The Sensitivity of HIV-1 gp120 Polymorphs to Inhibition by Temsavir Correlates to Temsavir Binding On-rate.

Temsavir binds directly to the HIV-1 envelope glycoprotein gp120 and selectively inhibits interactions between HIV-1 and CD4 receptors. Previous studies identified gp120 amino acid positions where substitutions are associated with reduced susceptibility to temsavir. The mechanism by which temsavir susceptibility is altered in these envelope glycoproteins was evaluated. Pseudoviruses encoding gp120 substitutions alone (S375H/I/M/N, M426L, M434I, M475I) or in combination (S375H + M475I) were engineered on a wild-type JRFL background. Temsavir-gp120 and CD4-gp120 binding kinetics and ability of temsavir to block CD4-gp120 binding were evaluated using the purified polymorphic gp120 proteins and a Creoptix® WAVE Delta grating-coupled interferometry system. The fold-change in half-maximal inhibitory concentration (IC50) in JRFL-based pseudoviruses containing the aforementioned polymorphisms relative to that of wild-type ranged from 4-fold to 29,726-fold, while temsavir binding affinity for the polymorphic gp120 proteins varied from 0.7-fold to 73.7-fold relative to wild-type gp120. Strong correlations between temsavir IC50 and temsavir binding affinity (r=0.7332; P=0.0246) as well as temsavir binding on-rate (r=-0.8940; P=0.0011) were observed. Binding affinity of gp120 proteins for CD4 varied between 0.4-fold and 3.1-fold compared with wild-type gp120; no correlations between temsavir IC50 and CD4 binding kinetic parameters were observed. For all polymorphic gp120 proteins, temsavir was able to fully block CD4 binding; 3 polymorphs required higher temsavir concentrations. Loss of susceptibility to temsavir observed for gp120 polymorphisms strongly correlated with reductions in temsavir binding on-rate. Nonetheless, temsavir retained the ability to fully block CD4-gp120 engagement given sufficiently high concentrations.

The role of pets in the lives of people with dementia: a scoping review.

OBJECTIVES: This scoping review is designed to understand the role of pet ownership in the lives of people living in the community with dementia. METHOD: A five-stage framework for conducting a scoping review guided the review. Two research questions framed the study. Nine databases were searched, with six papers meeting the criteria for detailed review. RESULTS: Pets can play a central role in the lives of people living with dementia. These relationships can be profound and can provide companionship and a sense of purpose. The activities associated with pet ownership and possible benefits for the person living with dementia have been explored to varying degrees and some benefits have been shown regarding the impact on physical and mental well-being. However, little is known about the challenges that may be faced when caring for a pet. CONCLUSION: Despite the importance of pet ownership, experiences of ownership documented among people living with dementia is limited. Still, the studies indicate how pet ownership can support people to remain socially engaged. Future studies should seek to gain a broader understanding of pet ownership across environments such as care homes and hospitals and in the context of social citizenship, active participation and living well. Creative research methods should be adopted to support the inclusion of people living with dementia in research.

Characterization of Clinical Envelopes With Lack of Sensitivity to the HIV-1 Inhibitors Temsavir and Ibalizumab.

Previous data suggest a lack of cross-resistance between the gp120-directed attachment inhibitor temsavir (active moiety of fostemsavir) and the CD4-directed post-attachment inhibitor ibalizumab. Recently, analysis of HIV-1 envelopes with reduced sensitivity to both inhibitors was undertaken to determine whether they shared genotypic correlates of resistance. Sequences from 2 envelopes with reduced susceptibility to both agents were mapped onto a temsavir-bound gp120 structure. Residues within 5.0 Å of the temsavir binding site were evaluated using reverse genetics. Broader applicability and contextual determinants of key substitutions were further assessed using envelopes from participants in the phase 3 BRIGHTE study. Temsavir sensitivity was measured by half-maximal inhibitory concentration (IC50) and ibalizumab sensitivity by IC50 and maximum percent inhibition (MPI). One envelope required substitutions of E113D and T434M for full restoration of temsavir susceptibility. Neither substitution nor their combination affected ibalizumab sensitivity. However, in the second envelope, an E202 substitution (HXB2, T202) was sufficient for observed loss of susceptibility to both inhibitors. One BRIGHTE participant with no ibalizumab exposure had an emergent K202E substitution at protocol-defined virologic failure, with reduced sensitivity to both inhibitors. Introducing T202E into previously susceptible clinical isolates reduced temsavir potency by ≥40-fold and ibalizumab MPI from >99% to ∼80%. Interestingly, introduction of the gp120 V5 region from a highly ibalizumab-susceptible envelope mitigated the E202 effect on ibalizumab but not temsavir. A rare HIV-1 gp120 E202 mutation reduced temsavir susceptibility, and depending on sequence context, could result in reduced susceptibility to ibalizumab.

