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Context Peatlands in the Australian Alps are important ecologically and recognised in national environmental legislation. Increasing fire frequency over the past 40 years has put the community at greater risk of degradation. Aims Using published studies of fire effects in peatlands and new data, we investigate general responses of peatlands to fire so that risk can be evaluated and appropriate management adopted. Methods We present four case studies that employ repeated measures of floristic composition or chronosequences to assess fire-related changes. Key results Cover of frequently-occurring species declined after fire but most had returned to pre-fire cover after 10 years. Recovery of the obligate seeder shrub Dracophyllum continentis (B.L.Burtt) S.Venter and the dominant moss Sphagnum cristatum Hampe was much slower, but variable for the latter, apparently depending on fire intensity and post-fire moisture availability; both species favoured less frequently burnt peatlands with high soil moisture. Some herbs (including non-native species) benefitted from fire, briefly becoming abundant soon afterwards. Overall species richness and diversity were unaffected by fire. Conclusions Peatlands in the Australian Alps tend to be resilient to single fires with effects on species composition being short-lived. However, species cover (especially Sphagnum cristatum) requires perhaps 20 years between fires for full recovery. Fire can cause localised community extinction and this is likely to be exacerbated by other pressures such as trampling and drought. Implications Fire will be difficult to manage in peatlands but resilience might be built by removing other pressures such as trampling by feral animals.

We present the discovery and characterization of six short-period, transiting giant planets from NASA's Transiting Exoplanet Survey Satellite (TESS) -- TOI-1811 (TIC 376524552), TOI-2025 (TIC 394050135), TOI-2145 (TIC 88992642), TOI-2152 (TIC 395393265), TOI-2154 (TIC 428787891), & TOI-2497 (TIC 97568467). All six planets orbit bright host stars (8.9, Comment: 20 Pages, 6 Figures, 8 Tables, Accepted by MNRAS

Tasmania is an island state in south-eastern Australia that has a long and rich history of seaweed use, research, and development. It is a cool-temperate system with 750 macroalgal species currently described. Tasmanian Aboriginal peoples have lived on this land for at least 40,000 years utilising seaweed as food, shelter, water carriers and medicine, as well as for ceremonial reasons. Modern taxonomic investigations began with French naturalist Jacques-Julien Houtou de La Billardière in 1791, and there are 184 type specimens of seaweeds originating from Tasmania. Ecological and physiological studies of seaweed in Tasmania have focussed on the dominant large brown seaweeds (Laminariales and Fucales) and have contributed significantly to the global understanding of these systems, particularly related to community resilience, seaweed-urchin interactions, their habitat-forming role for other species, responses to global change, and restoration of lost habitat. Ocean warming and changing oceanography have caused a 95% decline in surface canopy cover of Macrocystis pyrifera in eastern Tasmania since the 1950s and led to a focus on restoring these lost forests. Tasmanian seaweed communities have a uniquely high proportion (up to ∼90%) of seaweeds that rely solely on CO2 for photosynthesis, which has implications for responses to ocean acidification. Tasmania has industries that use brown seaweeds for fucoidan extraction and beach-cast harvest for alginates, fertilisers, and feeds for agriculture. New aquaculture initiatives include integrated multi-trophic aquaculture, offshore kelp mariculture and Asparagopsis cultivation for bioactive products to reduce methane emissions in ruminants, as and the development of unexploited species including Caulerpa spp. for food.

The N-terminal half of the giant cytoskeletal protein obscurin is comprised of more than 50 Ig-like domains, arranged in tandem. Domains 18-51 are connected to each other through short 5-residue linkers, and this arrangement has been previously shown to form a semi-flexible rod in solution. Domains 1-18 generally have slightly longer ~7 residue interdomain linkers, and the multidomain structure and motion conferred by this kind of linker is understudied. Here, we use NMR, SAXS, and MD to show that these longer linkers are associated with significantly more domain/domain flexibility, with the resulting multidomain structure being moderately compact. Further examination of the relationship between interdomain flexibility and linker length shows there is a 5 residue "sweet spot" linker length that results in dual-domain systems being extended, and conversely that both longer or shorter linkers result in a less extended structure. This detailed knowledge of the obscurin N terminus structure and flexibility allowed for mathematical modeling of domains 1-18, which suggests that this region likely forms tangles if left alone in solution. Given how infrequently protein tangles occur in nature, and given the pathological outcomes that occur when tangles do arise, our data suggest that obscurin is likely either significantly scaffolded or else externally extended in the cell.

