Arabidopsis PROTODERMAL FACTOR2 binds lysophosphatidylcholines and transcriptionally regulates phospholipid metabolism.

Plant homeodomain leucine zipper IV (HD-Zip IV) transcription factors (TFs) contain an evolutionarily conserved steroidogenic acute regulatory protein (StAR)-related lipid transfer (START) domain. While the START domain is required for TF activity, its presumed role as a lipid sensor is not clear. Here we used tandem affinity purification from Arabidopsis cell cultures to demonstrate that PROTODERMAL FACTOR2 (PDF2), a representative member that controls epidermal differentiation, recruits lysophosphatidylcholines (LysoPCs) in a START-dependent manner. Microscale thermophoresis assays confirmed that a missense mutation in a predicted ligand contact site reduces lysophospholipid binding. We additionally found that PDF2 acts as a transcriptional regulator of phospholipid- and phosphate (Pi) starvation-related genes and binds to a palindromic octamer with consensus to a Pi response element. Phospholipid homeostasis and elongation growth were altered in pdf2 mutants according to Pi availability. Cycloheximide chase experiments revealed a role for START in maintaining protein levels, and Pi starvation resulted in enhanced protein destabilization, suggesting a mechanism by which lipid binding controls TF activity. We propose that the START domain serves as a molecular sensor for membrane phospholipid status in the epidermis. Our data provide insights toward understanding how the lipid metabolome integrates Pi availability with gene expression.

Azacitidine as epigenetic priming for chemotherapy is safe and well-tolerated in infants with newly diagnosed KMT2A-rearranged acute lymphoblastic leukemia: Children's Oncology Group trial AALL15P1.

Infants less than 1 year old diagnosed with KMT2A-rearranged (KMT2A-r) acute lymphoblastic leukemia (ALL) are at high risk of remission failure, relapse, and death due to leukemia, despite intensive therapies. Infant KMT2A-r ALL blasts are characterized by DNA hypermethylation. Epigenetic priming with DNA methyltransferase inhibitors increases the cytotoxicity of chemotherapy in preclinical studies. The Children's Oncology Group trial AALL15P1 tested the safety and tolerability of five days of azacitidine immediately prior to the start of chemotherapy on day six, in four post-induction chemotherapy courses for infants with newly diagnosed KMT2A-r ALL. The treatment was welltolerated, with only two of 31 evaluable patients (6.5%) experiencing dose-limiting toxicity. Whole genome bisulfite sequencing of peripheral blood mononuclear cells (PBMCs) demonstrated decreased DNA methylation in 87% of samples tested following five days of azacitidine. Event-free survival was similar to prior studies of newly diagnosed infant ALL. Azacitidine is safe and results in decreased DNA methylation of PBMCs in infants with KMT2A-r ALL, but the incorporation of azacitidine to enhance cytotoxicity did not impact survival. Clinicaltrials.gov identifier: NCT02828358.

Development and validation of the Trust in Multidimensional Healthcare Systems Scale (TIMHSS).

CONTEXT: The COVID-19 pandemic has reignited a commitment from the health policy and health services research communities to rebuilding trust in healthcare and created a renewed appetite for measures of trust for system monitoring and evaluation. The aim of the present paper was to develop a multidimensional measure of trust in healthcare that: (1) Is responsive to the conceptual and methodological limitations of existing measures; (2) Can be used to identify systemic explanations for lower levels of trust in equity-deserving populations; (3) Can be used to design and evaluate interventions aiming to (re)build trust. METHODS: We conducted a 2021 review of existing measures of trust in healthcare, 72 qualitative interviews (Aug-Dec 2021; oversampling for equity-deserving populations), an expert review consensus process (Oct 2021), and factor analyses and validation testing based on two waves of survey data (Nov 2021, n = 694; Jan-Feb 2022, n = 740 respectively). FINDINGS: We present the Trust in Multidimensional Healthcare Systems Scale (TIMHSS); a 38-item correlated three-factor measure of trust in doctors, policies, and the system. Measurement of invariance tests suggest that the TIMHSS can also be reliably administered to diverse populations. CONCLUSIONS: This global measure of trust in healthcare can be used to measure trust over time at a population level, or used within specific subpopulations, to inform interventions to (re)build trust. It can also be used within a clinical setting to provide a stronger evidence base for associations between trust and therapeutic outcomes.

