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Abstract Background Antibiotic resistance in uropathogens has rapidly escalated over time, complicating treatment and increasing morbidity and mortality. Few studies have explored how the social determinants of health may be associated with patients’ risks for acquiring antibiotic-resistant (AR) uropathogens. Methods We identified urine cultures collected from outpatients presenting to Tufts Medical Center Primary Care Practices between 2015 and 2020. Specimens were included if patients’ age, sex, and residential address were recorded in the electronic medical record (EMR) and if their urine culture yielded Enterococcus spp. or one or more gram-negative bacterial organism(s) or for which antibiotic susceptibility profiling and species identification was conducted. We abstracted patients’ sociodemographic characteristics from the EMR and used US Census Bureau data to identify characteristics about patients’ census tracts of residence. We evaluated associations between individual- and neighborhood-level characteristics and patients’ risk of having a urine culture resistant to (1) three or more antibiotic classes (i.e., multidrug resistant [MDR]), (2) first-line treatments, (3) fluoroquinolones, (4) aminoglycosides, or (5) ceftriaxone using logistic regression models and a Bonferroni correction to account for multiple hypothesis testing. Results We included urine cultures from 1,306 unique outpatients, most of whom were female (89%). Patients largely self-identified as Non-Hispanic White (36%), Asian (15%), or Non-Hispanic Black (11%). Over 60% lived in an environmental justice-designated census tract. Most included isolates were Escherichia coli (76%) or Klebsiella pneumoniae (7%). Using public insurance increased patients’ odds of having a uropathogen resistant to first-line antibiotics, but living in a limited-income neighborhood reduced patients’ odds of having a MDR uropathogen by 47%. We noted a strong but non-significant positive trend between speaking a language other than English and having an aminoglycoside-resistant uropathogen (p-value = 0.02). Most notably, after controlling for other factors, we observed no statistically significant associations between race or ethnicity and AR uropathogens. Conclusion The social determinants of health may play important and intersecting roles in determining a patient’s risk of having a resistant uropathogens that is more challenging or expensive to treat. It is crucial to acknowledge how race is likely to be a proxy for other factors affecting health, and to consider that some groups may be disproportionately impacted by antibiotic resistance.

Two rehydration protocols currently exist to treat diabetic ketoacidosis (DKA) in pediatric patients aged

Abstract Rifaximin is FDA-approved for treatment of irritable bowel syndrome with diarrhea (IBS-D), but poor solubility may limit its efficacy against microbes in the mucus layer, e.g. Escherichia coli. Here we evaluate adding the mucolytic N-acetylcysteine (NAC) to improve rifaximin efficacy. In a resazurin checkerboard assay, combining rifaximin with NAC had significant synergistic effects in reducing E. coli levels. The optimal rifaximin + NAC combination was then tested in a validated rat model of IBS-D (induced by cytolethal distending toxin [CdtB] inoculation). Rats were inoculated with vehicle and treated with placebo (Control-PBS) or rifaximin + NAC (Control-Rif + NAC, safety), or inoculated with CdtB and treated with placebo (CdtB-PBS), rifaximin (CdtB-Rifaximin), or rifaximin + NAC (CdtB-Rif + NAC) for 10 days. CdtB-inoculated rats (CdtB-PBS) developed wide variability in stool consistency (P = 0.0014) vs. controls (Control-PBS). Stool variability normalized in rats treated with rifaximin + NAC (CdtB-Rif + NAC) but not rifaximin alone (CdtB-Rifaximin). Small bowel bacterial levels were elevated in CdtB-PBS rats but normalized in CdtB-Rif + NAC but not CdtB-Rifaximin rats. E. coli and Desulfovibrio spp levels (each associated with different IBS-D microtypes) were also elevated in CdtB-inoculated (CdtB-PBS) but normalized in CdtB-Rif + NAC rats. Cytokine levels normalized only in CdtB-Rif + NAC rats, in a manner predicted to be associated with reduced diarrhea driven by reduced E. coli. These findings suggest that combining rifaximin with NAC may improve the percentage of IBS-D patients responding to treatment.

Mountain pine beetle (MPB; Dendroctonus ponderosae Hopkins) is a devastating forest insect pest that has killed millions of hectares of pines in western North America over the past two decades. Like other bark beetles, MPB vectors ophiostomatoid fungal species, some of which are pathogenic to host pine species. The phytopathogenicity of these fungal symbionts has sparked considerable debate regarding their role in facilitating MPB attack success. We tested the hypothesis that MPB ophiostomatoid fungal associates like Grosmannia clavigera (Robinson-Jeffrey and Davidson) Zipfel, de Beer and Wingfield contribute to overwhelming host defenses during MPB mass attack. We compared responses of mature lodgepole pine (Pinus contorta Dougl. ex Loud. var. latifolia Engelm.) trees growing in natural stands that were mass attacked by MPB with those inoculated with G. clavigera by examining host defense hormones, secondary metabolites, and gene expression profiles. The jasmonate and ethylene signatures of necrotrophic pathogen-triggered response were identified in G. clavigera-inoculated trees, but only the jasmonate signature of a herbivore-triggered response was measured in MPB-attacked trees. Several G. clavigera-induced changes in pine phenolic metabolite profiles and phenolic biosynthesis gene expression patterns were absent in MPB-attacked pines. These findings indicate that ophiostomatoid fungi like G. clavigera are not a major factor in overwhelming host defenses during MPB mass attack. Instead, fungal pathogenicity likely is more important in aiding MPB colonization and development within the host tree. Phenolics appear to play a larger role in the host response to G. clavigera than to MPB, although phenolics may also influence MPB feeding and behavior. [Graphic: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY 4.0 International license.

Abstract The measured carbon isotopic compositions of carbonate sediments (δ13Ccarb) on modern platforms are commonly 13C‐enriched compared to predicted values for minerals forming in isotopic equilibrium with the dissolved inorganic carbon (DIC) of modern seawater. This offset undermines the assumption that δ13Ccarb values of analogous facies in the rock record are an accurate archive of information about Earth's global carbon cycle. We present a new data set of the diurnal variation in carbonate chemistry and seawater δ13CDIC values on a modern carbonate platform. These data demonstrate that δ13Ccarb values on modern platforms are broadly representative of seawater, but only after accounting for the recent decrease in the δ13C value of atmospheric CO2 and shallow seawater DIC due to anthropogenic carbon release, a phenomenon commonly referred to as the 13C Suess effect. These findings highlight an important, yet overlooked, aspect of some modern carbonate systems, which must inform their use as ancient analogs.

ABSTRACTChildren living in low-resource settings are frequently gut-colonized with multidrug-resistant bacteria. We explored whether breastfeeding may protect against children’s incident gut colonization with extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-Ec) and Klebsiella, Enterobacter, or Citrobacter spp. (ESBL-KEC). We screened 937 monthly stool samples collected from 112 children aged 1–16 months during a 2016–19 prospective cohort study of enteric infections in peri-urban Lima. We used 52,816 daily surveys to examine how exposures to breastfeeding in the 30 days prior to a stool sample were associated with children’s risks of incident gut-colonization, controlling for antibiotic use and other covariates. We sequenced 78 ESBL-Ec from 47 children to explore their diversity. Gut-colonization with ESBL-Ec was increasingly prevalent as children aged, approaching 75% by 16 months, while ESBL-KEC prevalence fluctuated between 18% and 36%. Through 6 months of age, exclusively providing human milk in the 30 days prior to a stool sample did not reduce children’s risk of incident gut-colonization with ESBL-Ec or ESBL-KEC. From 6 to 16 months of age, every 3 additional days of breastfeeding in the prior 30 days was associated with 6% lower risk of incident ESBL-Ec gut-colonization (95% CI: 0.90, 0.98, p = .003). No effects were observed on incident ESBL-KEC colonization. We detected highly diverse ESBL-Ec among children and few differences between children who were predominantly breastfed (mean age: 4.1 months) versus older children (10.8 months). Continued breastfeeding after 6 months conferred protection against children’s incident gut colonization with ESBL-Ec in this setting. Policies supporting continued breastfeeding should be considered in efforts to combat antibiotic resistance.