A Two-Stage Approach Integrating Provisional Biomaterial-Mediated Stabilization Followed by a Definitive Treatment for Managing Volumetric Muscle Loss Injuries.

Treatment of volumetric muscle loss (VML) faces challenges due to its unique pathobiology and lower priority in severe musculoskeletal injury management. Consequently, a need exists for multi-stage VML treatment strategies to accommodate delayed interventions owing to comorbidity management or prolonged casualty care in combat settings. To this end, polyvinyl alcohol (PVA) was used at concentrations of 5%, 7.5%, and 10% to generate provisional muscle void fillers (MVFs) of varying stiffness values (1.125 kPa, 3.700 kPa, and 7.699 kPa) to stabilize VML injuries as part of a two-stage approach. These were implanted into a rat model for a duration of 4 weeks, then explanted and either left untreated (control) or treated through minced muscle grafting (MMG). Additional benchmarks included acute MMG and unrepaired groups. At the MVF explant, the 7.5% PVA group exhibited superior neuromuscular function compared to the 5% and 10% PVA groups, the least fibrosis, and the largest median myofiber size among all groups at the 12-week endpoint. Despite the 7.5% PVA's superiority amongst the two-stage treatment groups, neuromuscular function was neither improved nor impaired relative to acute treatment benchmarks. This suggests that the future success of a two-stage VML treatment strategy will necessitate a more effective definitive intervention.

A nationwide, population-based study on specialized care for acute heart failure throughout the COVID-19 pandemic.

AIMS: The COVID-19 pandemic disrupted the delivery of care for patients with heart failure (HF), leading to fewer HF hospitalizations and increased mortality. However, nationwide data on quality of care and long-term outcomes across the pandemic are scarce. METHODS AND RESULTS: We used data from the National Heart Failure Audit (NHFA) linked to national records for hospitalization and deaths. We compared pre-COVID (2018-2019), COVID (2020), and late/post-COVID (2021-2022) periods. Data for 227 250 patients admitted to hospital with HF were analysed and grouped according to the admission year and the presence of HF with (HFrEF) or without reduced ejection fraction (non-HFrEF). The median age at admission was 81 years (interquartile range 72-88), 55% were men (n = 125 975), 87% were of white ethnicity (n = 102 805), and 51% had HFrEF (n = 116 990). In-hospital management and specialized cardiology care were maintained throughout the pandemic with an increasing percentage of patients discharged on disease-modifying medications over time (p < 0.001). Long-term outcomes improved over time (hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.90-0.95, p < 0.001), mainly driven by a reduction in cardiovascular death. Receiving specialized cardiology care was associated with better long-term outcomes both for those who had HFrEF (HR 0.79, 95% CI 0.77-0.82, p < 0.001) and for those who had non-HFrEF (HR 0.87, 95% CI 0.85-0.90, p < 0.001). CONCLUSIONS: Despite the disruption of healthcare systems, the clinical characteristics of patients admitted with HF were similar and the overall standard of care was maintained throughout the pandemic. Long-term survival of patients hospitalized with HF continued to improve after COVID-19, especially for HFrEF.

