A new species and a new record of Phlomoides (Lamiaceae) from Xizang, China.

Phlomoidesbomiensis, a new species in Bomi County, Xizang, China, was described and illustrated. In addition, Phlomoideslongidentata, previously only known from Nepal and Bhutan, is newly recorded from Dingri County, Xizang, China. The phylogenetic placement of both species within the genus was analysed using nine plastid DNA markers (atpB-rbcL, psbA-trnH, rpl16, rpl32-trnL, rps16, trnK, trnL-trnF, trnS-trnG, trnT-trnL). Both species have brown-black trichomes inside the upper corolla lip and nested within the same subclade of Clade II. A diagnostic key to the Phlomoides species belonging to this subclade is provided.

Two functional forms of the Meckel-Gruber syndrome protein TMEM67 generated by proteolytic cleavage by ADAMTS9 mediate Wnt signaling and ciliogenesis.

TMEM67 mutations are the major cause of Meckel-Gruber syndrome. TMEM67 is involved in both ciliary transition zone assembly, and non-canonical Wnt signaling mediated by its extracellular domain. How TMEM67 performs these two separate functions is not known. We identify a novel cleavage motif in the extracellular domain of TMEM67 cleaved by the extracellular matrix metalloproteinase ADAMTS9. This cleavage regulates the abundance of two functional forms: A C-terminal portion which localizes to the ciliary transition zone regulating ciliogenesis, and a non-cleaved form which regulates Wnt signaling. By characterizing three TMEM67 ciliopathy patient variants within the cleavage motif utilizing mammalian cell culture and C. elegans, we show the cleavage motif is essential for cilia structure and function, highlighting its clinical significance. We generated a novel non-cleavable TMEM67 mouse model which develop severe ciliopathies phenocopying Tmem67 -/- mice, but in contrast, undergo normal Wnt signaling, substantiating the existence of two functional forms of TMEM67.

C-C Chemokine Receptor 7 Promotes T-Cell Acute Lymphoblastic Leukemia Invasion of the Central Nervous System via ß2-Integrins.

C-C Chemokine Receptor 7 (CCR7) mediates T-cell acute lymphoblastic leukemia (T-ALL) invasion of the central nervous system (CNS) mediated by chemotactic migration to C-C chemokine ligand 19 (CCL19). To determine if a CCL19 antagonist, CCL198-83, could inhibit CCR7-induced chemotaxis and signaling via CCL19 but not CCL21, we used transwell migration and Ca2+ mobilization signaling assays. We found that in response to CCL19, human T-ALL cells employ ß2 integrins to invade human brain microvascular endothelial cell monolayers. In vivo, using an inducible mouse model of T-ALL, we found that we were able to increase the survival of the mice treated with CCL198-83 when compared to non-treated controls. Overall, our results describe a targetable cell surface receptor, CCR7, which can be inhibited to prevent ß2-integrin-mediated T-ALL invasion of the CNS and potentially provides a platform for the pharmacological inhibition of T-ALL cell entry into the CNS.

Investigating Acoustic and Psycholinguistic Predictors of Cognitive Impairment in Older Adults: Modeling Study.

BACKGROUND: About one-third of older adults aged 65 years and older often have mild cognitive impairment or dementia. Acoustic and psycho-linguistic features derived from conversation may be of great diagnostic value because speech involves verbal memory and cognitive and neuromuscular processes. The relative decline in these processes, however, may not be linear and remains understudied. OBJECTIVE: This study aims to establish associations between cognitive abilities and various attributes of speech and natural language production. To date, the majority of research has been cross-sectional, relying mostly on data from structured interactions and restricted to textual versus acoustic analyses. METHODS: In a sample of 71 older (mean age 83.3, SD 7.0 years) community-dwelling adults who completed qualitative interviews and cognitive testing, we investigated the performance of both acoustic and psycholinguistic features associated with cognitive deficits contemporaneously and at a 1-2 years follow up (mean follow-up time 512.3, SD 84.5 days). RESULTS: Combined acoustic and psycholinguistic features achieved high performance (F1-scores 0.73-0.86) and sensitivity (up to 0.90) in estimating cognitive deficits across multiple domains. Performance remained high when acoustic and psycholinguistic features were used to predict follow-up cognitive performance. The psycholinguistic features that were most successful at classifying high cognitive impairment reflected vocabulary richness, the quantity of speech produced, and the fragmentation of speech, whereas the analogous top-ranked acoustic features reflected breathing and nonverbal vocalizations such as giggles or laughter. CONCLUSIONS: These results suggest that both acoustic and psycholinguistic features extracted from qualitative interviews may be reliable markers of cognitive deficits in late life.