ABSTRACTDiarrhea-predominant irritable bowel syndrome (IBS-D), associated with increased intestinal permeability, inflammation, and small intestinal bacterial overgrowth, can be triggered by acute gastroenteritis. Cytolethal distending toxin B (CdtB) is produced by gastroenteritis-causing pathogens and may underlie IBS-D development, through molecular mimicry with vinculin. Here, we examine the effects of exposure to CdtB alone on gut microbiome composition, host intestinal gene expression, and IBS-D-like phenotypes in a rat model. CdtB-inoculated rats exhibited increased anti-CdtB levels, which correlated with increased stool wet weights, pro-inflammatory cytokines (TNFα, IL2) and predicted microbial metabolic pathways including inflammatory responses, TNF responses, and diarrhea. Three distinct ileal microbiome profiles (microtypes) were identified in CdtB-inoculated rats. The first microtype (most like controls) had altered relative abundance (RA) of genera Bifidobacterium, Lactococcus, and Rothia. The second had lower microbial diversity, higher Escherichia-Shigella RA, higher absolute E. coli abundance, and altered host ileal tissue expression of immune-response and TNF-response genes compared to controls. The third microtype had higher microbial diversity, higher RA of hydrogen sulfide (H2S)-producer Desulfovibrio, and increased expression of H2S-associated pain/serotonin response genes. All CdtB-inoculated rats exhibited decreased ileal expression of cell junction component mRNAs, including vinculin-associated proteins. Significantly, cluster-specific microRNA-mRNA interactions controlling intestinal permeability, visceral hypersensitivity/pain, and gastrointestinal motility genes, including several previously associated with IBS were seen. These findings demonstrate that exposure to CdtB toxin alone results in IBS-like phenotypes including inflammation and diarrhea-like stool, decreased expression of intestinal barrier components, and altered ileal microtypes that influenced changes in microRNA-modulated gene expression and predicted metabolic pathways consistent with specific IBS-D symptoms.

Abstract Introduction Identifying the optimal approaches to offering HIV prevention to meet the needs of those at risk is a high priority, particularly given the expanding toolkit of biomedical HIV prevention options. An ongoing study in rural East African communities evaluated the uptake of choices in product, testing mode and location of care delivery through a structured patient‐centred HIV prevention delivery model. In this qualitative study, we sought to understand clients’ experiences of this “dynamic choice prevention model” (DCP) and highlight pathways of action to inform HIV prevention delivery models. Methods In‐depth semi‐structured interviews were conducted from November 2021 through March 2022 with a purposively selected sample of n = 56 participants in DCP trials (across outpatient departments, antenatal clinics and community settings), and n = 21 healthcare providers (total n = 77). A seven‐person multi‐regional team translated and inductively coded transcript data. We used a framework analysis approach to identify emergent themes. Results Individuals taking up HIV pre‐exposure prophylaxis (PrEP) reported feelings of relief, liberation from fears of acquiring HIV and satisfaction with being able to take action despite partners’ behaviours. Couples used a range of approaches afforded by the study to persuade partners to get tested and opt for PrEP. Post‐exposure prophylaxis (PEP) use was less common, although women welcomed it in the event of sexual coercion or assault. Participants discussed switching from PEP to PrEP after familiarizing themselves with usage and ascertaining ongoing risk. Participants felt respected by providers, trusted them and appreciated being able to contact them directly for telephone support. Prevention uptake was hindered by stigma, limited experience with and knowledge of prevention methods, gendered and generational power dynamics within intimate partnerships and families, and negative perceptions of methods due to the products themselves. Participants anticipated long‐acting injectable PrEP could solve their challenges regarding pill size, daily pill burden and the likelihood of unwanted disclosure. Conclusions Diverse preferences and barriers to uptake of prevention require a choice of HIV prevention options, locations and delivery modalities—but in addition, flexible, competent and friendly care provision is crucial to promote uptake. Helping clients feel valued, and addressing their unique needs and challenges, enables their agency to prioritize their health.

Introduction The term primary progressive aphasia (PPA) describes a group of language-led dementias. Disease-modifying treatments that delay, slow or reverse progression of PPA are currently lacking, though a number of interventions to manage the symptoms of PPA have been developed in recent years. Unfortunately, studies exploring the effectiveness of these interventions have used a variety of different outcome measures, limiting comparability. There are more constructs, apart from word retrieval, that are important for people with PPA that have not received much attention in the research literature. Existing core outcome sets (COS) for dementia and non-progressive aphasia do not meet the needs of people with PPA, highlighting a need to develop a specific COS for PPA.Methods and analysis This protocol describes a three-stage study to identify a COS for PPA interventions in research and clinical practice. The stage 1 systematic review will identify existing speech, language and communication measures used to examine the effectiveness of interventions for PPA in the research literature. Employing a nominal group technique, stage 2 will identify the most important outcomes for people with PPA and their families. The data collected in stages 1 and 2 will be jointly analysed with the project PPI group and will inform the stage 2 modified Delphi consensus study to identify a core outcome measurement set for PPA among a range of research disciplines undertaking intervention studies for people with PPA.Ethics and dissemination Ethical approval for stage 2 of the study has been sought individually in each country at collaborating institutions and is stated in detail in the manuscript. Stage 3 has been granted ethical approval by the Chairs of UCL Language and Cognition Department Ethics, Project ID LCD-2023-06. Work undertaken at stages 1, 2 and 3 will be published in open-access peer-reviewed journal articles and presented at international scientific conferences.PROSPERO registration number CRD42022367565.

Abstract Background Caesarean sections (CSs) constitute a large proportion of fetal deliveries, yet no consensus exists on optimal surgical method. Objectives To investigate the safety and efficacy of the Pfannenstiel‐Kerr method (PKM) in comparison to Misgav‐Ladach method (MLM) and Modified Misgav‐Ladach method (MMLM) for CS. Search Strategy Cochrane, Embase, PubMed, CiNAHL, Scopus, and Web of Science were searched from database inception to March 2023. Selection Criteria Prospective studies comparing MLM with PKM or MMLM with PKM. Data Collection and Analysis Three authors independently conducted data extraction and assessed quality. Pooled means and proportions were analyzed using inverse variance and Mantel‐Haenszel methods. Main Results Twenty‐seven studies with 15 251 patients, met the selection criteria. Both MLM (mean difference [MD]: −12.09 min, 95% confidence interval [CI]: −14.40, −9.77, Tau2 = 16.79, I2 = 97%), (MD: −125.98 mL, 95% CI: −172.13, −79.83, Tau2 = 3458.59, I2 = 87%) and MMLM (MD: −11.38 min, 95% CI: −14.72, −8.04, Tau2 = 30.56, I2 = 100%), (MD: −62.61 mL, 95% CI: −103.13, −22.09, Tau2 = 1451.35, I2 = 92%) demonstrated shorter operative time and decreased blood loss, respectively, compared to PKM. Similarly, both MLM (MD: −1.70 min, 95% CI: −2.26, −1.14, Tau2 = 0.51, I2 = 97%), (MD: −0.77 d, 95% CI: −1.35, −0.19, Tau2 = 0.60, I2 = 98%) and MMLM (MD: −2.80 min, 95% CI: −3.89, −1.70, Tau2 = 1.74, I2 = 100%), (MD: −0.58 d, 95% CI: −1.00, −0.17, Tau2 = 0.29, I2 = 100%) demonstrated shorter fetal extraction time and length of hospital stay, respectively, compared to PKM. Conclusions MLM and MMLM should be considered safe and effective alternative approaches to CSs.

