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α-l-(3-2)-Threofuranosyl nucleic acid (TNA) pairs with itself, cross-pairs with DNA and RNA, and shows promise as a tool in synthetic genetics, diagnostics, and oligonucleotide therapeutics. We studied in vitro primer insertion and extension reactions catalyzed by human trans-lesion synthesis (TLS) DNA polymerase η (hPol η) opposite a TNA-modified template strand without and in combination with O4-alkyl thymine lesions. Across TNA-T (tT), hPol η inserted mostly dAMP and dGMP, dTMP and dCMP with lower efficiencies, followed by extension of the primer to a full-length product. hPol η inserted dAMP opposite O4-methyl and -ethyl analogs of tT, albeit with reduced efficiencies relative to tT. Crystal structures of ternary hPol η complexes with template tT and O4-methyl tT at the insertion and extension stages demonstrated that the shorter backbone and different connectivity of TNA compared to DNA (3 → 2 versus 5 → 3, respectively) result in local differences in sugar orientations, adjacent phosphate spacings, and directions of glycosidic bonds. The 3-OH of the primers terminal thymine was positioned at 3.4 Å on average from the α-phosphate of the incoming dNTP, consistent with insertion opposite and extension past the TNA residue by hPol η. Conversely, the crystal structure of a ternary hPol η·DNA·tTTP complex revealed that the primers terminal 3-OH was too distant from the tTTP α-phosphate, consistent with the inability of the polymerase to incorporate TNA. Overall, our study provides a better understanding of the tolerance of a TLS DNA polymerase vis-à-vis unnatural nucleotides in the template and as the incoming nucleoside triphosphate.

Mindfulness witnessed a substantial popularity surge in the past decade, especially as digitally self-administered interventions became available at relatively low costs. Yet, it is uncertain whether they effectively help reduce stress. In a preregistered (OSF https://doi.org/10.17605/OSF.IO/UF4JZ ; retrospective registration at ClinicalTrials.gov NCT06308744 ) multi-site study (nsites = 37, nparticipants = 2,239, 70.4% women, Mage = 22.4, s.d.age = 10.1, all fluent English speakers), we experimentally tested whether four single, standalone mindfulness exercises effectively reduced stress, using Bayesian mixed-effects models. All exercises proved to be more efficacious than the active control. We observed a mean difference of 0.27 (d = -0.56; 95% confidence interval, -0.43 to -0.69) between the control condition (M = 1.95, s.d. = 0.50) and the condition with the largest stress reduction (body scan: M = 1.68, s.d. = 0.46). Our findings suggest that mindfulness may be beneficial for reducing self-reported short-term stress for English speakers from higher-income countries.

Nucleocapsid antibody assays can be used to estimate SARS-CoV-2 infection prevalence in regions implementing spike-based COVID-19 vaccines. However, poor sensitivity of nucleocapsid antibody assays in detecting infection after vaccination has been reported. We derived a lower cutoff for identifying previous infections in a large blood donor cohort (N = 142,599) by using the Ortho VITROS Anti-SARS-CoV-2 Total-N Antibody assay, improving sensitivity while maintaining specificity >98%. We validated sensitivity in samples donated after self-reported swab-confirmed infections diagnoses. Sensitivity for first infections in unvaccinated donors was 98.1% (95% CI 98.0-98.2) and for infection after vaccination was 95.6% (95% CI 95.6-95.7) based on the standard cutoff. Regression analysis showed sensitivity was reduced in the Delta compared with Omicron period, in older donors, in asymptomatic infections,

Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia after Alzheimer disease (AD). Efforts in the field mainly focus on familial forms of disease (fFTDs), while studies of the genetic etiology of sporadic FTD (sFTD) have been less common. In the current work, we analyzed 4,685 sFTD cases and 15,308 controls looking for common genetic determinants for sFTD. We found a cluster of variants at the MAPT (rs199443; p = 2.5 × 10-12, OR = 1.27) and APOE (rs6857; p = 1.31 × 10-12, OR = 1.27) loci and a candidate locus on chromosome 3 (rs1009966; p = 2.41 × 10-8, OR = 1.16) in the intergenic region between RPSA and MOBP, contributing to increased risk for sFTD through effects on expression and/or splicing in brain cortex of functionally relevant in-cis genes at the MAPT and RPSA-MOBP loci. The association with the MAPT (H1c clade) and RPSA-MOBP loci may suggest common genetic pleiotropy across FTD and progressive supranuclear palsy (PSP) (MAPT and RPSA-MOBP loci) and across FTD, AD, Parkinson disease (PD), and cortico-basal degeneration (CBD) (MAPT locus). Our data also suggest population specificity of the risk signals, with MAPT and APOE loci associations mainly driven by Central/Nordic and Mediterranean Europeans, respectively. This study lays the foundations for future work aimed at further characterizing population-specific features of potential FTD-discriminant APOE haplotype(s) and the functional involvement and contribution of the MAPT H1c haplotype and RPSA-MOBP loci to pathogenesis of sporadic forms of FTD in brain cortex.