Kelp aquaculture is an emerging industry outside of Asia. To be successful, this industry requires a reliable production of seedstock, the optimisation of which greatly benefits from a detailed physiological understanding of the microscopic life-cycle stages of the cultured species. This study investigated the impact of six zoospore densities (10–278 mm−2) on the subsequent development of Ecklonia radiata gametophytes and sporophytes. The results showed that germination rates and sex ratio were unaffected by initial zoospore density, but there were significant effects on gametophyte size and sporophyte production. After two weeks, female gametophytes were largest at an initial zoospore density of 40 mm−2 while male gametophytes grew largest at densities below 40 mm−2, but after four weeks gametophyte size showed a negative relationship with initial zoospore density. Significantly more sporophytes developed at initial zoospore densities below 40 individuals mm−2 and no sporophytes were observed at the highest density (271 zoospores mm−2). These results clearly show the importance of initial zoospore density in optimising the nursery stage of kelp aquaculture.

Background: The SPRINT (Systolic Blood Pressure Intervention Trial) demonstrated reductions in major cardiovascular disease events and mortality with an intensive systolic blood pressure (SBP) goal intervention. However, a detailed description of the blood pressure intervention, antihypertensive medication usage, blood pressure levels, and rates and predictors of blood pressure control has not been reported previously. Methods: Hypertensive participants (n=9361) 50 years and older with elevated cardiovascular disease risk were randomized 1:1 to SBP goal Results: Baseline blood pressure (median±interquartile range) was 138±19/78±16 mm Hg. For intensive group participants, percent at goal rose from 8.9% at baseline to 52.4% at 6 months and average antihypertensive medications rose from 2.2 to 2.7; SBP was Conclusions: These results may inform and help replicate the benefits of SPRINT in clinical practice. Registration: URL: http://www.clinicaltrials.gov ; Unique identifier: NCT01206062.

Communication of the benefits and harms of blood pressure lowering strategy is crucial for shared decision-making.To quantify the effect of intensive versus standard systolic blood pressure lowering in terms of the number of event-free days DESIGN: Post hoc analysis of the Systolic Blood Pressure Intervention Trial PARTICIPANTS: A total of 9361 adults 50 years or older without diabetes or stroke who had a systolic blood pressure of 130-180 mmHg and elevated cardiovascular risk INTERVENTIONS: Intensive (systolic blood pressure goal120 mmHg) versus standard blood pressure lowering (140 mmHg) MAIN MEASURES: Days free of major adverse cardiovascular events (MACE), serious adverse events (SAE), and monitored adverse events (hypotension, syncope, bradycardia, electrolyte abnormalities, injurious falls, or acute kidney injury) over a median follow-up of 3.33 years KEY RESULTS: The intensive treatment group gained 14.7 more MACE-free days over 4 years (difference, 14.7 [95% confidence interval: 5.1, 24.4] days) than the standard treatment group. The benefit of the intensive treatment varied by cognitive function (normal: difference, 40.7 [13.0, 68.4] days; moderate-to-severe impairment: difference, -15.0 [-56.5, 26.4] days; p-for-interaction=0.009) and self-rated health (excellent: difference, -22.7 [-51.5, 6.1] days; poor: difference, 156.1 [31.1, 281.2] days; p-for-interaction=0.001). The mean overall SAE-free days were not significantly different between the treatments (difference, -14.8 [-35.3, 5.7] days). However, the intensive treatment group had 28.5 fewer monitored adverse event-free days than the standard treatment group (difference, -28.5 [-40.3, -16.7] days), with significant variations by frailty status (non-frail: difference, 38.8 [8.4, 69.2] days; frail: difference, -15.5 [-46.6, 15.7] days) and self-rated health (excellent: difference, -12.9 [-45.5, 19.7] days; poor: difference, 180.6 [72.9, 288.4] days; p-for-interaction0.001).Over 4 years, intensive systolic blood pressure lowering provides, on average, 14.7 more MACE-free days than standard treatment, without any difference in SAE-free days. Whether this time-based effect summary improves shared decision-making remains to be elucidated.ClinicalTrials.gov Registration: NCT01206062.