Abstract Introduction Unhealthy alcohol use significantly contributes to viral non‐suppression among persons with HIV (PWH). It is unknown whether brief behavioural interventions to reduce alcohol use can improve viral suppression among PWH with unhealthy alcohol use in sub‐Saharan Africa (SSA). Methods As part of the SEARCH study (NCT04810650), we conducted an individually randomized trial in Kenya and Uganda of a brief, skills‐based alcohol intervention among PWH with self‐reported unhealthy alcohol use (Alcohol Use Disorders Identification Test–Consumption [AUDIT‐C], prior 3 months, ≥3/female; ≥4/male) and at risk of viral non‐suppression, defined as either recent HIV viral non‐suppression (≥400 copies/ml), missed visits, out of care or new diagnosis. The intervention included baseline and 3‐month in‐person counselling sessions with interim booster phone calls every 3 weeks. The primary outcome was HIV viral suppression (200 ng/ml (RR 0.97, 95% CI: 0.92–1.02). Conclusions In a randomized trial of 401 PWH with unhealthy alcohol use and risk for viral non‐suppression, a brief alcohol intervention reduced unhealthy alcohol use but did not affect viral suppression at 24 weeks. Brief alcohol interventions have the potential to improve the health of PWH in SSA by reducing alcohol use, a significant driver of HIV‐associated co‐morbidities.

Abstract Introduction Optimizing HIV prevention may require structured approaches for providing client‐centred choices as well as community‐based entry points and delivery. We evaluated the effect of a dynamic choice model for HIV prevention, delivered by community health workers (CHWs) with clinician support, on the use of biomedical prevention among persons at risk of HIV in rural East Africa. Methods We conducted a cluster randomized trial among persons (≥15 years) with current or anticipated HIV risk in 16 villages in Uganda and Kenya (SEARCH; NCT04810650). The intervention was a client‐centred HIV prevention model, including (1) structured client choice of product (pre‐exposure prophylaxis [PrEP] or post‐exposure prophylaxis [PEP]), service location (clinic or out‐of‐clinic) and HIV testing modality (self‐test or rapid test), with the ability to switch over time; (2) a structured assessment of patient barriers and development of a personalized support plan; and (3) phone access to a clinician 24/7. The intervention was delivered by CHWs and supported by clinicians who oversaw PrEP and PEP initiation and monitoring. Participants in control villages were referred to local health facilities for HIV prevention services, delivered by Ministry of Health staff. The primary outcome was biomedical prevention coverage: a proportion of 48‐week follow‐up with self‐reported PrEP or PEP use. Results From May to July 2021, we enrolled 429 people (212 intervention; 217 control): 57% women and 35% aged 15–24 years. Among intervention participants, 58% chose PrEP and 58% chose PEP at least once over follow‐up; self‐testing increased from 52% (baseline) to 71% (week 48); ≥98% chose out‐of‐facility service delivery. Among 413 (96%) participants with the primary outcome ascertained, average biomedical prevention coverage was 28.0% in the intervention versus 0.5% in the control: a difference of 27.5% (95% CI: 23.0–31.9%, p

Yes-associated protein (YAP), the downstream effector of the evolutionarily conserved Hippo pathway, promotes cellular proliferation and coordinates certain regenerative responses in mammals. Small molecule activators of YAP may, therefore, display therapeutic utility in treating disease states involving insufficient proliferative repair. From a high-throughput chemical screen of the comprehensive drug repurposing library ReFRAME, here we report the identification of SM04690, a clinical stage inhibitor of CLK2, as a potent activator of YAP-driven transcriptional activity in cells. CLK2 inhibition promotes alternative splicing of the Hippo pathway protein AMOTL2, producing an exon-skipped gene product that can no longer associate with membrane-bound proteins, resulting in decreased phosphorylation and membrane localization of YAP. This study reveals a novel mechanism by which pharmacological perturbation of alternative splicing inactivates the Hippo pathway and promotes YAP-dependent cellular growth.

Demonstration that SMAD2/3 regulate regeneration and differentiation of the endometrium in a manner important for suppression of endometrial carcinogenesis.

Summary: Background: Treatment options for premature ovarian insufficiency (POI) are limited to hormone replacement and donor oocytes. A novel induced pluripotent stem cell (iPSC) transplant paradigm in a mouse model has potential translational applications for management of POI. Methods: Mouse ovarian granulosa cell derived-iPSCS were labelled with green fluorescent protein (GFP) reporter and differentiated in vitro into oocytes. Differentiated cells were assayed for estradiol and progesterone secretion by enzyme-linked immunosorbent assays. After Fluorescence-Activated Cell Sorting (FACS) for the cell surface marker anti-Mullerian hormone receptor (AMHR2), enriched populations of differentiated cells were surgically transplanted into ovaries of mice that had POI secondary to gonadotoxic pre-treatment with alkylating agents. A total of 100 mice were used in these studies in five separate experiments with 56 animals receiving orthotopic ovarian injections of either FACS sorted or unsorted differentiated iPSCSs and the remaining animals receiving sham injections of PBS diluent. Following transplantation surgery, mice were stimulated with gonadotropins inducing oocyte development and underwent oocyte retrieval. Nine transplanted mice were cross bred with wild-type mice to assess fertility. Lineage tracing of resultant oocytes, F1 (30 pups), and F2 (42 pups) litters was interrogated by GFP expression and validation by short tandem repeat (STR) lineage tracing. Findings: [1] iPSCs differentiate into functional oocytes and steroidogenic ovarian cells which [2] express an ovarian (GJA1) and germ cell (ZP1) markers. [3] Endocrine function and fertility were restored in mice pretreated with gonadotoxic alkylating agents via orthotopic transplantation of differentiated iPSCS, thus generating viable, fertile mouse pups. Interpretation: iPSC-derived ovarian tissue can reverse endocrine and reproductive sequelae of POI. Funding: Center for Infertility and Reproductive Surgery Research Award, Siezen Foundation award (RMA). Reproductive Scientist Development Program, Marriott Foundation, Saltonstall Foundation, Brigham Ovarian Cancer Research Fund (K.E).

IntroductionSeagrass meadows serve as an integral component of coastal ecosystems but are declining rapidly due to numerous anthropogenic stressors including climate change. Eelgrass wasting disease, caused by opportunistic Labyrinthula spp., is an increasing concern with rising seawater temperature. To better understand the host-pathogen interaction, we paired whole organism physiological assays with dual transcriptomic analysis of the infected host and parasite. MethodsEelgrass (Zostera marina) shoots were placed in one of two temperature treatments, 11° C or 18° C, acclimated for 10 days, and exposed to a waterborne inoculation containing infectious Labyrinthula zosterae (Lz) or sterile seawater. At two- and five-days post-exposure, pathogen load, visible disease signs, whole leaf phenolic content, and both host- and pathogen- transcriptomes were characterized. ResultsTwo days after exposure, more than 90% of plants had visible lesions and Lz DNA was detectable in 100% percent of sampled plants in the Lz exposed treatment. Concentrations of total phenolic compounds were lower after 5 days of combined exposure to warmer temperatures and Lz, but were unaffected in other treatments. Concentrations of condensed tannins were not affected by Lz or temperature, and did not change over time. Analysis of the eelgrass transcriptome revealed 540 differentially expressed genes in response to Lz exposure, but not temperature. Lz-exposed plants had gene expression patterns consistent with increased defense responses through altered regulation of phytohormone biosynthesis, stress response, and immune function pathways. Analysis of the pathogen transcriptome revealed up-regulation of genes potentially involved in breakdown of host defense, chemotaxis, phagocytosis, and metabolism. DiscussionThe lack of a significant temperature signal was unexpected but suggests a more pronounced physiological response to Lz infection as compared to temperature. Pre-acclimation of eelgrass plants to the temperature treatments may have contributed to the limited physiological responses to temperature. Collectively, these data characterize a widespread physiological response to pathogen attack and demonstrate the value of paired transcriptomics to understand infections in a host-pathogen system.