PURPOSE: There is limited information on the clustering or co-occurrence of complications after spinal fusion surgery for neuromuscular disease in children. We aimed to identify the frequency and predictive factors of co-occurring perioperative complications in these children. METHODS: In this retrospective database cohort study, we identified children (ages 10-18 years) with neuromuscular scoliosis who underwent elective spinal fusion in 2012-2020 from the National Surgical Quality Improvement Program-Pediatric database. The rates of co-occurring complications within 30 days were calculated, and associated factors were identified by logistic regression analysis. Correlation between a number of complications and outcomes was assessed. RESULTS: Approximately 11% (709/6677 children with neuromuscular scoliosis undergoing spinal fusion had co-occurring complications: 7% experienced two complications and 4% experienced ≥ 3. The most common complication was bleeding/transfusion (80%), which most frequently co-occurred with pneumonia (24%) and reintubation (18%). Surgical time ≥ 400 min (odds ratio (OR) 1.49 [95% confidence interval (CI) 1.25-1.75]), fusion ≥ 13 levels (1.42 [1.13-1.79]), and pelvic fixation (OR 1.21 [1.01, 1.44]) were identified as procedural factors that independently predicted concurrent complications. Clinical risk factors for co-occurring complications included an American Society of Anesthesiologist physical status classification ≥ 3 (1.73 [1.27-2.37]), structural pulmonary/airway abnormalities (1.24 [1.01-1.52]), impaired cognitive status (1.80 [1.41-2.30]), seizure disorder (1.36 [1.12-1.67]), hematologic disorder (1.40 [1.03-1.91], preoperative nutritional support (1.34 [1.08-1.72]), and congenital malformations (1.20 [1.01-1.44]). Preoperative tracheostomy was protective against concurrent complications (0.62 [0.43-0.89]). Significant correlations were found between number of complications and length of stay, non-home discharge, readmissions, and death. CONCLUSION: Longer surgical time (≥ 400 min), fusion ≥ 13 levels and pelvic fixation are surgical risk factors independently associated with co-occurring complications, which were associated with poorer patient outcomes. Recognizing identified nonmodifiable risk factors might also be important for preoperative planning and risk stratification of children with neuromuscular scoliosis requiring spinal fusion. LEVEL OF EVIDENCE: Level IV evidence.

PURPOSE: The purpose of this review was to evaluate the effectiveness of patient-specific rods for adult spinal deformity. METHODS: A systematic review of the literature was performed through an electronic search of the PubMed, Scopus, and Web of Science databases. Human studies between 2012 and 2023 were included. Sample size, sagittal vertical axis (SVA), pelvic incidence-lumbar lordosis (PI-LL), pelvic tilt (PT), operation time, blood loss, follow-up duration, and complications were recorded for each study when available. RESULTS: Seven studies with a total of 304 adult spinal deformity patients of various etiologies were included. All studies reported SVA, and PT; two studies did not report PI-LL. Four studies reported planned radiographic outcomes. Two found a significant association between preoperative plan and postoperative outcome in all three outcomes. One found a significant association for PI-LL alone. The fourth found no significant associations. SVA improved in six of seven studies, PI-LL improved in all five, and three of seven studies found improved postoperative PT. Significance of these results varied greatly by study. CONCLUSION: Preliminary evidence suggests potential benefits of PSRs in achieving optimal spino-pelvic parameters in ASD surgery. Nevertheless, conclusions regarding the superiority of PSRs over traditional rods must be judiciously drawn, given the heterogeneity of patients and study methodologies, potential confounding variables, and the absence of robust randomized controlled trials. Future investigations should concentrate on enhancing preoperative planning, standardizing surgical methodologies, isolating specific patient subgroups, and head-to-head comparisons with traditional rods to fully elucidate the impact of PSRs in ASD surgery.