Alcohol and substance use in older adults with treatment-resistant depression.

INTRODUCTION: Alcohol and substance use are increasing in older adults, many of whom have depression, and treatment in this context may be more hazardous. We assessed alcohol and other substance use patterns in older adults with treatment-resistant depression (TRD). We examined patient characteristics associated with higher alcohol consumption and examined the moderating effect of alcohol on the association between clinical variables and falls during antidepressant treatment. METHODS: This secondary and exploratory analysis used baseline clinical data and data on falls during treatment from a large randomized antidepressant trial in older adults with TRD (the OPTIMUM trial). Multivariable ordinal logistic regression was used to identify variables associated with higher alcohol use. An interaction model was used to evaluate the moderating effect of alcohol on falls during treatment. RESULTS: Of 687 participants, 51% acknowledged using alcohol: 10% were hazardous drinkers (AUDIT-10 score ≥5) and 41% were low-risk drinkers (score 1-4). Benzodiazepine use was seen in 24% of all participants and in 21% of drinkers. Use of other substances (mostly cannabis) was associated with alcohol consumption: it was seen in 5%, 9%, and 15% of abstainers, low-risk drinkers, and hazardous drinkers, respectively. Unexpectedly, use of other substances predicted increased risk of falls during antidepressant treatment only in abstainers. CONCLUSIONS: One-half of older adults with TRD in this study acknowledged using alcohol. Use of alcohol concurrent with benzodiazepine and other substances was common. Risks-such as falls-of using alcohol and other substances during antidepressant treatment needs further study.

Transcriptomic Evidence of a Link between Cell Wall Biogenesis, Pathogenesis, and Vigor in Walnut Root and Trunk Diseases.

Crown gall disease (Agrobacterium tumefaciens), crown/root rot disease (Phytophthora spp.), root lesion disease (Pratylenchus vulnus) and tree vigor are key traits affecting the productivity and quality of walnuts in California. Unchallenged hybrid rootstocks were analyzed by RNA-seq to examine pre-formed factors affecting these traits. Enrichment analysis of the differentially expressed genes revealed that the increased expression of cell wall biogenesis-related genes plays a key role in susceptibility to A. tumefaciens, susceptibility to Phytophthora spp. and increased vigor. Analysis of the predicted subcellular loci of the encoded proteins revealed that many gene products associated with vigor and susceptibility were targeted to the plasma membrane and extracellular space, connecting these traits to sustaining barrier function. We observed that RNA processing and splicing, along with predicted nuclear targeting, were associated with resistance to A. tumefaciens, resistance to Phytophthora spp. and low vigor. Four genes within the J. microcarpa QTL region for resistance to A. tumefaciens and Phytophthora spp. were represented among our transcripts, with two of the genes being differentially expressed in association with resistance to A. tumefaciens and decreased vigor. No differential expression related to Phytophthora spp. or P. vulnus resistance was observed in this region. Additionally, the J. microcarpa haplotype expressed more transcripts associated with resistance to A. tumefaciens, Phytophthora spp. and low vigor, but not P. vulnus, than the J. regia haplotype. We also report unique and shared hormone and defense responses associated with each trait. This research suggests a link between cell wall biogenesis, vigor and critical root diseases of walnut.

Excess deaths in China during SARS-CoV-2 viral waves in 2022-2023.

Background: The extent to which the Omicron variant of SARS-CoV-2 raised death rates in China during its viral wave of December 2022-January 2023 remains largely undocumented. Methods: We worked with an established national survey organization to survey 8,004 adults in all 31 administrative areas of China to ask about deaths in families since January 2020. We examined age-specific death rates, focusing on deaths above age 60 years, and at 15-59 years. We compared these to the United Nations (UN) estimates of age-specific mortality in 2019. Findings: The survey participants were broadly similar to the 2020 census and other national surveys in age, sex, region, and smoking status, but had lower SARS-CoV-2 vaccination rates and higher education levels. There were no differences in reporting of deaths during the Omicron period (after November 2021) versus earlier. The survey captured 456 deaths, of which 329 occurred at ages 60+ years and 212 were of women. At ages 60+ years, death rates approximately doubled during December 2022-January 2023. Deaths at ages 15-59 years did not rise appreciably. The UN estimates approximately 675,000 deaths per month at ages 60+ years in 2019. If rates doubled nationally as in our survey, China had approximately 1.35 million excess deaths from December 2022-January 2023. Interpretation: China experienced a sharp but short increase in excess deaths among its elderly during the Omicron wave. If death registry data corroborate our estimates of substantial excess deaths in China, the worldwide estimates of excess deaths due to SARS-CoV-2 in 2022-2023 may need upward adjustment.