Protein amyloid-β (Aβ) oligomers with β-sheet-like backbone (β-structured) form extracellular amyloid plaques associated with Alzheimer’s disease (AD). However, the relationship to AD is not known. Some investigations suggest that the toxic Aβ component has α-sheet-like backbone (α-structured) subsequently detoxified by intracellular α-to-β conversion before plaque formation. Our objective is to compare this latter hypothesis with observations made by electron microscopy of thin sections of AD-cerebral cortex. We observe irregular, 200–2,000 nm, intracellular, lipofuscin-like inclusions. Some are light-staining and smooth. Others are dark-staining and made granular by fibers that are usually overlapping and are sometimes individually seen. Aspects unusual for lipofuscin include 1) dark and light inclusions interlocking as though previously one inclusion, 2) dark inclusion-contained 2.6 nm thick sub-fibers that are bent as though α-structured, and 3) presence of inclusions in lysosomes and apparent transfer of dark inclusion material to damaged, nearby lysosomal membranes. These data suggest the following additions to α-structure-based hypotheses: 1) Lipofuscin-associated, α-structured protein toxicity to lysosomal membranes is in the chain of AD causation; 2) α-to-β detoxification of α-structured protein occurs in lipofuscin and causes dark-to-light transition that, when incomplete, is the origin of cell-to-cell transmission essential for development of AD.

The red algal genus Asparagopsis produces secondary metabolites that when fed to ruminants reduce methane production by up to 98%. However, cultivation methods for Asparagopsis are nascent and fundamental information on reproduction, which is essential for large-scale cultivation, is lacking. In this study we examined asexual propagation in Asparagopsis armata, the regrowth of fragments and mechanisms of attachment to assess the potential for fragments to be used in sea-based cultivation. Asparagopsis armata gametophytes grow specialised structures, barbs, that hook fragments onto substrata. Surveys revealed barbs were abundant occurring at ~ 1 barb every 3–4 cm on gametophyte branches. Barbs did not regrow, but fronds did, either when attached to a barb or on their own. In contrast, fronds doubled in size with most developing barbs within 4 weeks. Barbs were, however, critical for the reattachment of fragments: barbs attached to substrata at four times the rate of frond fragments without barbs and they also attached in higher proportions to mussel rope than polypropylene rope, and two types of net. Utilising fragmentation for the propagation of A. armata gametophytes in sea-based cultivation requires that fragments can attach to a substratum and regrow once attached. We have shown that A. armata fragments in Tasmania require barbs for attachment and frond tissue for growth, which has implications for cultivation. Optimising fragmentation, attachment and out-planting methods are important future steps in establishing fragmentation as a method for sea-based cultivation in A. armata.

The timing and mechanisms of past hydroclimate change in northeast Mexico are poorly constrained, limiting our ability to evaluate climate model performance. To address this, we present a multiproxy speleothem record of past hydroclimate variability spanning 62.5 to 5.1 ka from Tamaulipas, Mexico. Here we show a strong influence of Atlantic and Pacific sea surface temperatures on orbital and millennial scale precipitation changes in the region. Multiple proxies show no clear response to insolation forcing, but strong evidence for dry conditions during Heinrich Stadials. While these trends are consistent with other records from across Mesoamerica and the Caribbean, the relative importance of thermodynamic and dynamic controls in driving this response is debated. An isotope-enabled climate model shows that cool Atlantic SSTs and stronger easterlies drive a strong inter-basin sea surface temperature gradient and a southward shift in moisture convergence, causing drying in this region.

Lessonia (order Laminariales) is a kelp genus restricted to the temperate southern hemisphere, where species form dense forests from the low intertidal to 25 m depth at wave exposed sites. Lessonia spp. are among the most harvested kelps globally due to their importance in providing raw materials for food, cosmetics, bioactive and biomedical industries. Over-harvesting of natural beds can negatively affect Lessonia populations and the many species that depend on these habitats, including commercially important fish and molluscs, but good harvest management plans reduce these impacts on natural Lessonia stocks. However, the increasing demand for raw materials will likely only be met by aquaculture for which Lessonia shows high potential in pilot scale studies undertaken in Chile, New Zealand, and Australia. In this concise review, we highlight the current knowledge of Lessonia spp. taxonomy and distribution, life history, ecology and ecosystem services, wild harvest, aquaculture, and commercial applications. We discuss future research directions.

