neurochemicals i.e. neuroactive gut brain modules, new predictive tools can be applied to existing datasets such as those harvested from dietary fiber interventions. We endeavor to perform a systematic review in order to identify studies reporting compositional gut microbiota alterations after interventions with dietary fiber in healthy individuals. We aim to also extract from the selected studies publicly available microbial genomic sequence datasets for reanalysis with a consistent bioinformatics pipeline, with the ultimate intention of identifying altered gut brain modules following dietary fiber interventions. Methods Interventional trials and randomized controlled studies that are originally published, including cross-over and non-crossover design and involving healthy adult humans will be included. A systematic search of PubMed/MEDLINE and EMBASE, two electronic databases, will be completed. Discussion Various types of dietary fiber have an impact on the gut microbiota composition, with some promoting the growth of particular taxa while others are reduced in relative abundance. Our search focuses on the impact of this food component on the microbiota of healthy individuals. Compositional gut microbial changes have been reported and our review will compile and update these observations after reanalysis of their datasets with a consistent bioinformatic pipeline. From this it may be possible to predict more detailed functional consequences in terms of neuroactive gut brain modules, of the compositional alterations in gut microbial taxa.

Introduction: Poststroke cognitive impairment is common, but the trajectory and magnitude of cognitive change after stroke are unclear. We aimed to measure changes in the trajectory of cognitive function following a first stroke, controlling for pre-stroke cognitive performance using diverse population-based studies from the Cohort Studies of Memory in an International Consortium (COSMIC). Methods: Fourteen longitudinal cohorts from 11 countries from Asia, Africa, North America, South America, Europe, and Australia contributed data. Cognitive domain scores were formed by selecting the most common test administered amongst studies in each domain (memory, processing speed, language, and executive function) and the scores standardised; global cognition was the standardised average of the 4 domains and the primary outcome. One-stage IPD meta- analysis with linear mixed model and regression discontinuity design was used to model the change in cognitive function. Time-dependent incident stroke, age, time in study, and time since stroke were included in the basic model. In the full model we adjusted for sex, education, ethno- racial group, study period and potential confounders significant in the basic model at p

Abstract Background Although there are already success stories, population health management in Belgium is still in its infancy. A health system transformation approach such as population health management may be suited to address the public health issue of atherosclerotic cardiovascular disease, as this is one of the main causes of mortality in Belgium. This article aims to raise awareness about population health management in Belgium by: (a) eliciting barriers and recommendations for its implementation as perceived by local stakeholders; (b) developing a population health management approach to secondary prevention of atherosclerotic cardiovascular disease; and (c) providing a roadmap to introduce population health management in Belgium. Methods Two virtual focus group discussions were organized with 11 high-level decision makers in medicine, policy and science between October and December 2021. A semi-structured guide based on a literature review was used to anchor discussions. These qualitative data were studied by means of an inductive thematic analysis. Results Seven inter-related barriers and recommendations towards the development of population health management in Belgium were identified. These related to responsibilities of different layers of government, shared responsibility for the health of the population, a learning health system, payment models, data and knowledge infrastructure, collaborative relationships and community involvement. The introduction of a population health management approach to secondary prevention of atherosclerotic cardiovascular disease may act as a proof-of-concept with a view to roll out population health management in Belgium. Conclusions There is a need to instill a sense of urgency among all stakeholders to develop a joint population-oriented vision in Belgium. This call-to-action requires the support and active involvement of all Belgian stakeholders, both at the national and regional level.

Sex trafficking victims are often advertised through online escort sites. These ads can be publicly accessed, but law enforcement lacks the resources to comb through hundreds of ads to identify those that may feature sex-trafficked individuals. The purpose of this study was to implement and test multi-input, deep learning (DL) binary classification models to predict the probability of an online escort ad being associated with sex trafficking (ST) activity and aid in the detection and investigation of ST. Data from 12,350 scraped and classified ads were split into training and test sets (80% and 20%, respectively). Multi-input models that included recurrent neural networks (RNN) for text classification, convolutional neural networks (CNN, specifically EfficientNetB6 or ENET) for image/emoji classification, and neural networks (NN) for feature classification were trained and used to classify the 20% test set. The best-performing DL model included text and imagery inputs, resulting in an accuracy of 0.82 and an F1 score of 0.70. More importantly, the best classifier (RNN + ENET) correctly identified 14 of 14 sites that had classification probability estimates of 0.845 or greater (1.0 precision); precision was 96% for the multi-input model (NN + RNN + ENET) when only the ads associated with the highest positive classification probabilities (>0.90) were considered (n = 202 ads). The models developed could be productionalized and piloted with criminal investigators, as they could potentially increase their efficiency in identifying potential ST victims.