Protocol for a type 3 hybrid implementation cluster randomized clinical trial to evaluate the effect of patient and clinician nudges to advance the use of genomic medicine across a diverse health system.

BACKGROUND: Germline genetic testing is recommended for an increasing number of conditions with underlying genetic etiologies, the results of which impact medical management. However, genetic testing is underutilized in clinics due to system, clinician, and patient level barriers. Behavioral economics provides a framework to create implementation strategies, such as nudges, to address these multi-level barriers and increase the uptake of genetic testing for conditions where the results impact medical management. METHODS: Patients meeting eligibility for germline genetic testing for a group of conditions will be identified using electronic phenotyping algorithms. A pragmatic, type 3 hybrid cluster randomization study will test nudges to patients and/or clinicians, or neither. Clinicians who receive nudges will be prompted to either refer their patient to genetics or order genetic testing themselves. We will use rapid cycle approaches informed by clinician and patient experiences, health equity, and behavioral economics to optimize these nudges before trial initiation. The primary implementation outcome is uptake of germline genetic testing for the pre-selected health conditions. Patient data collected through the electronic health record (e.g. demographics, geocoded address) will be examined as moderators of the effect of nudges. DISCUSSION: This study will be one of the first randomized trials to examine the effects of patient- and clinician-directed nudges informed by behavioral economics on uptake of genetic testing. The pragmatic design will facilitate a large and diverse patient sample, allow for the assessment of genetic testing uptake, and provide comparison of the effect of different nudge combinations. This trial also involves optimization of patient identification, test selection, ordering, and result reporting in an electronic health record-based infrastructure to further address clinician-level barriers to utilizing genomic medicine. The findings may help determine the impact of low-cost, sustainable implementation strategies that can be integrated into health care systems to improve the use of genomic medicine. TRIAL REGISTRATION: ClinicalTrials.gov. NCT06377033. Registered on March 31, 2024. https://clinicaltrials.gov/study/NCT06377033?term=NCT06377033&rank=1.

How hot is too hot? Thermal tolerance, performance, and preference in juvenile mangrove whiprays, Urogymnus granulatus.

Mangrove habitats can serve as nursery areas for sharks and rays. Such environments can be thermally dynamic and extreme; yet, the physiological and behavioural mechanisms sharks and rays use to exploit such habitats are understudied. This study aimed to define the thermal niche of juvenile mangrove whiprays, Urogymnus granulatus. First, temperature tolerance limits were determined via the critical thermal maximum (CTMax) and minimum (CTMin) of mangrove whiprays at summer acclimation temperatures (28 °C), which were 17.5 °C and 39.9 °C, respectively. Then, maximum and routine oxygen uptake rates (MO2max and MO2routine, respectively), post-exercise oxygen debt, and recovery were estimated at current (28 °C) and heatwave (32 °C) temperatures, revealing moderate temperature sensitivities (i.e., Q10) of 2.4 (MO2max) and 1.6 (MO2routine), but opposing effects on post-exercise oxygen uptake. Finally, body temperatures (Tb) of mangrove whiprays were recorded using external temperature loggers, and environmental temperatures (Te) were recorded using stationary temperature loggers moored in three habitat zones (mangrove, reef flat, and reef crest). As expected, environmental temperatures varied between sites depending on depth. Individual mangrove whiprays presented significantly lower Tb relative to Te during the hottest times of the day. Electivity analysis showed tagged individuals selected temperatures from 24.0 to 37.0 °C in habitats that ranged from 21.1 to 43.5 °C. These data demonstrate that mangrove whiprays employ thermotaxic behaviours and a thermally insensitive aerobic metabolism to thrive in thermally dynamic and extreme habitats. Tropical nursery areas may, therefore, offer important thermal refugia for young rays. However, these tropical nursery areas could become threatened by mangrove and coral habitat loss, and climate change.