Understanding the penetrance of pathogenic variants identified as secondary findings (SFs) is of paramount importance with the growing availability of genetic testing. We estimated penetrance through large-scale analyses of patients referred for diagnostic sequencing for hypertrophic cardiomyopathy (HCM; 10,400 cases, 1,340 variants) and dilated cardiomyopathy (DCM; 2,564 cases, 665 variants), using a cross-sectional approach comparing allele frequencies against reference populations (293,226 participants from UK Biobank and gnomAD). We generated updated prevalence estimates for HCM (1:543) and DCM (1:220).In aggregate, the penetrance by late adulthood of rare, pathogenic variants (23% for HCM, 35% for DCM) and likely pathogenic variants (7% for HCM, 10% for DCM) was substantial for dominant CM. Penetrance was significantly higher for variant subgroups annotated as loss of function or ultra-rare, and for males compared to females for variants in HCM-associated genes.We estimated variant-specific penetrance for 316 recurrent variants most likely to be identified as SFs (51% HCM and 17% DCM cases). 49 variants were observed at least ten times (14% of cases) in HCM-associated genes. Median penetrance was 14.6% (±14.4% SD). We explore estimates of penetrance by age, sex, and ancestry, and simulate the impact of including future cohorts.This dataset is the first to report penetrance of individual variants at scale and will inform the management of individuals undergoing genetic screening for SFs. While most variants had low penetrance and the costs and harms of screening are unclear, some carriers of highly penetrant variants may benefit from SFs.Graphical AbstractA flowchart of the estimated penetrance for dominant cardiomyopathy by late adulthood for a variant of interest. The estimates of penetrance in this study are for carriers identified from unselected populations (e.g., consumer-initiated elective genomic testing or as secondary (2°) findings in clinical settings). If the variant is ultra-rare (i.e., identified once or less in population datasets), only estimates by variant subgroup in aggregate are available. If the variant is identified multiple times in both case and population datasets, variant-specific penetrance estimates may be available. If the variant is curated as a variant of uncertain significance (VUS), the penetrance estimate is low. If the variant is a likely pathogenic predicted loss of function (pLoF) variant and is identifiable multiple times in cases and population cohorts, penetrance estimates vary by gene (Figure 2). High aggregate penetrance represents an estimate of >25%; moderate aggregate penetrance represents 10%-25%, and low penetrance represents

IMPORTANCE: Antihypertensive treatments benefit cerebrovascular health and cognitive function in patients with hypertension, but it is uncertain whether an intensive blood pressure target leads to potentially harmful cerebral hypoperfusion. OBJECTIVE: To investigate the association of intensive systolic blood pressure (SBP) control vs standard control with whole-brain cerebral blood flow (CBF). DESIGN, SETTING, AND PARTICIPANTS: This substudy of the Systolic Blood Pressure Intervention Trial (SPRINT) randomized clinical trial compared the efficacy of 2 different blood pressure–lowering strategies with longitudinal brain magnetic resonance imaging (MRI) including arterial spin labeled perfusion imaging to quantify CBF. A total of 1267 adults 50 years or older with hypertension and increased cardiovascular risk but free of diabetes or dementia were screened for the SPRINT substudy from 6 sites in the US. Randomization began in November 2010 with final follow-up MRI in July 2016. Analyses were performed from September 2020 through December 2021. INTERVENTIONS: Study participants with baseline CBF measures were randomized to an intensive SBP target less than 120 mm Hg or standard SBP target less than 140 mm Hg. MAIN OUTCOMES AND MEASURES: The primary outcome was change in whole-brain CBF from baseline. Secondary outcomes were change in gray matter, white matter, and periventricular white matter CBF. RESULTS: Among 547 participants with CBF measured at baseline, the mean (SD) age was 67.5 (8.1) years and 219 (40.0%) were women; 315 completed follow-up MRI at a median (IQR) of 4.0 (3.7-4.1) years after randomization. Mean whole-brain CBF increased from 38.90 to 40.36 (difference, 1.46 [95% CI, 0.08-2.83]) mL/100 g/min in the intensive treatment group, with no mean increase in the standard treatment group (37.96 to 37.12; difference, –0.84 [95% CI, –2.30 to 0.61] mL/100 g/min; between-group difference, 2.30 [95% CI, 0.30-4.30; P = .02]). Gray, white, and periventricular white matter CBF showed similar changes. The association of intensive vs standard treatment with CBF was generally similar across subgroups defined by age, sex, race, chronic kidney disease, SBP, orthostatic hypotension, and frailty, with the exception of an indication of larger mean increases in CBF associated with intensive treatment among participants with a history of cardiovascular disease (interaction P = .05). CONCLUSIONS AND RELEVANCE: Intensive vs standard antihypertensive treatment was associated with increased, rather than decreased, cerebral perfusion, most notably in participants with a history of cardiovascular disease. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01206062