Distinct ancient structural polymorphisms control heterodichogamy in walnuts and hickories.

The maintenance of stable mating type polymorphisms is a classic example of balancing selection, underlying the nearly ubiquitous 50/50 sex ratio in species with separate sexes. One lesser known but intriguing example of a balanced mating polymorphism in angiosperms is heterodichogamy - polymorphism for opposing directions of dichogamy (temporal separation of male and female function in hermaphrodites) within a flowering season. This mating system is common throughout Juglandaceae, the family that includes globally important and iconic nut and timber crops - walnuts (Juglans), as well as pecan and other hickories (Carya). In both genera, heterodichogamy is controlled by a single dominant allele. We fine-map the locus in each genus, and find two ancient (>50 Mya) structural variants involving different genes that both segregate as genus-wide trans-species polymorphisms. The Juglans locus maps to a ca. 20 kb structural variant adjacent to a probable trehalose phosphate phosphatase (TPPD-1), homologs of which regulate floral development in model systems. TPPD-1 is differentially expressed between morphs in developing male flowers, with increased allele-specific expression of the dominant haplotype copy. Across species, the dominant haplotype contains a tandem array of duplicated sequence motifs, part of which is an inverted copy of the TPPD-1 3' UTR. These repeats generate various distinct small RNAs matching sequences within the 3' UTR and further downstream. In contrast to the single-gene Juglans locus, the Carya heterodichogamy locus maps to a ca. 200-450 kb cluster of tightly linked polymorphisms across 20 genes, some of which have known roles in flowering and are differentially expressed between morphs in developing flowers. The dominant haplotype in pecan, which is nearly always heterozygous and appears to rarely recombine, shows markedly reduced genetic diversity and is over twice as long as its recessive counterpart due to accumulation of various types of transposable elements. We did not detect either genetic system in other heterodichogamous genera within Juglandaceae, suggesting that additional genetic systems for heterodichogamy may yet remain undiscovered.

Smoking Cessation and Short- and Longer-Term Mortality.

BACKGROUND: Smoking cessation reduces mortality and morbidity. However, the extent and rapidity at which cessation reduces contemporary death rates from smoking-related illnesses remain uncertain. METHODS: We pooled current or former versus never cigarette smoker hazard ratios from four national cohorts with linkage to death registries in the United States, United Kingdom, Norway, and Canada among adults 20 to 79 years of age from 1974 to 2018. We calculated excess risk differences and survival, comparing current or never smokers with age-specific cessation and cessation fewer than 3, 3 to 9, or 10 or more years earlier. RESULTS: Among 1.48 million adults followed for 15 years, 122,697 deaths occurred. Adjusting for age, education, alcohol use, and obesity, current smokers had higher hazard ratios for death compared with never smokers (2.8 for women, 2.7 for men). Survival between 40 and 79 years of age was 12 and 13 years less in women and men, respectively, who smoked compared with never smokers (about 24 to 26 years of life lost for smokers who died from smoking combined with zero loss for smokers who did not die from smoking). Former smokers showed lower hazard ratios (1.3 in both women and men). Short-term cessation for fewer than 3 years was associated with a lower excess risk of 95% in women and 90% in men younger than 40 years of age, with notable beneficial associations also in women and men 40 to 49 years of age (81% and 61%, respectively) and 50 to 59 years of age (63% and 54%, respectively). Cessation at every age was associated with longer survival, particularly cessation before 40 years of age. Among all ages and compared with continued smoking, cessation of fewer than 3 years potentially averted 5 years of life lost and cessation for 10 or more years averted about 10 years of life lost, yielding survival similar to that of never smokers. CONCLUSIONS: Quitting smoking at any age, but particularly in younger years, was associated with lower excess mortality overall and from vascular, respiratory, and neoplastic diseases. Beneficial associations were evident as early as 3 years after cessation. (Funded by Canadian Institutes of Health Research [FDN-154277].)