TiO2 has demonstrated outstanding performance in electrochemical advanced oxidation processes (EAOPs) due to its structural stability and high oxygen overpotential. However, there is still much room for improving its electrochemical activity. Herein, narrow bandgap manganese oxide (MnOx) was composited with TiO2 nanotube arrays (TiO2 NTAs) that in-situ oxidized on porous Ti sponge, forming the MnOx-TiO2 NTAs anode. XANES and XPS analysis further proved that the composition of MnOx is Mn2O3. Electrochemical characterizations revealed that increasing the composited concentration of MnOx can improve the conductivity and reduce oxygen evolution potential so as to improve the electrochemical activity of the composited MnOx-TiO2 NTAs anode. Meanwhile, the optimal degradation rate of benzoic acid (BA) was achieved using MnOx-TiO2 NTAs with a MnOx concentration of 0.1 mmol L−1, and the role of MnOx was proposed based on DFT calculation. Additionally, the required electrical energy (EE/O) to destroy BA was optimized by varying the composited concentration of MnOx and the degradation voltage. These quantitative results are of great significance for the design and application of high-performance materials for EAOPs.

Abstract Ependymoma is a tumor of the brain or spinal cord. The two most common and aggressive molecular groups of ependymoma are the supratentorial ZFTA-fusion associated and the posterior fossa ependymoma group A. In both groups, tumors occur mainly in young children and frequently recur after treatment. Although molecular mechanisms underlying these diseases have recently been uncovered, they remain difficult to target and innovative therapeutic approaches are urgently needed. Here, we use genome-wide chromosome conformation capture (Hi-C), complemented with CTCF and H3K27ac ChIP-seq, as well as gene expression and DNA methylation analysis in primary and relapsed ependymoma tumors, to identify chromosomal conformations and regulatory mechanisms associated with aberrant gene expression. In particular, we observe the formation of new topologically associating domains (‘neo-TADs’) caused by structural variants, group-specific 3D chromatin loops, and the replacement of CTCF insulators by DNA hyper-methylation. Through inhibition experiments, we validate that genes implicated by these 3D genome conformations are essential for the survival of patient-derived ependymoma models in a group-specific manner. Thus, this study extends our ability to reveal tumor-dependency genes by 3D genome conformations even in tumors that lack targetable genetic alterations.

Clustered outbreaks of multi-drug resistant (MDR) Shigella are on the rise among men who have sex with men (MSM). Identification of MDR sub-lineages is critical for clinical management and public health interventions. Here, we describe a novel MDR sub-lineage of Shigella flexneri isolated from an MSM patient without a travel history in Southern California. Detailed genomic characterization of this novel strain would serve as a reference to aid monitoring and future outbreak investigation of MDR Shigella among MSM.

Human induced pluripotent stem cell (hiPSC)-derived kidney organoids have prospective applications ranging from basic disease modelling to personalised medicine. However, there remains a necessity to refine the biophysical and biochemical parameters that govern kidney organoid formation. Differentiation within fully-controllable and physiologically relevant 3D growth environments will be critical to improving organoid reproducibility and maturation. Here, we matured hiPSC-derived kidney organoids within fully synthetic self-assembling peptide hydrogels (SAPHs) of variable stiffness (storage modulus, G′). The resulting organoids contained complex structures comparable to those differentiated within the animal-derived matrix, Matrigel. Single-cell RNA sequencing (scRNA-seq) was then used to compare organoids matured within SAPHs to those grown within Matrigel or at the air-liquid interface. A total of 13,179 cells were analysed, revealing 14 distinct clusters. Organoid compositional analysis revealed a larger proportion of nephron cell types within Transwell-derived organoids, while SAPH-derived organoids were enriched for stromal-associated cell populations. Notably, differentiation within a higher G’ SAPH generated podocytes with more mature gene expression profiles. Additionally, maturation within a 3D microenvironment significantly reduced the derivation of off-target cell types, which are a known limitation of current kidney organoid protocols. This work demonstrates the utility of synthetic peptide-based hydrogels with a defined stiffness, as a minimally complex microenvironment for the selected differentiation of kidney organoids.