Endophthalmitis in Eyes Treated with the Port Delivery System with Ranibizumab: Summary of Cases during Clinical Trial Development.

PURPOSE: The Port Delivery System with ranibizumab (PDS) is approved in the United States for neovascular age-related macular degeneration. The United States Prescribing Information has a Boxed Warning for endophthalmitis and reports the incidence rate in patients developing endophthalmitis after receiving the PDS compared with monthly intravitreal ranibizumab. Endophthalmitis cases noted in the Boxed Warning, treatment outcomes, potential contributing factors, and potential mitigations are summarized. DESIGN: Retrospective review of endophthalmitis cases in PDS-treated patients in the phase II Ladder (NCT02510794) and phase III Archway (NCT03677934) and Portal (NCT03683251) trials. PARTICIPANTS: Endophthalmitis cases in the pooled all-PDS safety population (N = 555) including PDS patients in Ladder, Archway, or Portal. METHODS: Ladder patients received PDS (10, 40, or 100 mg/ml) with pro re nata refill-exchanges. Archway patients received PDS 100 mg/ml with fixed refill-exchanges every 24 weeks (PDS Q24W). Portal patients received PDS Q24W from day 1. MAIN OUTCOME MEASURES: Clinical features, management, and visual outcomes were summarized. Cases were summarized by date of PDS implant and/or refill, other prior invasive procedures/refills, and preceding/concurrent conjunctival complications. RESULTS: Twelve endophthalmitis events were reported in 11 patients (11/555 [2.0%]) through March 12, 2021. All were cultured (3 were culture positive) and treated with intravitreal antibiotics. Two cases (2/555 [0.4%]) occurred in the immediate postoperative period (days 5 and 6). Nine cases occurred later (day range: 57-853), including 4 before the first refill-exchange (day range: 57-161). Five patients received between 1 and 11 refill-exchanges before the event (onset: 6-168 days after last refill-exchange). Seven cases (7/11 [63.6%]) had preceding/concurrent conjunctival complications. At last follow-up, 7 patients recovered vision to study baseline levels or ≥20/40; 4 patients experienced vision loss of ≥15 ETDRS letters. CONCLUSIONS: Endophthalmitis is a serious complication that can endanger vision after any ocular procedure, including PDS implantation. Most, but not all, of this limited series of endophthalmitis cases were late onset, associated with conjunctival breach, and recovered vision with treatment. Meticulous attention to PDS surgical techniques with vigilant monitoring of conjunctiva during follow-up may minimize risk of endophthalmitis. Prompt treatment is critical for optimizing patient outcomes. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

A European Consensus on the Consistent Use of the Term "Keratinocyte Cancer".

Keratinocyte-derived skin cancers comprise basal cell carcinoma, squamous cell carcinoma, its precursor actinic keratosis, and Bowen's disease. Historically, this group of neoplasms has been subsumed under the term non-melanoma skin cancer. However, the term non-melanoma skin cancer can be misleading and lacks precision. Therefore, more precise and reasonable terminology, valuing the relevance of keratinocyte-derived cancer, appears pertinent to meet its clinical and scientific significance. A group of experienced dermato-oncologists initiated a consensus approach to promote the use of the term "keratinocyte cancer" instead of "non-melanoma skin cancer" when referring to carcinomas and their precursors that are derived from keratinocytes. The vote among members of the consensus group indicated unanimous agreement on the consistent use of the term "keratinocyte cancer" instead of "non-melanoma skin cancer". International delegates also voted in favour of the revised terminology. The more precise and, by means of etiopathogenesis, correct term "keratinocyte cancer" should be consistently used for malignancies originated from keratinocytes. This is expected to have a positive impact on patient-physician communication and gives better justice to this important group of keratinocyte-derived cancers.

Foam fractionation studies of recombinant human apolipoprotein A-I.