Adolescent Residential Addiction Treatment In The US: Uneven Access, Waitlists, And High Costs.

Drug overdose deaths among adolescents are increasing in the United States. Residential treatment facilities are one treatment option for adolescents with substance use disorders, yet little is known about their accessibility or cost. Using the Substance Abuse and Mental Health Services Administration's treatment locator and search engine advertising data, we identified 160 residential addiction treatment facilities that treated adolescents with opioid use disorder as of December 2022. We called facilities while role-playing as the aunt or uncle of a sixteen-year-old child with a recent nonfatal overdose, to inquire about policies and costs. Eighty-seven facilities (54.4 percent) had a bed immediately available. Among sites with a waitlist, the mean wait time for a bed was 28.4 days. Of facilities providing cost information, the mean cost of treatment per day was $878. Daily costs among for-profit facilities were triple those of nonprofit facilities. Half of facilities required up-front payment by self-pay patients. The mean up-front cost was $28,731. We were unable to identify any facilities for adolescents in ten states or Washington, D.C. Access to adolescent residential addiction treatment centers in the United States is limited and costly.

Safety and efficacy of fedratinib in patients with myelofibrosis previously treated with ruxolitinib: primary analysis of FREEDOM trial.

The phase 3b FREEDOM trial (ClinicalTrials.gov: NCT03755518) evaluates efficacy/safety of fedratinib in intermediate- or high-risk myelofibrosis patients with platelet count ≥50 × 109/L, previously treated with ruxolitinib. The trial design included protocol specified strategies to mitigate the risk for gastrointestinal (GI) adverse events (AEs), thiamine supplementation, and encephalopathy surveillance. Due to COVID-19, accrual was cut short with 38 patients enrolled. In the efficacy evaluable population (n = 35), nine (25.7%; 95% confidence interval 12.5-43.3) patients achieved primary endpoint of ≥35% spleen volume reduction (SVR) at end of cycle (EOC) 6; and 22 (62.9%) patients showed best overall response of ≥35% SVR up to end of treatment. Sixteen (44.4%) patients showed ≥50% reduction in total symptom score at EOC6 (n = 36). Compared to previously reported JAKARTA-2 trial, rates of GI AEs were lower, and no patient developed encephalopathy. Overall, FREEDOM study showed clinically relevant spleen and symptom responses with fedratinib, and effective mitigation of GI AEs.

Relationship between Patient Health Questionnaire (PHQ-9) and Montgomery-Asberg Depression Rating Scale (MADRS) total scores in older adults with major depressive disorder: An analysis of the OPTIMUM clinical trial.

BACKGROUND: The Patient Health Questionnaire (PHQ-9) and Montgomery-Asberg Depression Rating Scale (MADRS) are commonly used scales to measure depression severity in older adults. METHODS: We utilized data from the Optimizing Outcomes of Treatment-Resistant Depression in Older Adults (OPTIMUM) clinical trial to produce conversion tables relating PHQ-9 and MADRS total scores. We split the sample into training (N = 555) and validation samples (N = 187). Equipercentile linking was performed on the training sample to produce conversion tables for PHQ-9 and MADRS. We compared the original and estimated scores in the validation sample with Bland-Altman analysis. We compared the depression severity level using the original and estimated scores with Chi-square tests. RESULTS: The Bland-Altman analysis confirmed that differences between the original and estimated scores for at least 95 % of the sample fit within 1.96 standard deviations of the mean difference. Chi-square tests showed a significant difference in the proportion of participants at each depression severity category determined using the original and estimated scores. LIMITATIONS: The conversion tables should be used with caution when comparing depression severity at the individual level. CONCLUSIONS: Our conversion tables relating PHQ-9 and MADRS scores can be used to compare treatment outcomes using aggregate data in studies that only used one of these scales.