The greater antihypertensive responses to initial therapy with calcium channel blockers (CCBs) or thiazide-type diuretics than renin-angiotensin system blockers as initial therapy in non-Hispanic Black (NHB) adults was recognized in the US High BP guidelines from 1988 to 2003. The 2014 Report from Panel Members Appointed to the Eighth Joint National Committee (2014 aJNC8 Report) and the 2017 American College of Cardiology/American Heart Association High Blood Pressure Guideline were the first to recommend CCBs or thiazide-type diuretics rather than renin-angiotensin system blockers as initial therapy in NHB. We assessed the temporal relationship of these recommendations on self-reported CCB or thiazide-type diuretics monotherapy by NHB and NHW adults with hypertension absent compelling indications for β-blockers or renin-angiotensin system blockers in National Health and Nutrition Examination Surveys 2015 to 2018 versus 2007 to 2012 (after versus before 2014 aJNC8 Report). CCB or thiazide-type diuretics monotherapy was unchanged in NHW adults (17.1% versus 18.1%, P =0.711) and insignificantly higher after 2014 among NHB adults (43.7% versus 38.2%, P =0.204), although CCB monotherapy increased (29.5% versus 21.0%, P =0.021) and renin-angiotensin system blocker monotherapy fell (44.5% versus 31.0%, P =0.008). Although evidence-based CCB monotherapy increased among NHB adults in 2015 to 2018, hypertension control declined as untreated hypertension and monotherapy increased. While a gap between recommended and actual monotherapy persists, evidence-based monotherapy appears insufficient to improve hypertension control in NHB adults, especially given evidence for worsening therapeutic inertia. Initiating treatment with single-pill combinations and timely therapeutic intensification when required to control hypertension are evidence-based, race-neutral options for improving hypertension control among NHB adults.

Recently published national data demonstrate inadequate and worsening control of high blood pressure (HBP) in the United States, outcomes that likely have been made even worse by the coronavirus disease 2019 (COVID-19) pandemic. This major public health crisis exposes shortcomings of the US health care delivery system and creates an urgent opportunity to reduce mortality, major cardiovascular events, and costs for 115 million Americans. Ending this crisis will require a more coherent and systemic change to traditional patterns of care. The authors present an evidence-based Blueprint for Change for comprehensive health delivery system redesign based on current national clinical practice guidelines and quality measures. This innovative model includes a systems-based approach to ensuring proper BP measurement, assessment of cardiovascular risk, effective patient-centered team-based care, addressing social determinants of health, and shared decision-making. The authors also propose building on current national quality improvement initiatives designed to better control HBP.

Motivation The vast expansion of sequence data generated from single organisms and microbiomes has precipitated the need for faster and more sensitive methods to assess evolutionary and functional relationships between proteins. Representing proteins as sets of short peptide sequences (kmers) has been used for rapid, accurate classification of proteins into functional categories; however, this approach employs an exact-match methodology and thus may be limited in terms of sensitivity and coverage. We have previously used similarity groupings, based on the chemical properties of amino acids, to form reduced character sets and recode proteins. This amino acid recoding (AAR) approach simplifies the construction of protein representations in the form of kmer vectors, which can link sequences with distant sequence similarity and provide accurate classification of problematic protein families. Results Here, we describe Snekmer, a software tool for recoding proteins into AAR kmer vectors and performing either (i) construction of supervised classification models trained on input protein families or (ii) clustering for de novo determination of protein families. We provide examples of the operation of the tool against a set of nitrogen cycling families originally collected using both standard hidden Markov models and a larger set of proteins from Uniprot and demonstrate that our method accurately differentiates these sequences in both operation modes. Availability and implementation Snekmer is written in Python using Snakemake. Code and data used in this article, along with tutorial notebooks, are available at http://github.com/PNNL-CompBio/Snekmer under an open-source BSD-3 license. Supplementary information Supplementary data are available at Bioinformatics Advances online.

This review summarizes published findings of the beneficial and harmful effects on the heart, lungs, immune system, kidney, liver, and central nervous system of 47 drugs that have been proposed to treat COVID-19. Many of the repurposed drugs were chosen for their benefits to the pulmonary system, as well as immunosuppressive and anti-inflammatory effects. However, these drugs have mixed effects on the heart, liver, kidney, and central nervous system. Drug treatments are critical in the fight against COVID-19, along with vaccines and public health protocols. Drug treatments are particularly needed as variants of the SARS-Cov-2 virus emerge with some mutations that could diminish the efficacy of the vaccines. Patients with comorbidities are more likely to require hospitalization and greater interventions. The combination of treating severe COVID-19 symptoms in the presence of comorbidities underscores the importance of understanding the effects of potential COVID-19 treatments on other organs. Supplementary Information The online version contains supplementary material available at 10.1007/s42399-021-00874-8.