Apolipoprotein A-I (apoA-I), the primary protein component of plasma high-density lipoproteins (HDL), is comprised of two structural regions, an N-terminal amphipathic α-helix bundle domain (residues 1-184) and a hydrophobic C-terminal domain (residues 185-243). When a recombinant fusion protein construct [bacterial pelB leader sequence - human apoA-I (1-243)] was expressed in Escherichia coli shaker flask cultures, apoA-I was recovered in the cell lysate. By contrast, when the C-terminal domain was deleted from the construct, large amounts of the truncated protein, apoA-I (1-184), were recovered in the culture medium. Consequently, following pelB leader sequence cleavage in the E. coli periplasmic space, apoA-I (1-184) was secreted from the bacteria. When the pelB-apoA-I (1-184) fusion construct was expressed in a 5 L bioreactor, substantial foam production (~30 L) occurred. Upon foam collection and collapse into a liquid foamate, SDS-PAGE revealed that apoA-I (1-184) was the sole major protein present. Incubation of apoA-I (1-184) with phospholipid vesicles yielded reconstituted HDL (rHDL) particles that were similar in size and cholesterol efflux capacity to those generated with full-length apoA-I. Mass spectrometry analysis confirmed that pelB leader sequence cleavage occurred and that foam fractionation did not result in unwanted protein modifications. The facile nature and scalability of bioreactor-based apolipoprotein foam fractionation provide a novel means to generate a versatile rHDL scaffold protein.

Diagnostic and clinical utility of comprehensive multigene panel testing for patients with neuropathy.

BACKGROUND AND AIMS: Prior to next-generation sequencing (NGS), the evaluation of a patient with neuropathy typically consisted of screening for acquired causes, followed by clinical genetic testing of PMP22, MFN2, GJB1, and MPZ in patients with a positive family history and symptom onset prior to age 50. In this study, we examined the clinical utility of NGS in a large cohort of patients analyzed in a commercial laboratory. METHODS: A cohort of 6849 adult patients underwent clinician-ordered peripheral neuropathy multigene panel testing ranging from 66 to 111 genes that included NGS and intragenic deletion/duplication analysis. RESULTS: A molecular diagnosis was identified for 8.4% of the cohort (n = 573/6849). Variants in PMP22, MFN2, GJB1, MPZ, and TTR accounted for 73.8% of molecular diagnoses. Results had potential clinical actionability for 398 (69.5%) patients. Our results suggest that 225/573 (39.3%) of molecular diagnoses and 113/398 (28.4%) of clinical interventions would have been missed if the testing approach had been restricted to older guidelines. INTERPRETATION: Our results highlight the need for expanded genetic testing guidelines that account for the increased number of genes associated with hereditary neuropathy, address the overlap of acquired and hereditary neuropathy, and provide broader access to genetic diagnosis for patients.

The Sleep Condition Indicator (SCI): Psychometric properties of the European Portuguese version.

Insomnia is a highly prevalent sleep disorder. It is the most frequent sleep complaint among Higher Education students. The Sleep Condition Indicator is a self-report tool aimed at assessing insomnia based on the DSM-5 criteria. The principal goal of this study was to establish preliminary psychometric properties of the European Portuguese version of the Sleep Condition Indicator in a sample of Higher Education students. Data from a diverse pool of Higher Education students (N = 537) were collected online over a month. Most participants were women (75%) and aged approximately 27 years. The Sleep Condition Indicator demonstrated good internal consistency (α = 0.85), with all the items accounting significantly for the scale reliability. The most appropriate factor structure considering the ordinal nature of the items was unidimensional, with all items explaining 64% of the total variance. However, a two-factor structure (sleep pattern and sleep-related impact) was also plausible when other statistical estimators were used. The Sleep Condition Indicator correlated significantly with insomnia severity, vulnerability to stress-related sleep disturbance, and self-reported daytime sleepiness. The optimal cut-off point established based on the receiver operating characteristic curve analysis was ≤ 16. A short version comprising only two items was also viable as suggested by the literature. The Sleep Condition Indicator is a reliable and valid tool for screening for insomnia. More studies with other groups are now required, specifically with clinical samples.