Activated red mud (RM) has been proved to be a promising base material for the selective catalysis reduction (SCR) of NOx. The inherent low reducibility and acidity limited its low–temperature activity. In this work, molybdenum oxide, tungsten oxide, and cerium oxide were used to reconfigure the redox sites and acid sites of red mud based catalyst. When activated red mud was reconfigured by cerium-tungsten oxide (Ce–W@RM), the NOx conversion kept above 90% at 219–480 °C. The existence of Ce3+/Ce4+ redox electron pairs provided more surface adsorbed oxygen (Oα) and served as a redox cycle. Positive interactions between Ce, W species and Fe oxide in red mud occurred, which led to the formation of unsaturated chemical bond and promoted the activation of adsorbed NH3 species. WO3 and Ce2(WO4)3 (formed by solid–state reaction between Ce and W species) could provide more Brønsted acid sites (W–O modes of WO3, WO or W–O–W modes of Ce2(WO4)3). CeO2 species could provide more Lewis acid sites. The Langmuir–Hinshelwood (L-H) routes and Eley-Rideal (E-R) routes occurred in the low-temperature SCR reaction on the Ce–W@RM surface. NH4+ species on Brønsted acid sites, NH3 species on Lewis acid sites, bidentate nitrate and bridging nitrate species were key active intermediates species.

No abstract available.

Lacticaseibacillus paracasei Lpc-37 (Lpc-37) has previously shown to reduce perceived stress in healthy adults. The ChillEx study investigated whether Lpc-37 reduces stress in a model of chronic examination stress in healthy students. One hundred ninety university students (18–40 y) were randomized to take 1.56 × 1010 colony-forming units of Lpc-37 or placebo (1:1) each day for 10 weeks, in a triple-blind, parallel, multicenter clinical trial consisting of six visits: two screening visits, a baseline visit, and visits at 4, 8, and 10 weeks after baseline. The primary objective was to demonstrate that Lpc-37 reduces stress, as measured by the change in state anxiety from baseline to just before the first examination, after 8 weeks using the State Trait Anxiety Inventory (STAI-state). Secondary objectives aimed to demonstrate that Lpc-37 modulates psychological stress-induced symptoms and biomarkers related to mood and sleep. An exploratory analysis of fecal microbiota composition was also conducted. There was no difference between Lpc-37 and placebo groups in the change of STAI-state score (estimate 1.03; 95% confidence interval [CI]: -1.62, 3.67; p = 0.446). None of the secondary outcomes resulted in significant results when corrected for multiplicity, but exploratory results were notable. Results showed an improvement in sleep-disturbance scores (odds ratio 0.30; 95% CI: 0.11, 0.82; p = 0.020) and reduction in duration of sleep (odds ratio 3.52; 95% CI: 1.46, 8.54; p = 0.005) on the Pittsburgh Sleep Quality Index questionnaire after 8 weeks in the Lpc-37 group compared to placebo. A reduction in Bond Lader VAS-alertness was also demonstrated in the Lpc-37 group compared to placebo (estimate −3.97; 95% CI: -7.78, −0.15; p = 0.042) just prior to the examination. Analysis of fecal microbiota found no differences between study groups for alpha and beta diversity or microbiota abundance. Adverse events were similar between groups. Vital signs, safety-related laboratory measures, and gastrointestinal parameters were stable during the trial. In conclusion, probiotic Lpc-37 was safe but had no effect on stress, mood, or anxiety in healthy university students in this model of chronic academic stress. ClinicalTrials.gov: NCT04125810.

Abstract Background and Aims There is a need for high utility and portability, and cost‐effective technologies that are suitable for assessing dual‐task gait after experiencing a concussion. Current technologies utilized such as 3D motion capture and force plates are too complex and expensive for most practitioners. The aim of this study was to quantify the variability of dual‐task walking gait parameters using in‐shoe inertial sensors in nonconcussed individuals. Methods This was a randomized within‐subject repeated measures design conducted within a sports laboratory. Twenty healthy, uninjured, nonconcussed participants were recruited for this study. Gait variables of interest were measured across three 2‐min continuous walking protocols (12 m, 30 m, 1 min out and back) while performing a cognitive task of counting backward in sevens from a randomly generated number between 300 and 500. Testing was completed over three occasions separated by 7 days, for a total of nine walking trials. Participants completed the testing protocols in a randomized, individual order. The primary outcome was to determine the variability of dual‐task walking gait parameters using in‐shoe inertial sensors in nonconcussed individuals across three protocols. Results Three to four participants were allocated to each randomized protocol order. Regarding the absolute consistency (coefficient of variation [CV]) between testing occasions, no gait measure was found to have variability above 6.5%. Relative consistency (intraclass correlation coefficient [ICC]) was acceptable (>0.70) in 95% of the variables of interest, with only three variables