Nivolumab Plus 5-Azacitidine in Pediatric Relapsed/Refractory Acute Myeloid Leukemia (AML): Phase I/II Trial Results from the Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) Consortium.

Improvements in survival have been made over the past two decades for childhood acute myeloid leukemia (AML), but the approximately 40% of patients who relapse continue to have poor outcomes. A combination of checkpoint-inhibitor nivolumab and azacitidine has demonstrated improvements in median survival in adults with AML. This phase I/II study with nivolumab and azacitidine in children with relapsed/refractory AML (NCT03825367) was conducted through the Therapeutic Advances in Childhood Leukemia & Lymphoma consortium. Thirteen patients, median age 13.7 years, were enrolled. Patients had refractory disease with multiple reinduction attempts. Twelve evaluable patients were treated at the recommended phase II dose (established at dose level 1, 3 mg/kg/dose). Four patients (33%) maintained stable disease. This combination was well tolerated, with no dose-limiting toxicities observed. Grade 3-4 adverse events (AEs) were primarily hematological. Febrile neutropenia was the most common AE ≥ grade 3. A trend to improved quality of life was noted. Increases in CD8+ T cells and reductions in CD4+/CD8+ T cells and demethylation were observed. The combination was well tolerated and had an acceptable safety profile in pediatric patients with relapsed/refractory AML. Future studies might explore this combination for the maintenance of remission in children with AML at high risk of relapse.

Canada's approach to SARS-CoV-2 sero-surveillance: Lessons learned for routine surveillance and future pandemics.

SETTING: In Canada's federated healthcare system, 13 provincial and territorial jurisdictions have independent responsibility to collect data to inform health policies. During the COVID-19 pandemic (2020-2023), national and regional sero-surveys mostly drew upon existing infrastructure to quickly test specimens and collect data but required cross-jurisdiction coordination and communication. INTERVENTION: There were 4 national and 7 regional general population SARS-CoV-2 sero-surveys. Survey methodologies varied by participant selection approaches, assay choices, and reporting structures. We analyzed Canadian pandemic sero-surveillance initiatives to identify key learnings to inform future pandemic planning. OUTCOMES: Over a million samples were tested for SARS-CoV-2 antibodies from 2020 to 2023 but siloed in 11 distinct datasets. Most national sero-surveys had insufficient sample size to estimate regional prevalence; differences in methodology hampered cross-regional comparisons of regional sero-surveys. Only four sero-surveys included questionnaires. Sero-surveys were not directly comparable due to different assays, sampling methodologies, and time-frames. Linkage to health records occurred in three provinces only. Dried blood spots permitted sample collection in remote populations and during stay-at-home orders. IMPLICATIONS: To provide timely, high-quality information for public health decision-making, routine sero-surveillance systems must be adaptable, flexible, and scalable. National capability planning should include consortiums for assay design and validation, defined mechanisms to improve test capacity, base documents for data linkage and material transfer across jurisdictions, and mechanisms for real-time communication of data. Lessons learned will inform incorporation of a robust sero-survey program into routine surveillance with strategic sampling and capacity to adapt and scale rapidly as a part of a comprehensive national pandemic response plan.