Commuting-driven competition between transmission chains shapes seasonal influenza virus epidemics in the United States.

Despite intensive study, much remains unknown about the dynamics of seasonal influenza virus epidemic establishment and spread in the United States (US) each season. By reconstructing transmission lineages from seasonal influenza virus genomes collected in the US from 2014 to 2023, we show that most epidemics consisted of multiple distinct transmission lineages. Spread of these lineages exhibited strong spatiotemporal hierarchies and lineage size was correlated with timing of lineage establishment in the US. Mechanistic epidemic simulations suggest that mobility-driven competition between lineages determined the extent of individual lineages' geographical spread. Based on phylogeographic analyses and epidemic simulations, lineage-specific movement patterns were dominated by human commuting behavior. These results suggest that given the locations of early-season epidemic sparks, the topology of inter-state human mobility yields repeatable patterns of which influenza viruses will circulate where, but the importance of short-term processes limits predictability of regional and national epidemics.

Ecological roles and importance of sharks in the Anthropocene Ocean.

In ecosystems, sharks can be predators, competitors, facilitators, nutrient transporters, and food. However, overfishing and other threats have greatly reduced shark populations, altering their roles and effects on ecosystems. We review these changes and implications for ecosystem function and management. Macropredatory sharks are often disproportionately affected by humans but can influence prey and coastal ecosystems, including facilitating carbon sequestration. Like terrestrial predators, sharks may be crucial to ecosystem functioning under climate change. However, large ecosystem effects of sharks are not ubiquitous. Increasing human uses of oceans are changing shark roles, necessitating management consideration. Rebuilding key populations and incorporating shark ecological roles, including less obvious ones, into management efforts are critical for retaining sharks' functional value. Coupled social-ecological frameworks can facilitate these efforts.

CREMP: Conformer-rotamer ensembles of macrocyclic peptides for machine learning.

Computational and machine learning approaches to model the conformational landscape of macrocyclic peptides have the potential to enable rational design and optimization. However, accurate, fast, and scalable methods for modeling macrocycle geometries remain elusive. Recent deep learning approaches have significantly accelerated protein structure prediction and the generation of small-molecule conformational ensembles, yet similar progress has not been made for macrocyclic peptides due to their unique properties. Here, we introduce CREMP, a resource generated for the rapid development and evaluation of machine learning models for macrocyclic peptides. CREMP contains 36,198 unique macrocyclic peptides and their high-quality structural ensembles generated using the Conformer-Rotamer Ensemble Sampling Tool (CREST). Altogether, this new dataset contains nearly 31.3 million unique macrocycle geometries, each annotated with energies derived from semi-empirical extended tight-binding (xTB) DFT calculations. Additionally, we include 3,258 macrocycles with reported passive permeability data to couple conformational ensembles to experiment. We anticipate that this dataset will enable the development of machine learning models that can improve peptide design and optimization for novel therapeutics.

Inflation of polygenic risk scores caused by sample overlap and relatedness: Examples of a major risk of bias.

Polygenic risk scores (PRSs) are an important tool for understanding the role of common genetic variants in human disease. Standard best practices recommend that PRSs be analyzed in cohorts that are independent of the genome-wide association study (GWAS) used to derive the scores without sample overlap or relatedness between the two cohorts. However, identifying sample overlap and relatedness can be challenging in an era of GWASs performed by large biobanks and international research consortia. Although most genomics researchers are aware of best practices and theoretical concerns about sample overlap and relatedness between GWAS and PRS cohorts, the prevailing assumption is that the risk of bias is small for very large GWASs. Here, we present two real-world examples demonstrating that sample overlap and relatedness is not a minor or theoretical concern but an important potential source of bias in PRS studies. Using a recently developed statistical adjustment tool, we found that excluding overlapping and related samples was equal to or more powerful than adjusting for overlap bias. Our goal is to make genomics researchers aware of the magnitude of risk of bias from sample overlap and relatedness and to highlight the need for mitigation tools, including independent validation cohorts in PRS studies, continued development of statistical adjustment methods, and tools for researchers to test their cohorts for overlap and relatedness with GWAS cohorts without sharing individual-level data.