Long-term safety and impact of immune recovery in heavily treatment-experienced adults receiving fostemsavir for up to 5 years in the phase 3 BRIGHTE study.

Introduction: Fostemsavir is a gp120-directed attachment inhibitor approved for heavily treatment-experienced (HTE) adults with multidrug-resistant HIV-1. We provide detailed week 240 safety results from the BRIGHTE study and evaluate the impact of immune recovery on safety outcomes. Methods: The phase 3 BRIGHTE trial is ongoing; data for this analysis were collected from the first participant's first visit (February 23, 2015) through the last participant's last visit for week 240 (March 22, 2021). Safety endpoints were assessed in participants who received fostemsavir + optimized background therapy. In participants with baseline CD4+ T-cell count <200 cells/mm3, exposure-adjusted adverse event (AE) rates were assessed among subgroups with or without CD4+ T-cell count ≥200 cells/mm3 at any time during 48-week analysis periods through week 192. Results: Through a median of 258 weeks (range, 0.14-319) of treatment, discontinuations due to AEs occurred in 30/371 (8%) participants. Serious AEs were reported in 177/371 (48%) participants, including 16 drug-related events in 13 (4%) participants. Thirty-five (9%) deaths occurred, primarily related to AIDS or acute infections. COVID-19-related events occurred in 25 (7%) participants; all resolved without sequelae. Among participants with baseline CD4+ T-cell count <200 cells/mm3, 122/162 (75%) achieved CD4+ T-cell count ≥200 cells/mm3 at week 192. Exposure-adjusted AE rates were markedly lower among participants achieving CD4+ T-cell count ≥200 cells/mm3 at any time vs those sustaining <200 cells/mm3. No new AIDS-defining events were reported after week 48 in participants with CD4+ T-cell count ≥200 cells/mm3. Conclusions: Cumulative safety findings through the BRIGHTE 240-week interim analysis are consistent with other trials in HTE participants with advanced HIV-1 and comorbid disease. Reduced rates of AIDS-defining events and AEs were observed in participants with immunologic recovery on fostemsavir-based treatment. Clinical trial number: NCT02362503, https://clinicaltrials.gov/study/NCT02362503.

Rapid evolution of piRNA clusters in the Drosophila melanogaster ovary.

The piRNA pathway is a highly conserved mechanism to repress transposable element (TE) activity in the animal germline via a specialized class of small RNAs called piwi-interacting RNAs (piRNAs). piRNAs are produced from discrete genomic regions called piRNA clusters (piCs). Although the molecular processes by which piCs function are relatively well understood in Drosophila melanogaster, much less is known about the origin and evolution of piCs in this or any other species. To investigate piC origin and evolution, we use a population genomic approach to compare piC activity and sequence composition across eight geographically distant strains of D. melanogaster with high-quality long-read genome assemblies. We perform annotations of ovary piCs and genome-wide TE content in each strain. Our analysis uncovers extensive variation in piC activity across strains and signatures of rapid birth and death of piCs. Most TEs inferred to be recently active show an enrichment of insertions into old and large piCs, consistent with the previously proposed "trap" model of piC evolution. In contrast, a small subset of active LTR families is enriched for the formation of new piCs, suggesting that these TEs have higher proclivity to form piCs. Thus, our findings uncover processes leading to the origin of piCs. We propose that piC evolution begins with the emergence of piRNAs from individual insertions of a few select TE families prone to seed new piCs that subsequently expand by accretion of insertions from most other TE families during evolution to form larger "trap" clusters. Our study shows that TEs themselves are the major force driving the rapid evolution of piCs.

Programming Probiotics: Diet-Responsive Gene Expression and Colonization Control in Engineered S. boulardii.