Psychosis risk prediction is one of the leading challenges in psychiatry. Previous investigations have suggested that plasma proteomic data may be useful in accurately predicting transition to psychosis in individuals at clinical high risk (CHR). We hypothesized that an a priori-specified proteomic prediction model would have strong predictive accuracy for psychosis risk and aimed to replicate longitudinal associations between plasma proteins and transition to psychosis. This study used plasma samples from participants in 3 CHR cohorts: the North American Prodrome Longitudinal Studies 2 and 3, and the NEURAPRO randomized control trial (total n = 754). Plasma proteomic data were quantified using mass spectrometry. The primary outcome was transition to psychosis over the study follow-up period. Logistic regression models were internally validated, and optimism-corrected performance metrics derived with a bootstrap procedure. In the overall sample of CHR participants (age: 18.5, SD: 3.9; 51.9% male), 20.4% (n = 154) developed psychosis within 4.4 years. The a priori-specified model showed poor risk-prediction accuracy for the development of psychosis (C-statistic: 0.51 [95% CI: 0.50, 0.59], calibration slope: 0.45). At a group level, Complement C8B, C4B, C5, and leucine-rich α-2 glycoprotein 1 (LRG1) were associated with transition to psychosis but did not surpass correction for multiple comparisons. This study did not confirm the findings from a previous proteomic prediction model of transition from CHR to psychosis. Certain complement proteins may be weakly associated with transition at a group level. Previous findings, derived from small samples, should be interpreted with caution.

This article describes the rationale, aims, and methodology of the Accelerating Medicines Partnership® Schizophrenia (AMP® SCZ). This is the largest international collaboration to date that will develop algorithms to predict trajectories and outcomes of individuals at clinical high risk (CHR) for psychosis and to advance the development and use of novel pharmacological interventions for CHR individuals. We present a description of the participating research networks and the data processing analysis and coordination center, their processes for data harmonization across 43 sites from 13 participating countries (recruitment across North America, Australia, Europe, Asia, and South America), data flow and quality assessment processes, data analyses, and the transfer of data to the National Institute of Mental Health (NIMH) Data Archive (NDA) for use by the research community. In an expected sample of approximately 2000 CHR individuals and 640 matched healthy controls, AMP SCZ will collect clinical, environmental, and cognitive data along with multimodal biomarkers, including neuroimaging, electrophysiology, fluid biospecimens, speech and facial expression samples, novel measures derived from digital health technologies including smartphone-based daily surveys, and passive sensing as well as actigraphy. The study will investigate a range of clinical outcomes over a 2-year period, including transition to psychosis, remission or persistence of CHR status, attenuated positive symptoms, persistent negative symptoms, mood and anxiety symptoms, and psychosocial functioning. The global reach of AMP SCZ and its harmonized innovative methods promise to catalyze the development of new treatments to address critical unmet clinical and public health needs in CHR individuals.

Storylines of Family Medicine is a 12-part series of thematically linked mini-essays with accompanying illustrations that explore the many dimensions of family medicine as interpreted by individual family physicians and medical educators in the USA and elsewhere around the world. In VIII: clinical approaches, authors address the following themes: Evaluation, diagnosis and management I-toward a working diagnosis, Evaluation, diagnosis and management II-process steps, Interweaving integrative medicine and family medicine, Halfway-the art of clinical judgment, Seamless integration in family medicine-team-based care, Technology-uncovering stories from noise and Caring for patients with multiple long-term conditions. May readers recognise in these essays the uniqueness of a family medicine approach to care.

Storylines of Family Medicine is a 12-part series of thematically linked essays with accompanying illustrations that explore the many dimensions of family medicine, as interpreted by individual family physicians and medical educators in the USA and elsewhere around the world. In 'V: ways of thinking-honing the therapeutic self', authors present the following sections: 'Reflective practice in action', 'The doctor as drug-Balint groups', 'Cultivating compassion', 'Towards a humanistic approach to doctoring', 'Intimacy in family medicine', 'The many faces of suffering', 'Transcending suffering' and 'The power of listening to stories.' May readers feel a deeper sense of their own therapeutic agency by reflecting on these essays.

Storylines of Family Medicine is a 12-part series of thematically linked mini-essays with accompanying illustrations that explore the many dimensions of family medicine as interpreted by individual family physicians and medical educators in the USA and elsewhere around the world. In 'IX: people and places-diverse populations and locations of care', authors address the following themes: 'LGBTQIA+health in family medicine', 'A family medicine approach to substance use disorders', 'Shameless medicine for people experiencing homelessness', '''Difficult" encounters-finding the person behind the patient', 'Attending to patients with medically unexplained symptoms', 'Making house calls and home visits', 'Family physicians in the procedure room', 'Robust rural family medicine' and 'Full-spectrum family medicine'. May readers appreciate the breadth of family medicine in these essays.