Hydrogel biomaterials that stiffen and soften on demand reveal that skeletal muscle stem cells harbor a mechanical memory.

Muscle stem cells (MuSCs) are specialized cells that reside in adult skeletal muscle poised to repair muscle tissue. The ability of MuSCs to regenerate damaged tissues declines markedly with aging and in diseases such as Duchenne muscular dystrophy, but the underlying causes of MuSC dysfunction remain poorly understood. Both aging and disease result in dramatic increases in the stiffness of the muscle tissue microenvironment from fibrosis. MuSCs are known to lose their regenerative potential if cultured on stiff plastic substrates. We sought to determine whether MuSCs harbor a memory of their past microenvironment and if it can be overcome. We tested MuSCs in situ using dynamic hydrogel biomaterials that soften or stiffen on demand in response to light and found that freshly isolated MuSCs develop a persistent memory of substrate stiffness characterized by loss of proliferative progenitors within the first three days of culture on stiff substrates. MuSCs cultured on soft hydrogels had altered cytoskeletal organization and activity of Rho and Rac guanosine triphosphate hydrolase (GTPase) and Yes-associated protein mechanotransduction pathways compared to those on stiff hydrogels. Pharmacologic inhibition identified RhoA activation as responsible for the mechanical memory phenotype, and single-cell RNA sequencing revealed a molecular signature of the mechanical memory. These studies highlight that microenvironmental stiffness regulates MuSC fate and leads to MuSC dysfunction that is not readily reversed by changing stiffness. Our results suggest that stiffness can be circumvented by targeting downstream signaling pathways to overcome stem cell dysfunction in aged and disease states with aberrant fibrotic tissue mechanics.

Nurse-delivered sleep restriction therapy to improve insomnia disorder in primary care: the HABIT RCT.

Background: Insomnia is a prevalent and distressing sleep disorder. Multicomponent cognitive-behavioural therapy is the recommended first-line treatment, but access remains extremely limited, particularly in primary care where insomnia is managed. One principal component of cognitive-behavioural therapy is a behavioural treatment called sleep restriction therapy, which could potentially be delivered as a brief single-component intervention by generalists in primary care. Objectives: The primary objective of the Health-professional Administered Brief Insomnia Therapy trial was to establish whether nurse-delivered sleep restriction therapy in primary care improves insomnia relative to sleep hygiene. Secondary objectives were to establish whether nurse-delivered sleep restriction therapy was cost-effective, and to undertake a process evaluation to understand intervention delivery, fidelity and acceptability. Design: Pragmatic, multicentre, individually randomised, parallel-group, superiority trial with embedded process evaluation. Setting: National Health Service general practice in three regions of England. Participants: Adults aged ≥ 18 years with insomnia disorder were randomised using a validated web-based randomisation programme. Interventions: Participants in the intervention group were offered a brief four-session nurse-delivered behavioural treatment involving two in-person sessions and two by phone. Participants were supported to follow a prescribed sleep schedule with the aim of restricting and standardising time in bed. Participants were also provided with a sleep hygiene leaflet. The control group received the same sleep hygiene leaflet by e-mail or post. There was no restriction on usual care. Main outcome measures: Outcomes were assessed at 3, 6 and 12 months. Participants were included in the primary analysis if they contributed at least one post-randomisation outcome. The primary end point was self-reported insomnia severity with the Insomnia Severity Index at 6 months. Secondary outcomes were health-related and sleep-related quality of life, depressive symptoms, work productivity and activity impairment, self-reported and actigraphy-defined sleep, and hypnotic medication use. Cost-effectiveness was evaluated using the incremental cost per quality-adjusted life-year. For the process evaluation, semistructured interviews were carried out with participants, nurses and practice managers or general practitioners. Due to the nature of the intervention, both participants and nurses were aware of group allocation. Results: We recruited 642 participants (n = 321 for sleep restriction therapy; n = 321 for sleep hygiene) between 29 August 2018 and 23 March 2020. Five hundred and eighty participants (90.3%) provided data at a minimum of one follow-up time point; 257 (80.1%) participants in the sleep restriction therapy arm and 291 (90.7%) participants in the sleep hygiene arm provided primary outcome data at 6 months. The estimated adjusted mean difference on the Insomnia Severity Index was -3.05 (95% confidence interval -3.83 to -2.28; p < 0.001, Cohen's d = -0.74), indicating that participants in the sleep restriction therapy arm [mean (standard deviation) Insomnia Severity Index = 10.9 (5.5)] reported lower insomnia severity compared to sleep hygiene [mean (standard deviation) Insomnia Severity Index = 13.9 (5.2)]. Large treatment effects were also found at 3 (d = -0.95) and 12 months (d = -0.72). Superiority of sleep restriction therapy over sleep hygiene was evident at 3, 6 and 12 months for self-reported sleep, mental health-related quality of life, depressive symptoms, work productivity impairment and sleep-related quality of life. Eight participants in each group experienced serious adverse events but none were judged to be related to the intervention. The incremental cost per quality-adjusted life-year gained was £2075.71, giving a 95.3% probability that the intervention is cost-effective at a cost-effectiveness threshold of £20,000. The process evaluation found that sleep restriction therapy was acceptable to both nurses and patients, and delivered with high fidelity. Limitations: While we recruited a clinical sample, 97% were of white ethnic background and 50% had a university degree, which may limit generalisability to the insomnia population in England. Conclusions: Brief nurse-delivered sleep restriction therapy in primary care is clinically effective for insomnia disorder, safe, and likely to be cost-effective. Future work: Future work should examine the place of sleep restriction therapy in the insomnia treatment pathway, assess generalisability across diverse primary care patients with insomnia, and consider additional methods to enhance patient engagement with treatment. Trial registration: This trial is registered as ISRCTN42499563. Funding: The award was funded by the National Institute of Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/84/01) and is published in full in Health Technology Assessment; Vol. 28, No. 36. See the NIHR Funding and Awards website for further award information.