In order to understand the coordinated proteome changes associated with differentiation of a cultured cell pluripotency model, protein expression changes induced by treatment of NT2 embryonal carcinoma cells with retinoic acid were monitored by mass spectrometry. The relative levels of over 5000 proteins were mapped across distinct cell fractions. Analysis of the chromatin fraction revealed major abundance changes among chromatin proteins and epigenetic pathways between the pluripotent and differentiated states. Protein complexes associated with epigenetic regulation of gene expression, chromatin remodelling (e.g., SWI/SNF, NuRD) and histone-modifying enzymes (e.g., Polycomb, MLL) were found to be extensively regulated. We therefore investigated histone modifications before and after differentiation, observing changes in the global levels of lysine acetylation and methylation across the four canonical histone protein families, as well as among variant histones. We identified the set of proteins with affinity to peptides housing the histone marks H3K4me3 and H3K27me3, and found increased levels of chromatin-associated histone H3 tail trimming following differentiation that correlated with increased expression levels of cathepsin proteases. We further found that inhibition of cathepsins B and D reduces histone H3 clipping. Overall, the work reveals a global reorganization of the cell proteome congruent with differentiation, highlighting the key role of multiple epigenetic pathways, and demonstrating a direct link between cathepsin B and D activity and histone modification.

In the Hokitika region, on the west coast of the South Island of New Zealand on 18 June 2015, very heavy stratiform precipitation (>200 mm/per day) occurred under north-westerlies with small CAPE (Fm ranges 0.61–1.21). However, the rainfall amount and distribution on the windward side of the mountains varied significantly. Our new findings were that the Southern Alps can have significant indirect effects on heavy rainfall by altering the speed and strength of the cold front, in addition to the well-known direct dynamical effects (i.e., orographic lifting and mountain blocking). A combination of these direct and indirect effects makes the heavy rainfall simulation sensitive to mountain heights even under the same “flow-over” regime.

Multimodal single-cell analysis on iPSC-derived kidney organoids shows that inhibiting EZH2 attenuates TGFβ1-induced fibrotic gene expression and changes in chromatin accessibility, highlighting a potential therapeutic strategy for renal fibrosis.

BackgroundThe anti-seizure medication vigabatrin (VGB) is effective for controlling seizures, especially infantile spasms. However, use is limited by VGB-associated visual field loss (VAVFL). The mechanisms by which VGB causes VAVFL remains unknown. Average peripapillary retinal nerve fibre layer (ppRNFL) thickness correlates with the degree of visual field loss (measured by mean radial degrees). Duration of VGB exposure, maximum daily VGB dose, and male sex are associated with ppRNFL thinning. Here we test the hypothesis that common genetic variation is a predictor of ppRNFL thinning in VGB exposed individuals. Identifying pharmacogenomic predictors of ppRNFL thinning in VGB exposed individuals could potentially enable safe prescribing of VGB and broader use of a highly effective drug.MethodsOptical coherence topography (OCT) and GWAS data were processed from VGB-exposed individuals (n = 71) recruited through the EpiPGX Consortium. We conducted quantitative GWAS analyses for the following OCT measurements: (1) average ppRNFL, (2) inferior quadrant, (3) nasal quadrant, (4) superior quadrant, (5) temporal quadrant, (6) inferior nasal sector, (7) nasal inferior sector, (8) superior nasal sector, and (9) nasal superior sector. Using the summary statistics from the GWAS analyses we conducted gene-based testing using VEGAS2. We conducted nine different PRS analyses using the OCT measurements. To determine if VGB-exposed individuals were predisposed to having a thinner RNFL, we calculated their polygenic burden for retinal thickness. PRS alleles for retinal thickness were calculated using published summary statistics from a large-scale GWAS of inner retinal morphology using the OCT images of UK Biobank participants.ResultsThe GWAS analyses did not identify a significant association after correction for multiple testing. Similarly, the gene-based and PRS analyses did not reveal a significant association that survived multiple testing.ConclusionWe set out to identify common genetic predictors for VGB induced ppRNFL thinning. Results suggest that large-effect common genetic predictors are unlikely to exist for ppRNFL thinning (as a marker of VAVFL). Sample size was a limitation of this study. However, further recruitment is a challenge as VGB is rarely used today because of this adverse reaction. Rare variants may be predictors of this adverse drug reaction and were not studied here.

Children with Down syndrome (DS, trisomy 21) are at a significantly higher risk of developing acute leukemia compared to the overall population. Many studies investigating the link between trisomy 21 and leukemia initiation and progression have been conducted over the last two decades. Despite improved treatment regimens and significant progress in iden - tifying genes on chromosome 21 and the mechanisms by which they drive leukemogenesis, there is still much that is unknown. A focused group of scientists and clinicians with expertise in leukemia and DS met in October 2022 at the Jérôme Lejeune Foundation in Paris, France for the 1st International Symposium on Down Syndrome and Leukemia. This meeting was held to discuss the most recent advances in treatment regimens and the biology underlying the initiation, progression, and relapse of acute lymphoblastic leukemia and acute myeloid leukemia in children with DS. This review provides a summary of what is known in the field, challenges in the management of DS patients with leukemia, and key questions in the field.