Abstract Introduction Person‐centred HIV prevention delivery models that offer structured choices in product, testing and visit location may increase coverage. However, data are lacking on the actual uptake of choices among persons at risk of HIV in southern Africa. In an ongoing randomized study (SEARCH; NCT04810650) in rural East Africa, we evaluated the uptake of choices made when offered in a person‐centred, dynamic choice model for HIV prevention. Methods Using the PRECEDE framework, we developed a persont‐centred, Dynamic Choice HIV Prevention (DCP) intervention for persons at risk of HIV in three settings in rural Kenya and Uganda: antenatal clinic (ANC), outpatient department (OPD) and in the community. Components include: provider training on product choice (predisposing); flexibility and responsiveness to client desires and choices (pre‐exposure prophylaxis [PrEP]/post‐exposure prophylaxis [PEP], clinic vs. off‐site visits and self‐ or clinician‐based HIV testing) (enabling); and client and staff feedback (reinforcing). All clients received a structured assessment of barriers with personalized plans to address them, mobile phone access to clinicians (24 hours/7 days/week) and integrated reproductive health services. In this interim analysis, we describe the uptake of choices of product, location and testing during the first 24 weeks of follow‐up (April 2021−March 2022). Results A total of 612 (203 ANC, 197 OPD and 212 community) participants were randomized to the person‐centred DCP intervention. We delivered the DCP intervention in all three settings with diverse populations: ANC: 39% pregnant; median age: 24 years; OPD: 39% male, median age 27 years; and community: 42% male, median age: 29 years. Baseline choice of PrEP was highest in ANC (98%) vs. OPD (84%) and community (40%); whereas the proportion of adults selecting PEP was higher in the community (46%) vs. OPD (8%) and ANC (1%). Personal preference for off‐site visits increased over time (65% at week 24 vs. 35% at baseline). Interest in alternative HIV testing modalities grew over time (38% baseline self‐testing vs. 58% at week 24). Conclusions A person‐centred model incorporating structured choice in biomedical prevention and care delivery options in settings with demographically diverse groups, in rural Kenya and Uganda, was responsive to varying personal preferences over time in HIV prevention programmes.

Objectives To identify incident SARS-CoV-2 infections and inform effective mitigation strategies in university settings, we piloted an integrated symptom and exposure monitoring and testing system among a cohort of university students and employees.Design Prospective cohort study.Setting A public university in California from June to August 2020.Participants 2180 university students and 738 university employees.Primary outcome measures At baseline and endline, we tested participants for active SARS-CoV-2 infection via quantitative PCR (qPCR) test and collected blood samples for antibody testing. Participants received notifications to complete additional qPCR tests throughout the study if they reported symptoms or exposures in daily surveys or were selected for surveillance testing. Viral whole genome sequencing was performed on positive qPCR samples, and phylogenetic trees were constructed with these genomes and external genomes.Results Over the study period, 57 students (2.6%) and 3 employees (0.4%) were diagnosed with SARS-CoV-2 infection via qPCR test. Phylogenetic analyses revealed that a super-spreader event among undergraduates in congregate housing accounted for at least 48% of cases among study participants but did not spread beyond campus. Test positivity was higher among participants who self-reported symptoms (incidence rate ratio (IRR) 12.7; 95% CI 7.4 to 21.8) or had household exposures (IRR 10.3; 95% CI 4.8 to 22.0) that triggered notifications to test. Most (91%) participants with newly identified antibodies at endline had been diagnosed with incident infection via qPCR test during the study.Conclusions Our findings suggest that integrated monitoring systems can successfully identify and link at-risk students to SARS-CoV-2 testing. As the study took place before the evolution of highly transmissible variants and widespread availability of vaccines and rapid antigen tests, further research is necessary to adapt and evaluate similar systems in the present context.

The dimensional model of adversity proposes that experiences of threat and deprivation have distinct neurodevelopmental consequences. We examined these dimensions, separately and jointly, with brain structure in a sample of 149 youth aged 8–17—half recruited based on exposure to threat-related experiences. We predicted that greater threat would be uniquely associated with reduced cortical thickness and surface area in brain regions associated with salience processing including ventromedial prefrontal cortex (vmPFC), anterior cingulate cortex (ACC), and insula, and that deprivation experiences would be uniquely associated with reductions in cortical thickness and surface area in frontoparietal areas associated with cognitive control. As predicted, greater threat was associated with thinner cortex in a network including areas involved in salience processing (anterior insula, vmPFC), and smaller amygdala volume (particularly in younger participants), after controlling for deprivation. Contrary to our hypotheses, threat was also associated with thinning in the frontoparietal control network. However, these associations were reduced following control for deprivation. No associations were found between deprivation and brain structure. This examination of deprivation and threat concurrently in the same sample provided further evidence that threat-related experiences influence the structure of the developing brain independent of deprivation.

Abstract Tobacco use is the leading preventable cause of cancer, and affects the respiratory, oral, fecal, and duodenal mucosa-associated microbiota. However, the effects of smoking on the duodenal luminal microbiome have not been studied directly. We aimed to compare the duodenal luminal microbiome in never-smokers, current smokers, and ex-smokers who quit ≥ 10 years ago. In a cross-sectional study, current smokers (CS, n = 24) were identified and matched to never-smokers (NS, n = 27) and ex-smokers (XS, n = 27) by age (± 5 years), body mass index (BMI, ± 3 kg/m2), and sex. Current antibiotic users were excluded. The duodenal luminal microbiome was analysed in 1 aspirate sample per subject by 16S rRNA gene sequencing. Relative abundances (RA) of families associated with increased duodenal microbial diversity, Prevotellaceae, Neisseriaceae, and Porphyromonadaceae, were significantly lower in CS vs. NS. This was driven by lower RA of unknown Prevotella and Porphyromonas species, and Neisseria subflava and N. cinerea, in CS. In contrast, RA of Enterobacteriaceae and Lactobacillaceae (associated with decreased diversity), were significantly higher in CS, due to higher RA of Escherichia-Shigella, Klebsiella and Lactobacillus species. Many of these changes were absent or less pronounced in XS, who exhibited a duodenal luminal microbiome more similar to NS. RA of taxa previously found to be increased in the oral and respiratory microbiota of smokers were also higher in the duodenal luminal microbiome, including Bulledia extructa and an unknown Filifactor species. In conclusion, smoking is associated with an altered duodenal luminal microbiome. However, ex-smokers have a duodenal luminal microbiome that is similar to never-smokers.

BackgroundAntiretroviral therapy (ART) assures major gains in health outcomes among people living with HIV, however, this benefit may not be realized by all due to care interruptions. Mobile populations comprise a subgroup that is likely to have sub-optimal care engagement, resulting in discontinuation of ART. We sought to evaluate the barriers to care engagement among highly mobile individuals living with HIV and explore options aimed at improving engagement in care for this group.MethodsQualitative in-depth interviews were conducted in 2020 among a purposive sample of twelve persons living with HIV and eight health care providers in western Kenya, within a mixed methods study of mobility in communities participating in the SEARCH trial (NCT01864603). We explored the barriers to care engagement among mobile individuals living with HIV and explored different options aimed at enhancing care engagement. These included options such as a coded card containing treatment details, alternative drug packaging to conceal drug identity, longer refills to cover travel period, wrist bands with data storage capability to enable data transfer and "warm handoff" by providers to new clinics upon transfer. Data were inductively analyzed to understand the barriers and acceptability of potential interventions to address them.ResultsStigma and lack of disclosure, rigid work schedules, and unpredictability of travel were major barriers to care engagement for highly mobile individuals living with HIV. Additionally, lack of flexibility in clinic schedules and poor provider attitude were identified as health-system-associated barriers to care engagement. Options that enhance flexibility, convenience and access to care were viewed as the most effective means of addressing the barriers to care by both patients and providers. The most preferred option was a coded card with treatment details followed by alternative drug packaging to conceal drug identity due to stigma and longer refills to cover travel periods.ConclusionHighly mobile individuals living with HIV desire responsive, flexible, convenient and patient-centered care delivery models to enhance care engagement. They embraced simple health delivery improvements such as coded cards, alternative drug packaging and longer refills to address challenges of mobility.