Insomnia refers to problems with falling asleep or staying asleep, which affects 10% of the adult population. The recommended treatment for insomnia is a psychological treatment called cognitive­behavioural therapy. Research shows this to be a very effective and long-lasting treatment, but there are not enough trained therapists to support the large number of poor sleepers in the United Kingdom. We have developed a brief version of cognitive­behavioural therapy, called sleep restriction therapy, which involves supporting the patient to follow a new sleep­wake pattern. We carried out this study to see if sleep restriction therapy, given by nurses working in general practice, can improve insomnia and quality of life. We searched general practice records and invited people with insomnia to take part. Six hundred and forty-two participants were assigned, by chance, to either sleep restriction therapy or a comparison treatment, called sleep hygiene. Sleep restriction therapy involved meeting with a nurse on four occasions and following a prescribed sleep schedule. Sleep hygiene involved receiving a leaflet of sleep 'do's and dont's'. Those receiving sleep restriction therapy were also provided with the same sleep hygiene leaflet so that the difference between the two groups was whether or not they received nurse treatment. We measured sleep, quality of life, daytime functioning and use of sleep medication through questionnaires, before and after treatment. We calculated the cost to deliver the treatment, as well as the cost of other National Health Service treatments that participants accessed during the study. We also interviewed participants and nurses to understand their views of the treatment. We found that participants in the sleep restriction therapy group experienced greater reduction in their insomnia symptoms compared to sleep hygiene. They also experienced improved sleep, mental health, quality of life and work productivity. The two groups did not differ in their use of prescribed sleep medication. Our results suggest that the treatment is likely to represent good value for money for the National Health Service. Both nurses and participants considered the treatment to be acceptable and beneficial, and they suggested some potential refinements. The study shows that nurse-delivered sleep restriction therapy is likely to be a clinically effective approach to the treatment of insomnia, and good value for money for the National Health Service.

Door-to-antibiotic time and mortality in patients with sepsis: Systematic review and meta-analysis.