RéSUMé: CONTEXTE: Au Canada, où le système de santé est fédéré, les 13 juridictions provinciales et territoriales ont la responsabilité individuelle de recueillir les données qui leur permettent d'élaborer leurs politiques de santé. Lors de la pandémie de COVID-19 (2020­2023), pour réaliser les enquêtes de séroprévalence à l'échelle régionale et nationale, les autorités ont principalement utilisé l'infrastructure existante pour pouvoir analyser les échantillons et recueillir des données rapidement, mais cela a également nécessité de la communication et de la coordination entre les différentes juridictions. INTERVENTION: Au Canada, il y a eu quatre enquêtes nationales et sept enquêtes régionales sur la séroprévalence du SARS-CoV-2 dans la population générale. Les méthodologies utilisées différaient selon la méthode de sélection des participants, le choix des tests d'analyses et les structures de rapports. Nous avons analysé la façon dont ces enquêtes avaient été réalisées afin d'en dégager des éléments essentiels qui permettront de planifier pour les futures pandémies. RéSULTATS: Entre 2020 et 2023, plus d'un million d'échantillons, répartis en 11 ensembles de données distincts, ont été analysés afin de rechercher la présence d'anticorps au SARS-CoV-2. Dans la plupart des enquêtes nationales, la taille de l'échantillon était insuffisante pour pouvoir estimer la prévalence à l'échelle régionale. La disparité des méthodologies utilisées a entravé la comparaison des enquêtes régionales. Seules quatre enquêtes fournissaient les données recueillies à partir des questionnaires. Il a été impossible de comparer les enquêtes entre elles en raison de la diversité des tests d'analyse utilisés, des méthodes d'échantillonnage et de la durée des enquêtes. Seules trois provinces avaient couplé leurs données avec les archives médicales. Pour réaliser les enquêtes dans les populations éloignées et lors des périodes de confinement, la méthode d'analyse sur gouttes de sang séché a été utilisée. CONCLUSION: Afin de pouvoir fournir, en temps et en heure, des données de haute qualité pour la prise de décisions en matière de santé publique, un système de sérosurveillance continuelle doit être adaptable, modulable et évolutif. En cas de pandémie, un plan national doit prévoir des consortiums pour la conception et la validation des tests d'analyse, des moyens d'amélioration de la capacité de dépistage, des documents de base pour le couplage des données, un mode de transfert du matériel entre les différentes juridictions et des moyens pour une communication en temps réel des données. Les leçons tirées de cette analyse permettront de mettre en place un solide programme d'enquêtes de séroprévalence au sein des systèmes de sérosurveillance continuelle, et que ce programme sera accompagné d'une stratégie d'échantillonnage et d'un plan d'intervention national, rapide et complet en cas de pandémie.

Hybrid immunity from severe acute respiratory syndrome coronavirus 2 infection and vaccination in Canadian adults: A cohort study.

Background: Few national-level studies have evaluated the impact of 'hybrid' immunity (vaccination coupled with recovery from infection) from the Omicron variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Methods: From May 2020 to December 2022, we conducted serial assessments (each of ~4000-9000 adults) examining SARS-CoV-2 antibodies within a mostly representative Canadian cohort drawn from a national online polling platform. Adults, most of whom were vaccinated, reported viral test-confirmed infections and mailed self-collected dried blood spots (DBSs) to a central lab. Samples underwent highly sensitive and specific antibody assays to spike and nucleocapsid protein antigens, the latter triggered only by infection. We estimated cumulative SARS-CoV-2 incidence prior to the Omicron period and during the BA.1/1.1 and BA.2/5 waves. We assessed changes in antibody levels and in age-specific active immunity levels. Results: Spike levels were higher in infected than in uninfected adults, regardless of vaccination doses. Among adults vaccinated at least thrice and infected more than 6 months earlier, spike levels fell notably and continuously for the 9-month post-vaccination. In contrast, among adults infected within 6 months, spike levels declined gradually. Declines were similar by sex, age group, and ethnicity. Recent vaccination attenuated declines in spike levels from older infections. In a convenience sample, spike antibody and cellular responses were correlated. Near the end of 2022, about 35% of adults above age 60 had their last vaccine dose more than 6 months ago, and about 25% remained uninfected. The cumulative incidence of SARS-CoV-2 infection rose from 13% (95% confidence interval 11-14%) before omicron to 78% (76-80%) by December 2022, equating to 25 million infected adults cumulatively. However, the coronavirus disease 2019 (COVID-19) weekly death rate during the BA.2/5 waves was less than half of that during the BA.1/1.1 wave, implying a protective role for hybrid immunity. Conclusions: Strategies to maintain population-level hybrid immunity require up-to-date vaccination coverage, including among those recovering from infection. Population-based, self-collected DBSs are a practicable biological surveillance platform. Funding: Funding was provided by the COVID-19 Immunity Task Force, Canadian Institutes of Health Research, Pfizer Global Medical Grants, and St. Michael's Hospital Foundation. PJ and ACG are funded by the Canada Research Chairs Program.

Association between precipitation and mortality due to diarrheal diseases by climate zone: A multi-country modeling study.