While appraisal and coping are known to impact adolescent psychopathology, more vulnerable or resilient responses to stress may depend on individual temperament. This study examined early life temperament as a moderator of the prospective relations of pre-adolescent appraisal and coping with adolescent psychopathology. The sample included 226 (62% female, 14–15 years) adolescents with assessments starting at 3 years of age. Adolescents were predominately White (12% Black 9% Asian, 11% Latinx, 4% Multiracial, and 65% White). Observed early-childhood temperament (fear, frustration, executive control, and delay ability) were tested as moderators of pre-adolescent coping (active and avoidant) and appraisal (threat, positive) on internalizing and externalizing symptoms during the pandemic. Interaction effects were tested using regression in R. Sex and family context of stress were covariates. Early-childhood temperament was correlated with pre-adolescent symptoms, however, pre-adolescent appraisal and coping but not temperament predicted adolescent psychopathology. Frustration moderated the relations of active and avoidant coping and positive appraisal to symptoms such that coping and appraisal related to lower symptoms only for those low in frustration. Executive control moderated the associations of avoidant coping with symptoms such that avoidance reduced the likelihood of symptoms for youth low in executive control. Findings underscore the role of emotionality and self-regulation in youth adjustment, with the impact of coping differing with temperament. These findings suggest that equipping youth with a flexible assortment of coping skills may serve to reduce negative mental health outcomes.

Pediatric chronic pain is a significant global issue, with biopsychosocial factors contributing to the complexity of the condition. Studies have explored behavioral treatments for pediatric chronic pain, but these treatments have mixed efficacy for improving functional and psychological outcomes. Furthermore, the literature lacks an understanding of the biobehavioral mechanisms contributing to pediatric chronic pain treatment response. In this mini review, we focus on how neuroimaging has been used to identify biobehavioral mechanisms of different conditions and how this modality can be used in mechanistic clinical trials to identify markers of treatment response for pediatric chronic pain. We propose that mechanistic clinical trials, utilizing neuroimaging, are warranted to investigate how to optimize the efficacy of behavioral treatments for pediatric chronic pain patients across pain types and ages.

Cross-reactive immunity between SARS-CoV-2 and other related coronaviruses has been well-documented, and it may play a role in preventing severe COVID-19. Epidemiological studies early in the pandemic showed a geographical association between high influenza vaccination rates and lower incidence of SARS-CoV-2 infection. We, therefore, analyzed whether exposure to influenza A virus (IAV) antigens could influence the T cell repertoire in response to SARS-CoV-2, indicating a heterologous immune response between these 2 unrelated viruses. Using artificial antigen-presenting cells (aAPCs) combined with real-time reverse-transcription PCR (RT-qPCR), we developed a sensitive assay to quickly screen for antigen-specific T cell responses and detected a significant correlation between responses to SARS-CoV-2 epitopes and IAV dominant epitope (M158–66). Further analysis showed that some COVID-19 convalescent donors exhibited both T cell receptor (TCR) specificity and functional cytokine responses to multiple SARS-CoV-2 epitopes and M158–66. Utilizing an aAPC-based stimulation/expansion assay, we detected cross-reactive T cells with specificity to SARS-CoV-2 and IAV. In addition, TCR sequencing of the cross-reactive and IAV-specific T cells revealed similarities between the TCR repertoires of the two populations. These results indicate that heterologous immunity shaped by our exposure to other unrelated endemic viruses may affect our immune response to novel viruses such as SARS-CoV-2.

Abstract Background We report a case of osteitis fibrosa cystica, a rare benign resorptive bone lesion caused by hyperparathyroidism, that presented on imaging as an aggressive bone tumor. Case presentation The patient is a 51-year-old male complaining of severe sustained pain of the right hip region. Imaging studies were suspicious for a malignant tumor of the right iliac bone. Biopsy under CT guidance was performed and showed remodeled bone trabeculae with numerous osteoclasts, excluding bone tumor and raising the possibility of osteitis fibrosa cystica. Complementary tests disclosed elevated blood level of parathyroid hormone and a partially cystic enlarged left inferior parathyroid gland consistent with adenoma. After parathyroidectomy, the clinical symptoms were relieved and the radiological findings were significantly improved, which confirmed the diagnosis. Conclusions Metabolic diseases-associated bone lesions should always be considered in the differential diagnosis of bone tumors, to avoid unnecessary surgeries and treatments.

Present et al. examine the processes controlling lithification of microbial mats in a Caribbean peritidal carbonate environment. The authors present sedimentological and geochemical evidence of a surprising bias against preserving the most robust, widespread microbial ecosystems in the sedimentary record.

Root exudates are thought to play an important role in plant-microbial interactions. In return for nutrition, soil bacteria can increase the bioavailability of soil nutrients. However, root exudates typically decrease in situations such as drought, calling into question the efficacy of solvation and bacteria-dependent mineral uptake in such stress. Here, we tested the hypothesis of exudate-driven microbial priming on Cupressus saplings grown in forest soil in custom-made rhizotron boxes. A 1-month imposed drought and concomitant inoculations with a mix of Bacillus subtilis and Pseudomonas stutzeri, bacteria species isolated from the forest soil, were applied using factorial design. Direct bacteria counts and visualization by confocal microscopy showed that both bacteria associated with Cupressus roots. Interestingly, root exudation rates increased 2.3-fold with bacteria under drought, as well as irrigation. Forty-four metabolites in exudates were significantly different in concentration between irrigated and drought trees, including phenolic acid compounds and quinate. When adding these metabolites as carbon and nitrogen sources to bacterial cultures of both bacterial species, eight of nine metabolites stimulated bacterial growth. Importantly, soil phosphorous bioavailability was maintained only in inoculated trees, mitigating drought-induced decrease in leaf phosphorus and iron. Our observations of increased root exudation rate when drought and inoculation regimes were combined support the idea of root recruitment of beneficial bacteria, especially under water stress.

Gut microbiome composition is different in males and females, but sex is rarely considered when prescribing antibiotics, and sex-based differences in gut microbiome recovery following antibiotic treatment are poorly understood. Here, we compared the effects of broad-spectrum antibiotics on both the stool and small bowel microbiomes in male and female rats. Adult male and female Sprague Dawley rats were exposed to a multi-drug antibiotic cocktail for 8 days, or remained unexposed as controls. Following cessation of antibiotics, rats were monitored for an additional 13-day recovery period prior to euthanasia. Baseline stool microbiome composition was similar in males and females. By antibiotic exposure day 8 (AbxD8), exposed male rats exhibited greater loss of stool microbial diversity compared to exposed females, and the relative abundance (RA) of numerous taxa were significantly different in exposed males vs. exposed females. Specifically, RA of phylum Proteobacteria and genera Lactobacillus, Sutterella, Akkermansia, and Serratia were higher in exposed males vs. exposed females, whereas RA of phyla Firmicutes and Actinobacteria and genera Turicibacter and Enterococcus were lower. By 13 days post antibiotics cessation (PAbxD13), the stool RA of these and other taxa remained significantly different from baseline, and also remained significantly different between exposed males and exposed females. RA of phyla Firmicutes and Actinobacteria and genus Enterococcus remained lower in exposed males vs. exposed females, and genus Sutterella remained higher. However, RA of phylum Proteobacteria and genus Akkermansia were now also lower in exposed males vs. females, whereas RA of phylum Bacteroidetes and genus Turicibacter were now higher in exposed males. Further, the small bowel microbiome of exposed rats on PAbxD13 was also significantly different from unexposed controls, with higher RA of Firmicutes, Turicibacter and Parabacteroides in exposed males vs. females, and lower RA of Bacteroidetes, Proteobacteria, Actinobacteria, Oscillospira, Sutterella, and Akkermansia in exposed males vs. females. These findings indicate that broad-spectrum antibiotics have significant and sex-specific effects on gut microbial populations in both stool and the small bowel, and that the recovery of gut microbial populations following exposure to broad-spectrum antibiotics also differs between sexes. These findings may have clinical implications for the way antibiotics are prescribed.

Transmission of livestock-associated Staphylococcus aureus clonal complex 9 (LA-SA CC9) between pigs raised on industrial hog operations (IHOs) and humans in the United States is poorly understood. We analyzed whole-genome sequences from 32 international S. aureus CC9 isolates and 49 LA-SA CC9 isolates from IHO pigs and humans who work on or live near IHOs in 10 pig-producing counties in North Carolina, USA. Bioinformatic analysis of sequence data from the 81 isolates demonstrated 3 major LA-SA CC9 clades. North Carolina isolates all fell within a single clade (C3). High-resolution phylogenetic analysis of C3 revealed 2 subclades of intermingled IHO pig and human isolates differing by 0–34 single-nucleotide polymorphisms. Our findings suggest that LA-SA CC9 from pigs and humans share a common source and provide evidence of transmission of antimicrobial-resistant LA-SA CC9 between IHO pigs and humans who work on or live near IHOs in North Carolina.