OBJECTIVES: To evaluate whether the timing of initial antibiotic administration in patients with sepsis in hospital affects mortality. METHODS: This systematic review and meta-analysis included studies from inception up to 19 May 2022. Interventional and observational studies including adult human patients with suspected or confirmed sepsis and reported time of antibiotic administration with mortality were included. Data were extracted by two independent reviewers. Summary estimates were calculated by using random-effects model. The primary outcome was mortality. RESULTS: We included 42 studies comprising 190,896 patients with sepsis. Pooled data showed that the OR for patient mortality who received antibiotics ≤1 hr was 0.83 (95 %CI: 0.67 to 1.04) when compared with patients who received antibiotics >1hr. Significant reductions in the risk of death in patients with earlier antibiotic administration were observed in patients ≤3 hrs versus >3 hrs (OR: 0.80, 95 %CI: 0.68 to 0.94) and ≤6 hrs vs 6 hrs (OR: 0.57, 95 %CI: 0.39 to 0.82). CONCLUSIONS: Our findings show an improvement in mortality in sepsis patients with early administration of antibiotics at <3 and <6 hrs. Thus, these results suggest that antibiotics should be administered within 3 hrs of sepsis recognition or ED arrival regardless of the presence or absence of shock.

Performance and detection range of acoustic receivers in mangrove habitats.

Acoustic telemetry has been used to monitor the movement of aquatic animals in a broad range of aquatic environments. Despite their importance, mangrove habitats are understudied for the spatial ecology of elasmobranchs, with acoustic telemetry rarely used inside mangrove habitats. One reason for this may be a general assumption that acoustic signals would not be able to be detected by receivers in such shallow, structurally complex, environments. This study tested whether acoustic receivers can be used inside mangrove habitats to track the movement of sharks and rays. Thirty-eight receivers were deployed in a mangrove system in Pioneer Bay, Orpheus Island, Great Barrier Reef, including inside mangroves, mangrove edges, and adjacent reef flat areas. The detection range and receiver performance metrics, such as code detection efficiency, rejection coefficient, and noise quotient, were examined and tested among habitats. The results highlighted that the signal from transmitters was successfully detected inside mangrove habitats as well as on the adjacent reef flat. The range to detect at least 50% of transmissions was up to 20 m inside mangroves and up to 120 m outside mangroves. The performance metrics of acoustic receivers inside the mangrove habitat were characterized by low background noise, low rejection rates, and reasonably high code detection efficiency. Furthermore, this study tested the application of this method on juvenile blacktip reef shark Carcharhinus melanopterus and mangrove whipray Urogymnus granulatus, and demonstrated that it can be used to successfully track animals inside mangrove habitat. This novel method could reveal further information on how sharks and rays use mangrove habitats.

Interaction between visual impairment and genetic risk of dementia and psychosis in older adults.

BACKGROUND: Visual impairment (VI) is associated with dementia and other neuropsychiatric outcomes, but previous studies have not considered genetic sources of confounding or effect modification. METHODS: We analysed data from the Health and Retirement Study, an ongoing nationally representative survey of older US adults, a subset of whom underwent genetic testing from 2006 to 2012 (n = 13 465). Using discrete time proportional hazards models and generalised estimating equations, we measured the association between VI and dementia, depression and hallucinations adjusting for demographics and comorbidities, ancestry-specific principal components and polygenic risk scores (PRS) for Alzheimer's disease, major depressive disorder or schizophrenia. Effect modification was assessed using VI-PRS interaction terms and stratified analyses. RESULTS: VI was associated with dementia, depression and hallucinations after adjusting polygenic risk and other confounders. There was no VI-PRS interaction for dementia or depression. However, the association between VI and hallucinations varied by genetic risk of schizophrenia. Within the bottom four quintiles of schizophrenia PRS, VI was not associated with hallucinations among White (OR 1.16, 95% CI: 0.87-1.55) or Black participants (OR 0.96, 95% CI: 0.49-1.89). In contrast, VI was strongly associated with hallucinations among White (OR 2.08, 95% CI: 1.17-3.71) and Black (OR 10.63, 95% CI: 1.74-65.03) participants in the top quintile of schizophrenia PRS. CONCLUSIONS: The association between VI and neuropsychiatric outcomes is not explained by shared genetic risk factors, and there is a significant interaction between VI and polygenic risk of hallucinations in older adults.