Background: Precipitation could affect the transmission of diarrheal diseases. The diverse precipitation patterns across different climates might influence the degree of diarrheal risk from precipitation. This study determined the associations between precipitation and diarrheal mortality in tropical, temperate, and arid climate regions. Methods: Daily counts of diarrheal mortality and 28-day cumulative precipitation from 1997 to 2019 were analyzed across 29 locations in eight middle-income countries (Argentina, Brazil, Costa Rica, India, Peru, the Philippines, South Africa, and Thailand). A two-stage approach was employed: the first stage is conditional Poisson regression models for each location, and the second stage is meta-analysis for pooling location-specific coefficients by climate zone. Results: In tropical climates, higher precipitation increases the risk of diarrheal mortality. Under extremely wet conditions (95th percentile of 28-day cumulative precipitation), diarrheal mortality increased by 17.8% (95% confidence interval [CI] = 10.4%, 25.7%) compared with minimum-risk precipitation. For temperate and arid climates, diarrheal mortality increases in both dry and wet conditions. In extremely dry conditions (fifth percentile of 28-day cumulative precipitation), diarrheal mortality risk increases by 3.8% (95% CI = 1.2%, 6.5%) for temperate and 5.5% (95% CI = 1.0%, 10.2%) for arid climates. Similarly, under extremely wet conditions, diarrheal mortality risk increases by 2.5% (95% CI = -0.1%, 5.1%) for temperate and 4.1% (95% CI = 1.1%, 7.3%) for arid climates. Conclusions: Associations between precipitation and diarrheal mortality exhibit variations across different climate zones. It is crucial to consider climate-specific variations when generating global projections of future precipitation-related diarrheal mortality.

Functional in vitro diversity of an intrinsically disordered plant protein during freeze-thawing is encoded by its structural plasticity.

Intrinsically disordered late embryogenesis abundant (LEA) proteins play a central role in the tolerance of plants and other organisms to dehydration brought upon, for example, by freezing temperatures, high salt concentration, drought or desiccation, and many LEA proteins have been found to stabilize dehydration-sensitive cellular structures. Their conformational ensembles are highly sensitive to the environment, allowing them to undergo conformational changes and adopt ordered secondary and quaternary structures and to participate in formation of membraneless organelles. In an interdisciplinary approach, we discovered how the functional diversity of the Arabidopsis thaliana LEA protein COR15A found in vitro is encoded in its structural repertoire, with the stabilization of membranes being achieved at the level of secondary structure and the stabilization of enzymes accomplished by the formation of oligomeric complexes. We provide molecular details on intra- and inter-monomeric helix-helix interactions, demonstrate how oligomerization is driven by an α-helical molecular recognition feature (α-MoRF) and provide a rationale that the formation of noncanonical, loosely packed, right-handed coiled-coils might be a recurring theme for homo- and hetero-oligomerization of LEA proteins.

The co-construction and emotion management of hope within psychosis services.

Introduction: There is a growing acknowledgement of the salience of hope for mental health service-users, in influencing care outcomes and recovery. Understandings of the processes through which hopes are co-constructed, alongside specific conceptualisations of experiences of hoping, remain limited however. Methods: This qualitative study explored how a range of stakeholders experienced and dealt with uncertainty within three purposively selected psychosis services in southern England. In this article we focus particularly on the co-construction of hope within participants' narratives and how this emotion work shaped experiences of hoping. In-depth interviews (n = 23) with service-users, professionals, managers and other stakeholders were analysed following a phenomenological approach. Findings: Hope was spontaneously identified by participants as a fundamental mechanism through which service-users and professionals managed uncertainty when vulnerable. Professionals were influential in shaping users' hopes, both intentionally and unwittingly, while some professionals also referred to managing their own hopes and those of colleagues. Such management of expectations and emotions enabled motivation and coping amidst uncertainty, for users and professionals, but also entailed difficulties where hope was undermined, exaggerated, or involved tensions between desires and expectations. Discussion: Whereas, hope is usually reflected in the caring studies literature as distinctly positive, our findings point to a more ambivalent understanding of hope, as reflected in the accounts of both service-users and professionals where elevated hopes were described as unrealistic and harmful, to the well-being of professionals as well as of service-users. It is concluded that a greater awareness within care contexts of how hopes are co-constructed by professionals and service-users, explicitly and implicitly, can assist in improving health care and healthcare outcomes.