Saccharomyces boulardii (Sb) is an emerging probiotic chassis for delivering biomolecules to the mammalian gut, offering unique advantages as the only eukaryotic probiotic. However, precise control over gene expression and gut residence time in Sb have remained challenging. To address this, we developed five ligand-responsive gene expression systems and repaired galactose metabolism in Sb, enabling inducible gene expression in this strain. Engineering these systems allowed us to construct AND logic gates, control the surface display of proteins, and turn on protein production in the mouse gut in response to dietary sugar. Additionally, repairing galactose metabolism expanded Sb's habitat within the intestines and resulted in galactose-responsive control over gut residence time. This work opens new avenues for precise dosing of therapeutics by Sb via control over its in vivo gene expression levels and localization within the gastrointestinal tract.

Associations Between Genetically Predicted Iron Status and Cardiovascular Disease Risk: A Mendelian Randomization Study.

BACKGROUND: Mendelian randomization (MR) studies suggest a causal effect of iron status on cardiovascular disease (CVD) risk, but it is unknown if these associations are confounded by pleiotropic effects of the instrumental variables on CVD risk factors. We aimed to investigate the effect of iron status on CVD risk controlling for CVD risk factors. METHODS AND RESULTS: Iron biomarker instrumental variables (total iron-binding capacity [n=208 422], transferrin saturation [n=198 516], serum iron [n=236 612], ferritin [n=257 953]) were selected from a European genome-wide association study meta-analysis. We performed 2-sample univariate MR of each iron trait on CVD outcomes (all-cause ischemic stroke, cardioembolic ischemic stroke, large-artery ischemic stroke, small-vessel ischemic stroke, and coronary heart disease) from MEGASTROKE (n=440 328) and CARDIoGRAMplusC4D (Coronary Artery Disease Genome Wide Replication and Meta-Analysis Plus the Coronary Artery Disease Genetics) (n=183 305). We then implemented multivariate MR conditioning on 7 CVD risk factors from independent European samples to evaluate their potential confounding or mediating effects on the observed iron-CVD associations. With univariate MR analyses, we found higher genetically predicted iron status to be associated with a greater risk of cardioembolic ischemic stroke (transferrin saturation: odds ratio, 1.17 [95% CI, 1.03-1.33]; serum iron: odds ratio, 1.21 [95% CI, 1.02-1.44]; total iron-binding capacity: odds ratio, 0.81 [95% CI, 0.69-0.94]). The detrimental effects of iron status on cardioembolic ischemic stroke risk remained unaffected when adjusting for CVD risk factors (all P<0.05). Additionally, we found diastolic blood pressure to mediate between 7.1 and 8.8% of the total effect of iron status on cardioembolic ischemic stroke incidence. Univariate MR initially suggested a protective effect of iron status on large-artery stroke and coronary heart disease, but controlling for CVD factors using multivariate MR substantially diminished these associations (all P>0.05). CONCLUSIONS: Higher iron status was associated with a greater risk of cardioembolic ischemic stroke independent of CVD risk factors, and this effect was partly mediated by diastolic blood pressure. These findings support a role of iron status as a modifiable risk factor for cardioembolic ischemic stroke.

MAVMET trial: maraviroc and/or metformin for metabolic dysfunction-associated fatty liver disease(MAFLD) in adults with suppressed HIV.