Introduction Occupational therapy (OT) has a rich history of integrating physical and mental health care services, however, there is a limited evidence base regarding the effectiveness of OT interventions for mental health disorders in primary care. Methods A comprehensive systematic review was conducted from database inception through 31 January 2021. Eligible studies had to include: (1) an intervention that involved an occupational therapist in design and/or implementation; (2) a quantitative outcome assessing symptoms related to a mental health disorder; (3) a comparison group; and (4) primary care or community dwelling patients and/or primary care clinical settings. Results The researchers identified five studies and there was heterogeneity in the OT interventions. There were no significant differences between intervention and control groups in depression symptoms at different time intervals. Several trials employed interventions that involved interprofessional team members, including OTs, to provide training in specific strategies that promoted functioning. Other studies utilized only OTs within the intervention arm. OT interventions demonstrated no significant difference in anxiety in one study, however, another indicated a reduction in symptoms. The overall risk of bias was considered low in three studies and unclear in two studies. Conclusion There is limited evidence demonstrating the impact of OT interventions in primary care settings on quantitative outcomes measuring symptoms related to a mental health disorder. Given the heterogeneity of interventions and variation in reported findings, there is need for further pragmatic trials in this area.

The Systolic Blood Pressure Intervention Trial (SPRINT) results have influenced clinical practice but have also generated discussion regarding the validity, generalizability and importance of the findings. Following the SPRINT primary results manuscript in 2015, additional results and analyses of the data have addressed these concerns. The primary objective of this manuscript is to respond to key questions that have been raised. The Systolic Blood Pressure Intervention Trial (SPRINT) demonstrated the effectiveness of treating SBP to levels well below those previously recommended in US and European BP guidelines.(1) The SPRINT results have informed guideline committees in recommending treatment to SBP targets lower than previously advised.(2–4) However, some of the SPRINT findings have generated discussion, and questions have been raised regarding their application in clinical practice. These include generalizability, validity of the outcome measures (especially heart failure), the methods used for event ascertainment, the effect size of the intervention benefit, and safety and tolerability of the

Introduction: Longitudinal Integrated Clerkships (LICs) have demonstrated benefits for students' learning and development in medical education globally. The model emphasises importance with respect to continuity and time in the workplace for learners. There is a need to explore how LICs become a viable training model for learners. An amalgamative LIC model was drawn upon to inform the design of a placement for trainee pharmacists on a hospital ward. This study sought to determine the local viability of a longitudinal placement for trainee pharmacists, using communities of practice learning theory to interpret findings. Methods: A design-based research approach informed study design. A longitudinal placement was implemented on two hospital wards for 13 weeks. Trainees (n = 3) were interviewed four times over a 14-week period. Ward staff (n = 14) were interviewed at week 14. Interviews were transcribed verbatim. Qualitative longitudinal analysis, using the trajectory approach, was conducted using abductive analysis. The coded data were organised into a framework and subthemes were created. Results: Trainees acquired membership within the multi-disciplinary ward team over time. This led to an enriched learning experience and the trainee's professional development improved as they attained more responsibilities. This enabled them to make a greater contribution to patient care; more medication consultations occurred, and discharge times improved. Discussion: The local viability of the longitudinal placement appears to be linked to the trainee's ability to acquire membership within the ward community of practice. Membership gave trainee's access to learning opportunities, supporting their development, and they earnt the trust of staff, leading to more responsibilities for providing patient care. Further research into developing longitudinal placements that support trainee healthcare professionals to acquire membership within communities of practice is warranted.

To explore aged care nurses' awareness and experience of unwanted sexual behaviour (USB) in residential aged care services (RACS).An anonymous online questionnaire was administered to an opportunistic sample of RACS nurses enrolled to complete an e-learning course in Australia. From the 167 participants who expressed interest to enrol, 129 were eligible and 53 returned completed consent forms.46/53 responded of which most were females (41/45, 91.1%). Few respondents reported resident-resident USB (35%) or staff-resident USB (22%) happened once a year. Most respondents had not been informed by a resident of USB (75%) or had personally reported USB within their internal reporting system (77%). Respondents were also unaware if their facility had lodged an incident report to the regulator or law enforcement authorities within the past 12 months (34/46, 73.9%). Finally, most considered there to be no barriers to reporting USB (35/46, 77.8%).Respondents' awareness and estimates of USB directed at residents were much lower than known national prevalence rates. This lack of awareness could be a substantive barrier to recognition and optimal management of this form of abuse.

The kelp, Ecklonia radiata, is an abundant subtidal ecosystem engineer in southern Australia. Density-dependent changes in the abiotic environment engineered by Ecklonia may feedback to affect reproduction and subsequent recruitment. Here, we examined: 1) how the reproductive capacity of Ecklonia individuals in the field (zoospores released · mm-2 reproductive tissue) varied with adult density and time, and 2) how the recruitment of microscopic gametophytes and sporophytes was influenced by zoospore density at two times. Zoospore production did not vary with adult density, with only one month out of ten sampled over a 2-y period showing a significant effect of density. However, zoospore production varied hugely over time, being generally highest in mid-autumn and lowest in mid-late summer. There were strong effects of initial zoospore density on gametophyte and sporophyte recruitment with both a minimum and an optimum zoospore density for sporophyte recruitment, but these varied in time. Almost no sporophytes developed when initial zoospore density was 335 · mm-2 in spring and >261 · mm-2 in winter and was zero at very high zoospore densities. These findings suggest that although adult Ecklonia density does not affect per-capita zoospore production, because there is a minimum zoospore density for sporophyte production, a decline in population-level output could feedback to impact recruitment.