Abstract Background The proportion of infections among young children that are antimicrobial-resistant is increasing across the globe. Newborns may be colonized with enteric antimicrobial-resistant pathogens early in life, which is a risk factor for infection-related morbidity and mortality. Breastfeeding is actively promoted worldwide for its beneficial impacts on newborn health and gut health. However, the role of breastfeeding and human milk components in mitigating young children’s carriage of antimicrobial-resistant pathogens and antibiotic resistance genes has not been comprehensively explored. Main body Here, we review how the act of breastfeeding, early breastfeeding, and/or human milk components, such as the milk microbiota, secretory IgA, human milk oligosaccharides, antimicrobial peptides, and microRNA -bearing extracellular vesicles, could play a role in preventing the establishment of antimicrobial-resistant pathogens in young children’s developing gut microbiomes. We describe findings from recent human studies that support this concept. Conclusion Given the projected rise in global morbidity and mortality that will stem from antimicrobial-resistant infections, identifying behavioral or nutritional interventions that could decrease children’s susceptibility to colonization with antimicrobial-resistant pathogens may be one strategy for protecting their health. We suggest that breastfeeding and human milk supplements deserve greater attention as potential preventive measures in the global effort to combat antimicrobial resistance, particularly in low- and middle-income settings.

Environmental exposure to glyphosate and glyphosate-based herbicides has the potential to negatively influence neurodevelopment and behavior across generations indirectly through the gut-brain-microbiome axis. Potential mechanisms by which glyphosate may elicit these effects are through the disruption of the normally symbiotic relationship of the host and the gut microbiome. Given glyphosate can kill commensal members of the microbiome like Lactobacillus spp., Ruminococaeae and Butyricoccus spp., resulting in reductions in key microbial metabolites that act through the gut-brain-microbiome axis including indoles, L-glutamate and SCFAs. Glyphosate- resistant microbes in the gut have the potential to increase the production of pro-inflammatory cytokines and reactive oxygen species which may result in increased HPA activation, resulting in increased production of glucocorticoids which have implications on neurodevelopment. In addition, maternal transfer of the gut microbiome can affect immune and neurodevelopment, across generations. This perspective article weighs the evidence for chronic glyphosate exposure on the gut microbiome and the potential consequences on the gut-brain axis correlated with increased incidence of neuropsychiatric conditions.

Abstract Aim The aim of this study was to translate and culturally adapt the PCPI‐S into German and to eventually test its psychometric properties in long‐term care settings. Background Person‐centred practice has been widely adopted internationally as a best‐practice model in nursing and health care. To ensure a sustainable implementation of this practice and to successively promote it, person‐centred practice should be evaluated on a regular basis. The Person‐centred Practice Inventory—Staff (PCPI‐S), which is based on McCormack & McCance's Person‐centred Practice Framework, is a new instrument for this purpose by assessing perceptions of person‐centredness among healthcare staff. Design A two‐phase research design was used involving the translation and cultural adaption of the PCPI‐S from English to German (PCPI‐S‐G; Phase 1) and a quantitative cross‐sectional survey (Phase 2). Methods Construct validity was evaluated using confirmatory factor analysis (CFA), and internal consistency was calculated using Cronbach's α. Results Phase 1 was conducted using an internationally recommended checklist for translations and cultural adaptations. In Phase 2, the PCPI‐S‐G was tested in 15 residential care homes in Austria with a sample of 255 staff members. The CFA showed good construct validity and supported the theoretical framework. The internal consistency for the three constructs of the PCPI‐S was excellent, revealing Cronbach's α‐scores from 0.902–0.941.

The soil, Soul of Infinite Life, is the entity responsible for sustaining life on earth. In spite of significant advances in the service sector, agriculture remains the major provider of employment and source of revenue in India. Soil testing is a valuable tool for evaluating the available nutrient status of soil and helps to determine the proper amount of nutrients to be added to a given soil based on its fertility and crop needs. In the current study, the soil test report values are used to classify several significant soil features like village wise soil fertility indices of Available Phosphorus (P), Available Potassium (K), Organic Carbon (OC) and Boron (B), as well as the parameter Soil Reaction (pH). The classification and prediction of the village wise soil parameters aids in reducing wasteful expenditure on fertilizer inputs, increase profitability, save the time of chemical soil analysis experts, improves soil health and environmental quality. These five classification problems are solved using the fast learning classification technique known as Extreme Learning Machine (ELM) with different activation functions like gaussian radial basis, sine-squared, hyperbolic tangent, triangular basis, and hard limit. After the performance analysis of ELMs with diverse activation functions for these soil parameter classifications, the gaussian radial basis function attains the maximum performance for four out of five problems, which goes above 80% in most of the accuracy rate calculations in every problem, followed by hyperbolic tangent, hard limit, triangular basis, and sine-squared. However, the performance of the final classification problem, i.e. the pH classification, gives moderate values with the gaussian radial basis and best performance (near 90%), with the hyperbolic tangent. Keywords: Extreme learning machine, Activation functions, Soil fertility indices, Soil pH, Classification, Prediction

Growing literature has shown heterogenous effects of conditional cash incentives (CCIs) on HIV care retention. The field lacks insights into reasons why incentives impact various patients in different ways-differences that may be due to variations in psychological and social mechanisms of effect. A deeper understanding of patients' perceptions and experiences of CCIs for retention may help to clarify these mechanisms. We conducted a qualitative study embedded in the ADAPT-R trial (NCT#02338739), a sequential multiple assignment randomized trial (SMART) that evaluated economic incentives to support retention in HIV care among persons living with HIV (PLHIV) initiating antiretroviral therapy in Kenya. Participants who attended their scheduled clinic visits received an incentive of approximately $4 each visit. Interviews were conducted between July 2016 and June 2017 with 39 participants to explore attitudes and experiences with economic incentives conditional on care engagement. Analyses revealed that incentives helped PLHIV prioritize care-seeking by alleviating transport barriers and food insecurity: "I decided to forgo [work] and attend clinic […] the voucher relieved me". Patients who borrowed money for care-seeking reported feeling relieved from the burden of indebtedness to others: "I borrow with confidence that I will pay after my appointment." Incentives fostered their autonomy, and enabled them to support others: "I used the money to buy some clothes and Pampers for the children." Participants who were intrinsically motivated to engage in care ("my life depends on the drugs, not the incentive"), and those who mistrusted researchers, reported being less prompted by the incentive itself. For patients not already prioritizing care-seeking, incentives facilitated care engagement through alleviating transport costs, indebtedness and food insecurity, and also supported social role fulfillment. Conditional cash incentives may be an important cue to action to improve progression through the HIV treatment cascade, and contribute to better care retention.

BackgroundFewer than 10% of people with hypertension in sub-Saharan Africa are diagnosed, linked to care, and achieve hypertension control. We hypothesized that a one-time financial incentive and phone call reminder for missed appointments would increase linkage to hypertension care following community-based screening in rural Uganda and Kenya.MethodsIn a randomized controlled trial, we conducted community-based hypertension screening and enrolled adults ≥25 years with blood pressure ≥140/90 mmHg on three measures; we excluded participants with known hypertension or hypertensive emergency. The intervention was transportation reimbursement upon linkage (~$5 USD) and up to three reminder phone calls for those not linking within seven days. Control participants received a clinic referral only. Outcomes were linkage to hypertension care within 30 days (primary) and hypertension control ResultsWe screened 1,998 participants, identifying 370 (18.5%) with uncontrolled hypertension and enrolling 199 (100 control, 99 intervention). Reasons for non-enrollment included prior hypertension diagnosis (n = 108) and hypertensive emergency (n = 32). Participants were 60% female, median age 56 (range 27-99); 10% were HIV-positive and 42% had baseline blood pressure ≥160/100 mmHg. Linkage to care within 30 days was 96% in intervention and 66% in control (aRR 1.45, 95%CI 1.25-1.68). Hypertension control at 90 days was 51% intervention and 41% control (aRR 1.22, 95%CI 0.92-1.66).ConclusionA one-time financial incentive and reminder call for missed visits resulted in a 30% absolute increase in linkage to hypertension care following community-based screening. Financial incentives can improve the critical step of linkage to care for people newly diagnosed with hypertension in the community.