OBJECTIVE: Metabolic dysfunction-associated fatty liver disease (MAFLD) is over-represented in people living with HIV (PLWH). Maraviroc (MVC) and/or metformin (MET) may reduce MAFLD by influencing inflammatory pathways and fatty acid metabolism. DESIGN: Open-label, 48-week randomised trial with a 2x2 factorial design. SETTING: Multicentre HIV clinics. PARTICIPANTS: Nondiabetic, virologically-suppressed PLWH, aged ≥35 years, with confirmed/suspected MAFLD (≥1 biochemical/anthropometric/radiological/histological features). INTERVENTION: Adjunctive MVC; MET; MVC+MET vs. antiretroviral therapy (ART) alone. PRIMARY OUTCOME: Change in liver fat fraction (LFF) between baseline and week-48 using Magnetic Resonance Proton Density Fat Fraction (MR PDFF). RESULTS: Six sites enrolled 90 participants (93% male; 81% white; median age 52 [interquartile range, IQR 47-57] years) between 19-Mar-2018 and 11-November-2019. 70% had imaging/biopsy plus ≥1 MAFLD criteria. The analysis included 82/90 with week-0 and -48 scans. Median baseline MR PDFF was 8.9 (4.6-17.1); 40%, 38%, 8%, and 14% had grade zero, one, two, and three steatosis respectively. Mean LFF increased slightly between baseline and follow-up scans: 2.22% MVC, 1.26% MET, 0.81% MVC+MET, and 1.39% ART alone. Prolonged intervention exposure (delayed week-48 scans) exhibited greater increases in MR PDFF (estimated difference 4.23% [95% CI 2.97, 5.48], P  < 0.001). There were no differences in predicted change for any intervention compared to ART alone: MVC (-0.42% [95% CI -1.53-0.68, P  = 0.45]), MET (-0.62 [-1.81-0.56, P  = 0.30]), and MVC+MET (-1.04 [-2.74-0.65, P  = 0.23]). Steatosis grade remained unchanged in 55% and increased in 24%. CONCLUSIONS: Baseline levels of liver fat were lower than predicted. Contrary to our hypothesis, neither MVC, MET, or the combination significantly reduced MR PDFF compared to ART alone.

Urinary proteomic signature of mineralocorticoid receptor antagonism by spironolactone: evidence from the HOMAGE trial.

OBJECTIVE: Heart failure (HF) is characterised by collagen deposition. Urinary proteomic profiling (UPP) followed by peptide sequencing identifies parental proteins, for over 70% derived from collagens. This study aimed to refine understanding of the antifibrotic action of spironolactone. METHODS: In this substudy (n=290) to the Heart 'Omics' in Ageing Study trial, patients were randomised to usual therapy combined or not with spironolactone 25-50 mg/day and followed for 9 months. The analysis included 1498 sequenced urinary peptides detectable in ≥30% of patients and carboxyterminal propeptide of procollagen I (PICP) and PICP/carboxyterminal telopeptide of collagen I (CITP) as serum biomarkers of COL1A1 synthesis. After rank normalisation of biomarker distributions, between-group differences in their changes were assessed by multivariable-adjusted mixed model analysis of variance. Correlations between the changes in urinary peptides and in serum PICP and PICP/CITP were compared between groups using Fisher's Z transform. RESULTS: Multivariable-adjusted between-group differences in the urinary peptides with error 1 rate correction were limited to 27 collagen fragments, of which 16 were upregulated (7 COL1A1 fragments) on spironolactone and 11 downregulated (4 COL1A1 fragments). Over 9 months of follow-up, spironolactone decreased serum PICP from 81 (IQR 66-95) to 75 (61-90) µg/L and PICP/CITP from 22 (17-28) to 18 (13-26), whereas no changes occurred in the control group, resulting in a difference (spironolactone minus control) expressed in standardised units of -0.321 (95% CI 0.0007). Spironolactone did not affect the correlations between changes in urinary COL1A1 fragments and in PICP or the PICP/CITP ratio. CONCLUSIONS: Spironolactone decreased serum markers of collagen synthesis and predominantly downregulated urinary collagen-derived peptides, but upregulated others. The interpretation of these opposite UPP trends might be due to shrinking the body-wide pool of collagens, explaining downregulation, while some degree of collagen synthesis must be maintained to sustain vital organ functions, explaining upregulation. Combining urinary and serum fibrosis markers opens new avenues for the understanding of the action of antifibrotic drugs. TRIAL REGISTRATION NUMBER: NCT02556450.

Impact of light on protective fractions of Cu in white wine: Influence of oxygen and bottle colour.

Cu(II)-organic acid (fraction I) and Cu(I)-thiol (fraction II) complexes can suppress sulfhydryl off-aromas in wine. This study investigated the impact of light exposure on the protective fractions of Cu of bottled white wine. Fluorescent light-exposed Chardonnay with two initial concentrations of dissolved oxygen (0.5 and 10 mg/L) was stored in different coloured bottles and concentrations of Cu fractions and riboflavin, a photo-initiator at 370-440 nm, were measured during 110 days storage. Light-exposed wines with lower oxygen concentrations resulted in a 100-fold decrease in the Cu fraction I half-life, and a 60-fold decrease for Cu fractions I and II combined. The half-life for Cu fraction I decay during light exposure was extended 30-fold with the use of brown compared to flint glass. Light exposure can rapidly exhaust the protective Cu fractions in wine, and bottles with less light transmission below 440 nm can slow this loss.