Bacterial pathogens are confronted with a range of challenges at the site of infection, including exposure to antibiotic treatment and harsh physiological conditions, that can alter the fitness benefits and costs of acquiring antibiotic resistance. Here, we develop an experimental system to recapitulate resistance gene acquisition by Staphylococcus aureus and test how the subsequent evolution of the resistant bacterium is modulated by antibiotic treatment and oxygen levels, both of which are known to vary extensively at sites of infection. We show that acquiring tetracycline resistance was costly, reducing competitive growth against the isogenic strain without the resistance gene in the absence of the antibiotic, for S. aureus under hypoxic but not normoxic conditions. Treatment with tetracycline or doxycycline drove the emergence of enhanced resistance through mutations in an RluD-like protein-encoding gene and duplications of

Regenerative medicine, using cells as therapeutic agents for the repair or regeneration of tissues and organs, offers great hope for the future of medicine. Cell therapy for treating defects in articular cartilage has been an exemplar of translating this technology to the clinic, but it is not without its challenges. These include applying regulations, which were designed for pharmaceutical agents, to living cells. In addition, using autologous cells as the therapeutic agent brings additional costs and logistical challenges compared with using allogeneic cells. The main cell types used in treating chondral or osteochondral defects in joints to date are chondrocytes and mesenchymal stromal cells derived from various sources such as bone marrow, adipose tissue or umbilical cord. This review discusses some of their biology and pre-clinical studies before describing the most pertinent clinical trials in this area.

The microbiome is an underappreciated contributor to intestinal drug metabolism with broad implications for drug efficacy and toxicity. While considerable progress has been made towards identifying the gut bacterial genes and enzymes involved, the role of environmental factors in shaping their activity remains poorly understood. Here, we focus on the gut bacterial reduction of azo bonds (R-N=N-R’), found in diverse chemicals in both food and drugs. Surprisingly, the canonicalazoRgene inEscherichia coliwas dispensable for azo bond reduction. Instead, azo reductase activity was controlled by the fumarate and nitrate reduction (fnr) regulator, consistent with a requirement for the anoxic conditions found within the gastrointestinal tract. Paired transcriptomic and proteomic analysis of thefnrregulon revealed that in addition to altering the expression of multiple reductases, FNR is necessary for the metabolism of L-Cysteine to hydrogen sulfide, enabling the degradation of azo bonds. Taken together, these results show how gut bacteria sense and respond to their intestinal environment to enable the metabolism of chemical motifs found in both dietary and pharmaceutical compounds.IMPORTANCEThis work has broad relevance due to the ubiquity of dyes containing azo bonds in food and drugs. We report that azo dyes can be degraded by human gut bacteria through both enzymatic and non-enzymatic mechanisms, even from a single gut bacterial species. Furthermore, we revealed that environmental factors, oxygen and cysteine, control the ability ofE. colito degrade azo dyes due to their impacts on bacterial transcription and metabolism. These results open up new opportunities to manipulate the azoreductase activity of the gut microbiome through the manipulation of host diet, suggest that azoreductase potential may be altered in patients suffering from gastrointestinal disease, and highlight the importance of studying bacterial enzymes for drug metabolism in their natural cellular and ecological context.

Background Peripheral artery disease (PAD) increases the risk of cardiovascular events and limb events including amputations. PAD is twice as prevalent in Black compared with non‐Hispanic White individuals, especially among men. Screening for PAD using the ankle–brachial index in community settings, such as the barbershop, could lead to earlier diagnosis and treatment. Methods and Results A pilot study was conducted at 2 barbershops in Cleveland, OH from June to December 2020 to assess the feasibility of screening for PAD in the barbershop setting and the effect of an educational intervention on PAD awareness. After screening with both automated and Doppler ankle–brachial index, PAD was identified in 5/31 (16.1%) of participants. Baseline systolic blood pressure, low‐density lipoprotein cholesterol, and random blood glucose were higher in participants who screened positive for PAD ( P P =0.004). An association was found between PAD awareness at baseline and highest education level achieved: compared with those with some college/associate's degree or higher, non–high school graduates scored lower on PAD awareness ( P =0.022), as did those who only had a high school diploma or tests of General Educational Development ( P =0.049). Conclusions In a pilot study, barbershop‐based screening for PAD among Black men revealed a higher than expected PAD prevalence and low PAD awareness. An educational video was effective at increasing PAD awareness. Ankle–brachial index screening and educational outreach in the barbershop may be a feasible and effective tool to diagnose PAD and reduce PAD disparities among Black men at highest risk.