Cutworms and armyworms (Lepidoptera: Noctuidae) are a pest complex in North America that cause sporadic damage in field crops on the Canadian Prairies; however, no methods have been developed to reliably monitor population densities. Food-based semiochemicals attract both sexes of adult moths and could be used to monitor multiple species with a single lure in a single trap. Here, we focus on enhancing the attractiveness of acetic acid and 3-methyl-1-butanol (AAMB) lures to redbacked cutworm (Euxoa ochrogaster) (RBC) and other noctuid pests. Experiments conducted in canola and wheat fields tested AAMB lures at different release rates, from different devices and in combination with other semiochemicals. High-release lures captured more females in canola, while low-release lures captured more males in wheat. Thus, crop volatiles may influence response to lures. Semiochemicals embedded in an inert matrix caught more RBC moths than semiochemicals released from Nalgene or polyethylene dispensers did. More RBC females were attracted to AAMB lures with 2-methyl-1-propanol than phenylacetaldehyde. Fermented volatiles appear to be a more reliable attractant than floral volatiles for these species. RBC moth antennae produced significant responses to all doses of phenylacetaldehyde tested in electroantennogram assays, but only to higher doses of acetic acid and 3-methyl-1-butanol. Physiological state of the RBC moths also influenced responsiveness to the tested semiochemical. Feeding status did not influence the antennal response to acetic acid and phenylacetaldehyde in either sex, but it increased the response to 3-methyl-1-butanol in females when fed. AAMB lures should be further developed to monitor RBC moths and other noctuid pests in field crops.

Children from low-socioeconomic status (SES) households on average exhibit lower academic achievement than their higher-SES peers. We investigated a novel hypothesis that differences in early-developing sensory networks—specifically the ventral visual stream (VVS), which is involved in processing visual stimuli—contribute to SES-related disparities in executive functions (EF) and academic outcomes. We used fMRI to investigate SES-related differences in neural function in children (6–8 years, n = 62) during two attentional tasks involving attention to visual information: cued attention and memory-guided attention. Recruitment of VVS during both tasks was associated with EF and academic achievement, and SES-related differences in VVS activation during cued attention were marginally explained by differences in cognitive stimulation. VVS activation during cued attention mediated SES-related differences in academic achievement. Finally, the link between VVS activation during both tasks and academic achievement was mediated by differences in EF. We extend previous work by highlighting that: (i) early-developing visual processing regions play a role in supporting complex attentional processes, (ii) childhood SES is associated with VVS function, which is explained in part by SES-related differences in cognitive stimulation and (iii) provide preliminary evidence that individual differences in VVS function may play a role in the emergence of the income-achievement gap.

Over the past decade extensive research has examined the segregation of the human brain into large-scale functional networks. The resulting network maps, i.e. parcellations, are now commonly used for the a priori identification of functional networks. However, the use of these parcellations, particularly in developmental and clinical samples, hinges on four fundamental assumptions: (1) the various parcellations are equally able to recover the networks of interest; (2) adult-derived parcellations well represent the networks in children's brains; (3) network properties, such as within-network connectivity, are reliably measured across parcellations; and (4) parcellation selection does not impact the results with regard to individual differences in given network properties. In the present study we examined these assumptions using eight common parcellation schemes in two independent developmental samples. We found that the parcellations are equally able to capture networks of interest in both children and adults. However, networks bearing the same name across parcellations (e.g., default network) do not produce reliable within-network measures of functional connectivity. Critically, parcellation selection significantly impacted the magnitude of associations of functional connectivity with age, poverty, and cognitive ability, producing meaningful differences in interpretation of individual differences in functional connectivity based on parcellation choice. Our findings suggest that work employing parcellations may benefit from the use of multiple schemes to confirm the robustness and generalizability of results. Furthermore, researchers looking to gain insight into functional networks may benefit from employing more nuanced network identification approaches such as using densely-sampled data to produce individual-derived network parcellations. A transition towards precision neuroscience will provide new avenues in the characterization of functional brain organization across development and within clinical populations.

The Sustainable East Africa Research in Community Health (SEARCH), a universal test and treat (UTT) trial, implemented ‘Streamlined Care’—a multicomponent strategy including rapid linkage to care and antiretroviral therapy (ART) start, 3-monthly refills, viral load counseling, and accessible, patient-centered care provision. To understand patient and provider experiences of Streamlined Care to inform future care innovations, we conducted in-depth interviews with patients ( n = 18) and providers ( n = 28) at baseline (2014) and follow-up (2015) ( n = 17 patients; n = 21 providers). Audio recordings were transcribed, translated, and deductively and inductively coded. Streamlined Care helped to decongest clinic spaces and de-stigmatize human immunodeficiency virus (HIV) care. Patients credited the individualized counselling, provider-assisted HIV status disclosure, and providers’ knowledge of patient's drug schedules, availability, and phone call reminders for their care engagement. However, for some, denial (repeated testing to disprove HIV+ results), feeling healthy, limited understanding of the benefits of early ART, and anticipated side-effects, and mistrust of researchers hindered rapid ART initiation. Patients’ short and long-term mobility proved challenging for both patients and providers. Providers viewed viral load counselling as a powerful tool to convince otherwise healthy and high-CD4 patients to initiate ART. Patient-centered HIV care models should build on the successes of Streamlined Care, while addressing persistent barriers. #NCT01864683— https://clinicaltrials.gov/ct2/show/NCT01864603

Dispersal flights by the mountain pine beetle have allowed range expansion and major damage to pine stands in western Canada. We asked what the genetic and transcriptional basis of mountain pine beetle dispersal capacity is. Using flight mills, RNA-seq and a targeted association study, we compared strong-flying, weak-flying, and non-flying female beetles from the recently colonized northern end of their range. Nearly 3,000 genes were differentially expressed between strong and weak flying beetles, while weak fliers and nonfliers did not significantly differ. The differentially expressed genes were mainly associated with lipid metabolism, muscle maintenance, oxidative stress response, detoxification, endocrine function, and flight behavior. Three variant loci, two in the coding region of genes, were significantly associated with flight capacity but these genes had no known functional link to flight. Several differentially expressed gene systems may be important for sustained flight, while other systems are downregulated during dispersal and likely to conserve energy before host colonization. The candidate genes and SNPs identified here will inform further studies and management of mountain pine beetle, as well as contribute to understanding the mechanisms of insect dispersal flights.

BackgroundHypertension treatment reduces morbidity and mortality yet has not been broadly implemented in many low-resource settings, including sub-Saharan Africa (SSA). We hypothesized that a patient-centered integrated chronic disease model that included hypertension treatment and leveraged the HIV care system would reduce mortality among adults with uncontrolled hypertension in rural Kenya and Uganda.Methods and findingsThis is a secondary analysis of the SEARCH trial (NCT:01864603), in which 32 communities underwent baseline population-based multidisease testing, including hypertension screening, and were randomized to standard country-guided treatment or to a patient-centered integrated chronic care model including treatment for hypertension, diabetes, and HIV. Patient-centered care included on-site introduction to clinic staff at screening, nursing triage to expedite visits, reduced visit frequency, flexible clinic hours, and a welcoming clinic environment. The analytic population included nonpregnant adults (≥18 years) with baseline uncontrolled hypertension (blood pressure ≥140/90 mm Hg). The primary outcome was 3-year all-cause mortality with comprehensive population-level assessment. Secondary outcomes included hypertension control assessed at a population level at year 3 (defined per country guidelines as at least 1 blood pressure measure ConclusionsIn this cluster randomized comparison where both arms received population-level hypertension screening, implementation of a patient-centered hypertension care model was associated with a 21% reduction in all-cause mortality and a 22% improvement in hypertension control compared to standard care among adults with baseline uncontrolled hypertension. Patient-centered chronic care programs for HIV can be leveraged to reduce the overall burden of cardiovascular mortality in SSA.Trial registrationClinicalTrials.gov NCT01864603.