Comparison of Techniques for the Quantitation of Reductive Aroma Compounds in White Wine: Links to Sensory Analysis and Cu Fractions.

Multiple analytical methodologies allow quantitation of H2S and methanethiol (MeSH) in wine, but confirmation that the determined concentrations are related to perceived off-aromas, or "reductive" faults, is yet to be provided. Fifty white wines underwent sensory evaluation and measurement of free and salt-treated H2S and MeSH concentrations by gas chromatography with sulfur chemiluminescence detection and/or gas detection tubes. The determined concentrations were compared across techniques and different analysis laboratories. Sulfhydryl off-odors in the wines were best described by boiled and rotten egg and natural gas/sewerage/durian aroma attributes. The wines with the highest ratings for both aromas had high concentrations of free H2S, free MeSH, and/or salt-treated MeSH but were unrelated to salt-treated H2S. The free sulfhydryl concentrations and their associated aromas appeared to be suppressed by specific Cu fractions in the wines. This study provides evidence of the relevant measures of reductive aroma compounds and their relation to off-odors and Cu fractions.

Late Paleozoic oxygenation of marine environments supported by dolomite U-Pb dating.

Understanding causal relationships between evolution and ocean oxygenation hinges on reliable reconstructions of marine oxygen levels, typically from redox-sensitive geochemical proxies. Here, we develop a proxy, using dolomite U-Pb geochronology, to reconstruct seawater U/Pb ratios. Dolomite samples consistently give U-Pb dates and initial 207Pb/206Pb ratios lower than expected from their stratigraphic ages. These observations are explained by resetting of the U-Pb system long after deposition; the magnitude of deviations from expected initial 207Pb/206Pb are a function of the redox-sensitive U/Pb ratios during deposition. Reconstructed initial U/Pb ratios increased notably in the late-Paleozoic, reflecting an increase in oxygenation of marine environments at that time. This timeline is consistent with documented shifts in some other redox proxies and supports evolution-driven mechanisms for the oxygenation of late-Paleozoic marine environments, as well as suggestions that early animals thrived in oceans that on long time scales were oxygen-limited compared to today.

Preparing Patients for Oral Immunotherapy (PPOINT): International Delphi consensus for procedural preparation and consent.

BACKGROUND: Despite the promise of oral immunotherapy (OIT) to treat food allergies, this procedure is associated with potential risk. There is no current agreement about what elements should be included in the preparatory or consent process. OBJECTIVE: We developed consensus recommendations about the OIT process considerations and patient-specific factors that should be addressed before initiating OIT and developed a consensus OIT consent process and information form. METHODS: We convened a 36-member Preparing Patients for Oral Immunotherapy (PPOINT) panel of allergy experts to develop a consensus OIT patient preparation, informed consent process, and framework form. Consensus for themes and statements was reached using Delphi methodology, and the consent information form was developed. RESULTS: The expert panel reached consensus for 4 themes and 103 statements specific to OIT preparatory procedures, of which 76 statements reached consensus for inclusion specific to the following themes: general considerations for counseling patients about OIT; patient- and family-specific factors that should be addressed before initiating OIT and during OIT; indications for initiating OIT; and potential contraindications and precautions for OIT. The panel reached consensus on 9 OIT consent form themes: benefits, risks, outcomes, alternatives, risk mitigation, difficulties/challenges, discontinuation, office policies, and long-term management. From these themes, 219 statements were proposed, of which 189 reached consensus, and 71 were included on the consent information form. CONCLUSION: We developed consensus recommendations to prepare and counsel patients for safe and effective OIT in clinical practice with evidence-based risk mitigation. Adoption of these recommendations may help standardize clinical care and improve patient outcomes and quality of life.