To keep pace with the rapid advancements in molecular genetics and rare diseases research, we have updated the list of ectodermal dysplasias based on the latest classification approach that was adopted in 2017 by an international panel of experts. For this purpose, we searched the databases PubMed and OMIM for the term “ectodermal dysplasia”, referring mainly to changes in the last 5 years. We also tried to obtain information about those diseases on which the last scientific report appeared more than 15 years ago by contacting the authors of the most recent publication. A group of experts, composed of researchers who attended the 8th International Conference on Ectodermal Dysplasias and additional members of the previous classification panel, reviewed the proposed amendments and agreed on a final table listing all 49 currently known ectodermal dysplasias for which the molecular genetic basis has been clarified, including 15 new entities. A newly reported ectodermal dysplasia, linked to the gene LRP6, is described here in more detail. These ectodermal dysplasias, in the strict sense, should be distinguished from syndromes with features of ectodermal dysplasia that are related to genes extraneous to the currently known pathways involved in ectodermal development. The latter group consists of 34 syndromes which had been placed on the previous list of ectodermal dysplasias, but most if not all of them could actually be classified elsewhere. This update should streamline the classification of ectodermal dysplasias, provide guidance to the correct diagnosis of rare disease entities, and facilitate the identification of individuals who could benefit from novel treatment options.

SUMMARYMany cellular processes are governed by protein-protein interactions that require tight spatial and temporal regulation. Accordingly, it is necessary to understand the dynamics of protein interactions to fully comprehend and elucidate cellular processes and pathological disease states. To map de novo protein-protein interactions with time-resolution at an organelle-wide scale, we developed a quantitative mass-spectrometry method, time-resolved interactome profiling (TRIP). We apply TRIP to elucidate aberrant protein interaction dynamics that lead to the protein misfolding disease congenital hypothyroidism. We deconvolute altered temporal interactions of the thyroid hormone precursor thyroglobulin with pathways associated with hypothyroidism pathophysiology such as Hsp70/90 assisted folding, disulfide/redox processing, and N-glycosylation. Functional siRNA screening identified VCP and TEX264 as key protein degradation components whose inhibition selectively rescues mutant prohormone secretion. Ultimately, our results provide insight into the temporal coordination of protein homeostasis, and our TRIP method can have broad application in investigating protein folding diseases and cellular processes.HIGHLIGHTSMethod to map de novo protein-protein interactions with temporal resolutionCharacterization of the time-resolved interactome of a protein folding disease statesiRNA screening identifies VCP and TEX264 as major regulators of thyroglobulin processingVCP pharmacological inhibition rescues mutant thyroglobulin secretion

Background: In a recent individual level meta-analysis, intensive versus standard blood pressure (BP) treatment reduced participants’ risk of orthostatic hypotension (OH). Whether OH modified the relationship between intensive treatment and risk of cardiovascular disease (CVD) or death is unknown. Methods: We performed an individual participant data meta-analysis, updating a previous systematic review of MEDLINE, EMBASE, and CENTRAL databases through May 13, 2022, which included randomized trials of BP pharmacologic treatment (more intensive BP goal or active agent) on CVD or death. CVD events were adjudicated and included coronary heart disease, stroke, and congestive heart failure. OH was defined as a drop in SBP ≥20 mmHg and/or DBP ≥10 mmHg after changing positions from sitting to standing. Ultimately, 8 trials were identified with OH and outcomes data. Effects were examined overall and by trial type (BP goal or active agent), using Cox proportional hazard models adjusted for age and sex. Results: There were 27,974 participants followed for median of 4 years (mean age 69.5±10.7 years; 48.5% female; 8.6% with OH). Baseline OH was associated with a higher risk of CVD or death (HR 1.24; 95% CI: 1.10, 1.39). More intensive BP treatment or active therapy lowered risk of CVD or death among those without OH at baseline (HR 0.82; 95% CI: 0.76, 0.88) and with OH at baseline (HR 0.79; 95% CI: 0.63, 0.98). Effects did not differ by baseline OH ( P -interaction 0.78) ( Table ). Conclusion: While baseline OH was associated with CVD or death, it did not increase the risk of CVD or death from intensive treatment. OH prior to the initiation of intensive therapy should not be viewed as a reason to avoid BP treatment.