Caloptilia fraxinella Ely (Lepidoptera: Gracillariidae), the ash leaf-cone roller, is an aesthetic pest of horticultural ash trees (Oleaceae, Genus Fraxinus) in prairie communities across Canada. Because pesticide use is undesirable in urban centers, biological control of C. fraxinella is a preferred approach. The native parasitoid wasp, Apanteles polychrosidis Vierek (Hymenoptera: Braconidae), has shifted hosts and is the primary parasitoid of C. fraxinella in Edmonton, Alberta, Canada, and has potential as a biological control agent. Here, in an effort to increase parasitism of C. fraxinella, lures releasing methyl salicylate (MeSA) and two green leaf volatiles (GLVs), [(Z)-3-hexenol, and (Z)-3-hexenyl-acetate], at both low and high release rates, were tested to enhance attraction and retention of A. polychrosidis in infested ash trees. Attraction of A. polychrosidis to baited trees was measured by capture on yellow sticky cards positioned in the tree canopy, and wasp activity was assessed by the parasitism rate of C. fraxinella. More male and female A. polychrosidis were captured on yellow sticky traps positioned in trees baited with the low dose of both MeSA + GLVs than to unbaited, infested ash trees. The increased attraction of wasps did not correlate with an increase in parasitism of C. fraxinella. The high release rate lures did not enhance attraction of A. polychrosidis to infested ash trees. Parasitism rate, however, was negatively correlated with host density in both field experiments. There was no evidence of close-range attraction to lures in an olfactometer assay. Synthetic HIPVs attract A. polychrosidis to ash trees infested with C. fraxinella, but the effect of wasp attraction on parasitism rate requires further research if HIPVs are to be used to enhance biological control in this system.

Two key features of recombinant inbred panels are well-characterized genomes and reproducibility. Here we report on the sequenced genomes of six additional Collaborative Cross (CC) strains and on inbreeding progress of 72 CC strains. We have previously reported on the sequences of 69 CC strains that were publicly available, bringing the total of CC strains with whole genome sequence up to 75. The sequencing of these six CC strains updates the efforts toward inbreeding undertaken by the UNC Systems Genetics Core. The timing reflects our competing mandates to release to the public as many CC strains as possible while achieving an acceptable level of inbreeding. The new six strains have a higher than average founder contribution from non-domesticus strains than the previously released CC strains. Five of the six strains also have high residual heterozygosity (>14%), which may be related to non-domesticus founder contributions. Finally, we report on updated estimates on residual heterozygosity across the entire CC population using a novel, simple and cost effective genotyping platform on three mice from each strain. We observe a reduction in residual heterozygosity across all previously released CC strains. We discuss the optimal use of different genetic resources available for the CC population.

IntroductionIdentifying the optimal approaches to offering HIV prevention to meet the needs of those at risk is a high priority, particularly given the expanding toolkit of biomedical HIV prevention options. An ongoing study in rural East African communities evaluated the uptake of choices in product, testing mode and location of care delivery through a structured patient-centred HIV prevention delivery model. In this qualitative study, we sought to understand clients' experiences of this "dynamic choice prevention model" (DCP) and highlight pathways of action to inform HIV prevention delivery models.MethodsIn-depth semi-structured interviews were conducted from November 2021 through March 2022 with a purposively selected sample of n = 56 participants in DCP trials (across outpatient departments, antenatal clinics and community settings), and n = 21 healthcare providers (total n = 77). A seven-person multi-regional team translated and inductively coded transcript data. We used a framework analysis approach to identify emergent themes.ResultsIndividuals taking up HIV pre-exposure prophylaxis (PrEP) reported feelings of relief, liberation from fears of acquiring HIV and satisfaction with being able to take action despite partners' behaviours. Couples used a range of approaches afforded by the study to persuade partners to get tested and opt for PrEP. Post-exposure prophylaxis (PEP) use was less common, although women welcomed it in the event of sexual coercion or assault. Participants discussed switching from PEP to PrEP after familiarizing themselves with usage and ascertaining ongoing risk. Participants felt respected by providers, trusted them and appreciated being able to contact them directly for telephone support. Prevention uptake was hindered by stigma, limited experience with and knowledge of prevention methods, gendered and generational power dynamics within intimate partnerships and families, and negative perceptions of methods due to the products themselves. Participants anticipated long-acting injectable PrEP could solve their challenges regarding pill size, daily pill burden and the likelihood of unwanted disclosure.ConclusionsDiverse preferences and barriers to uptake of prevention require a choice of HIV prevention options, locations and delivery modalities-but in addition, flexible, competent and friendly care provision is crucial to promote uptake. Helping clients feel valued, and addressing their unique needs and challenges, enables their agency to prioritize their health.

This paper presents novel data from San Pablo Macuiltianguis Zapotec, a Sierra Juárez variety spoken in Oaxaca, Mexico. This language is ‘laryngeally complex’ (Silverman, 1997), exhibiting both contrastive tone and contrastive phonation. We examine the acoustic properties of the modal and checked vowels in this language, showing that this contrast is variably produced with several different acoustic cues. We analyze the distribution of these cues as an instance of phonetic enhancement and further show that the prosodic position of a given vowel determines which of several enhancement patterns is used. We argue that extant theories of phonetic enhancement, while able to explain the patterns described here, fall short of predicting the distribution of enhancing cues. We therefore propose that future models of phonetic enhancement could be expanded to predict patterns in which more than one acoustic dimension is available for phonetic enhancement.

BackgroundOral pre-exposure prophylaxis (PrEP) is highly effective for HIV prevention, but data are limited on HIV incidence among PrEP users in generalized epidemic settings, particularly outside of selected risk groups. We performed a population-based PrEP study in rural Kenya and Uganda and sought to evaluate both changes in HIV incidence and clinical and virologic outcomes following seroconversion on PrEP.Methods and findingsDuring population-level HIV testing of individuals ≥15 years in 16 communities in the Sustainable East Africa Research in Community Health (SEARCH) study (NCT01864603), we offered universal access to PrEP with enhanced counseling for persons at elevated HIV risk (based on serodifferent partnership, machine learning-based risk score, or self-identified HIV risk). We offered rapid or same-day PrEP initiation and flexible service delivery with follow-up visits at facilities or community-based sites at 4, 12, and every 12 weeks up to week 144. Among participants with incident HIV infection after PrEP initiation, we offered same-day antiretroviral therapy (ART) initiation and analyzed HIV RNA, tenofovir hair concentrations, drug resistance, and viral suppression (ConclusionsPopulation-level offer of PrEP with rapid start and flexible service delivery was associated with 74% lower HIV incidence among PrEP initiators compared to matched recent controls prior to PrEP availability. HIV infections were significantly lower among women who started PrEP. Universal HIV testing with linkage to treatment and prevention, including PrEP, is a promising approach to accelerate reductions in new infections in generalized epidemic settings.Trial registrationClinicalTrials.gov NCT01864603.

Logopenic variant primary progressive aphasia (lvPPA) is a neurodegenerative language disorder primarily characterized by impaired phonological processing. Sentence repetition and comprehension deficits are observed in lvPPA and linked to impaired phonological working memory, but recent evidence also implicates impaired speech perception. Currently, neural encoding of the speech envelope, which forms the scaffolding for perception, is not clearly understood in lvPPA. We leveraged recent analytical advances in electrophysiology to examine speech envelope encoding in lvPPA. We assessed cortical tracking of the speech envelope and in-task comprehension of two spoken narratives in individuals with lvPPA (n = 10) and age-matched (n = 10) controls. Despite markedly reduced narrative comprehension relative to controls, individuals with lvPPA had increased cortical tracking of the speech envelope in theta oscillations, which track low-level features (e.g., syllables), but not delta oscillations, which track speech units that unfold across a longer time scale (e.g., words, phrases, prosody). This neural signature was highly correlated across narratives. Results indicate an increased reliance on acoustic cues during speech encoding. This may reflect inefficient encoding of bottom-up speech cues, likely as a consequence of dysfunctional temporoparietal cortex.