Mismatched related donor allogeneic haematopoietic cell transplantation compared to other donor types for Ph+ chronic myeloid leukaemia: A retrospective analysis from the Chronic Malignancies Working Party of the EBMT.

Allogeneic haematopoietic cell transplantation (allo-HCT) remains an option for tyrosine kinase inhibitor-resistant chronic myeloid leukaemia (CML) in first chronic phase (CP1) and high-risk patients with advanced disease phases. In this European Society for Blood and Marrow Transplantation (EBMT) registry-based study of 1686 CML patients undergoing first allo-HCT between 2012 and 2019, outcomes were evaluated according to donor type, particularly focusing on mismatched related donors (MMRDs). Median age at allo-HCT was 46 years (IQR 36-55). Disease status was CP1 in 43%, second CP (CP2) or later in 27%, accelerated phase in 12% and blast crisis in 18%. Donor type was matched related (MRD) in 39.2%, MMRD in 8.1%, matched unrelated (MUD) in 40.2%, and mismatched unrelated (MMUD) in 12.6%. In 4 years, overall survival (OS) for MRD, MMRD, MUD and MMUD was 61%, 56%, 63% and 59% (p = 0.21); relapse-free survival (RFS) was 48%, 42%, 52% and 46% (p = 0.03); cumulative incidence of relapse (CIR) was 33%, 37%, 27% and 30% (p = 0.07); non-relapse mortality (NRM) was 19%, 21%, 21% and 24% (p = 0.21); and graft-versus-host disease (GvHD)-free/relapse-free survival (GRFS) was 16%, 18%, 22% and 15% (p = 0.05) respectively. On multivariate analysis, MMRD use associated with longer engraftment times and higher risk of graft failure compared to MRD or MUD. There was no statistical evidence that MMRD use associated with different OS, RFS and incidence of GvHD compared to other donor types.

Patient Characteristics, Treatment Patterns, and Outcomes for Patients With Renal Cell Carcinoma in England: A Retrospective Cohort Study.

BACKGROUND AND OBJECTIVE: Considering the rapidly evolving treatment landscape of renal cell carcinoma (RCC), recent descriptions of the RCC population in the UK are lacking, as are real-world data on treatment and patient outcomes. To analyse the demographic and clinical characteristics, treatment patterns, and overall survival of patients with RCC using national data sets in England. PATIENTS AND METHODS: This was a retrospective cohort study of patients diagnosed with RCC (all stages) between 2014-2018 using demographic, clinical, cancer registration, and treatment data. Patients were followed until death or study end (December 31, 2020). Treatments administered in each line were described to understand treatment sequencing. Kaplan-Meier methods were used for time-to-event analyses. Factors associated with discontinuation and survival were identified using Cox proportional hazard models. RESULTS AND LIMITATIONS: Among 32,577 included patients, the median age at diagnosis was 66 years, 63.4% were male, and 6,786 (20.8%) had metastatic RCC at diagnosis. Tyrosine kinase inhibitor (TKI) monotherapy was the most common treatment class across lines. Over three quarters of patients (78.5% [95% CI: 78.0-78.9]) were alive one year after diagnosis (93.2% in the non-metastatic at diagnosis subgroup and 37.1% among patients with metastases at diagnosis). At three years post initial diagnosis, 18.0% patients were alive in the metastatic at diagnosis subgroup. Rapid evolution of the treatment landscape limits the results regarding lines of therapy. CONCLUSION: This large-scale study provides insight on characteristics of patients with RCC, and it highlights the need for better treatment options to improve survival.

Outcomes in patients treated with loop diuretics without a diagnosis of heart failure: a retrospective cohort study.

BACKGROUND: Loop diuretics are commonly prescribed in the community, not always to patients with a recorded diagnosis of heart failure (HF). The rate of HF events in patients prescribed loop diuretics without a diagnosis of HF is unknown. METHODS: This was a propensity-matched cohort study using data from the Clinical Practice Research Datalink, Hospital Episode Statistics and Office of National Statistics in the UK. Patients prescribed a loop diuretic without a diagnosis of HF (loop diuretic group) between 1 January 2010 and 31 December 2015 were compared with patients with HF (HF group)-analysis A, and patients with risk factors for HF (either ischaemic heart disease, or diabetes and hypertension-at-risk group)-analysis B. The primary endpoint was an HF event (a composite of presentation with HF symptoms, HF hospitalisation, HF diagnosis (analysis B only) and all-cause mortality). RESULTS: From a total population of 180 384 patients (78 968 in the loop diuretic group, 28 177 in the HF group and 73 239 in the at-risk group), there were 59 694 patients, 22 352 patients and 57 219 patients in the loop diuretic, HF and at-risk groups, respectively, after exclusion criteria were applied. After propensity matching for age, sex and comorbidities, patients in the loop diuretic group had a similar rate of HF events as those in the HF group (71.9% vs 72.1%; HR=0.92 (95% CI 0.90 to 0.94); p<0.001), and twice as those in the at-risk group (59.2% vs 35.7%; HR=2.04 (95% CI 2.00 to 2.08); p<0.001). CONCLUSIONS: Patients prescribed a loop diuretic without a recorded diagnosis of HF experience HF events at a rate comparable with that of patients with a recorded diagnosis of HF; many of these patients may have undiagnosed HF.

From sub-Saharan Africa to China: Evolutionary history and adaptation of Drosophila melanogaster revealed by population genomics.

Drosophila melanogaster is a widely used model organism for studying environmental adaptation. However, the genetic diversity of populations in Asia is poorly understood, leaving a notable gap in our knowledge of the global evolution and adaptation of this species. We sequenced genomes of 292 D. melanogaster strains from various ecological settings in China and analyzed them along with previously published genome sequences. We have identified six global genetic ancestry groups, despite the presence of widespread genetic admixture. The strains from China represent a unique ancestry group, although detectable differentiation exists among populations within China. We deciphered the global migration and demography of D. melanogaster, and identified widespread signals of adaptation, including genetic changes in response to insecticides. We validated the effects of insecticide resistance variants using population cage trials and deep sequencing. This work highlights the importance of population genomics in understanding the genetic underpinnings of adaptation, an effort that is particularly relevant given the deterioration of ecosystems.

In vivo optogenetics using a Utah Optrode Array with enhanced light output and spatial selectivity.

Optogenetics allows manipulation of neural circuits in vivo with high spatial and temporal precision. However, combining this precision with control over a significant portion of the brain is technologically challenging (especially in larger animal models). Here, we have developed, optimised, and tested in vivo, the Utah Optrode Array (UOA), an electrically addressable array of optical needles and interstitial sites illuminated by 181 µLEDs and used to optogenetically stimulate the brain. The device is specifically designed for non-human primate studies. Thinning the combined µLED and needle backplane of the device from 300 µm to 230 µm improved the efficiency of light delivery to tissue by 80%, allowing lower µLED drive currents, which improved power management and thermal performance. The spatial selectivity of each site was also improved by integrating an optical interposer to reduce stray light emission. These improvements were achieved using an innovative fabrication method to create an anodically bonded glass/silicon substrate with through-silicon vias etched, forming an optical interposer. Optical modelling was used to demonstrate that the tip structure of the device had a major influence on the illumination pattern. The thermal performance was evaluated through a combination of modelling and experiment, in order to ensure that cortical tissue temperatures did not rise by more than 1°C. The device was tested in vivo in the visual cortex of macaque expressing ChR2-tdTomato in cortical neurons. It was shown that the strongest optogenetic response occurred in the region surrounding the needle tips, and that the extent of the optogenetic response matched the predicted illumination profile based on optical modelling - demonstrating the improved spatial selectivity resulting from the optical interposer approach. Furthermore, different needle illumination sites generated different patterns of low-frequency potential (LFP) activity.