Storylines of Family Medicine is a 12-part series of thematically linked mini-essays with accompanying illustrations that explore the many dimensions of family medicine as interpreted by individual family physicians and medical educators in the USA and elsewhere around the world. In 'X: standing up for diversity, equity and inclusion', authors address the following themes: 'The power of diversity-why inclusivity is essential to equity in healthcare', 'Medical education for whom?', 'Growing a diverse and inclusive workforce', 'Therapeutic judo-an inclusive approach to patient care', 'Global family medicine-seeing the world "upside down"', 'The inverse care law', 'Social determinants of health as a lens for care', 'Why family physicians should care about human rights' and 'Toward health equity-the opportunome'. May the essays that follow inspire readers to promote change.

Despite explicit expectations and accreditation requirements for integrated curriculum, there needs to be more clarity around an accepted common definition, best practices for implementation, and criteria for successful curriculum integration. To address the lack of consensus surrounding integration, we reviewed the literature and herein propose a definition for curriculum integration for the medical education audience. We further believe that medical education is ready to move beyond “horizontal” (1-dimensional) and “vertical” (2-dimensional) integration and propose a model of “6 degrees of curriculum integration” to expand the 2-dimensional concept for future designs of medical education programs and best prepare learners to meet the needs of patients. These 6 degrees include: interdisciplinary, timing and sequencing, instruction and assessment, incorporation of basic and clinical sciences, knowledge and skills-based competency progression, and graduated responsibilities in patient care. We encourage medical educators to look beyond 2-dimensional integration to this holistic and interconnected representation of curriculum integration.

INTRODUCTION: Micronutrient deficiencies are prevalent in West Africa, particularly among women of reproductive age (WRA) and young children. Bouillon is a promising food fortification vehicle due to its widespread consumption. This study aims to evaluate the impact of multiple micronutrient-fortified bouillon cubes, compared to control bouillon cubes (fortified with iodine only), on micronutrient status and hemoglobin concentrations among lactating and non-lactating WRA and young children in northern Ghana. METHODS: This randomized, controlled doubly-masked trial will be conducted in the Kumbungu and Tolon districts in the Northern Region of Ghana, where prior data indicate multiple micronutrient deficiencies are common. Participants will be: 1) non-pregnant non-lactating WRA (15-49 y), 2) children 2-5 y, and 3) non-pregnant lactating women 4-18 months postpartum. Eligible participants will be randomly assigned to receive household rations of one of two types of bouillon cubes: 1) a multiple micronutrient-fortified bouillon cube containing vitamin A, folic acid, vitamin B12, iron, zinc, and iodine, or 2) a control cube containing iodine only. Each participants household will receive a ration of bouillon cubes every 2 weeks, and households will be advised to prepare meals as usual, using the study-provided cubes. The trial duration will be 9 months for non-pregnant non-lactating WRA and children, and 3 months for lactating women. The primary outcomes will be changes in biomarkers of micronutrient status and hemoglobin among WRA and children and milk micronutrient concentrations among lactating women. Secondary outcomes will include change in prevalence of micronutrient deficiency and anemia; dietary intake of bouillon and micronutrients; inflammation, malaria, and morbidity symptoms; and child growth and development. DISCUSSION: Evidence from this study will inform discussions about bouillon fortification in Ghana and West Africa. TRIAL REGISTRATION: The trial was registered on ClinicalTrials.gov (NCT05178407) and the Pan-African Clinical Trial Registry (PACTR202206868437931). This manuscript reflects protocol version 4 (August 29, 2022).

Retrospective review of all spinal fusions > 3 levels involving the thoracolumbar and/or sacroiliac at a single institution, by a single surgeon between 3/12/2020 and 8/13/2021 were reviewed. All screws that were secondarily navigated after identified as misdirected on intraoperative CT scan were included. Neuromonitoring reports were culled for mA threshold to triggered EMG response for all redirected screws. Intraoperative, post-de novo screw placement images (fluoroscopy scout and intraoperative CT) and post-redirection intraoperative scoliosis films and post-operative scoliosis films were independently reviewed by a senior neuroradiologist. Fifty redirected screws in the thoracic, lumbar, sacral, and ilium were identified as misdirected and redirected via navigation. The new trajectory of all screws was confirmed satisfactory by independent review between a senior neuroradiologist and neurosurgeon. Four screws could not be verified by post-operative imaging (4/50, 8%). All triggered EMG stimulated > 15 mA. No screws required return to the operating room for revision. No patients experienced a post-operative deficit. Redirection of misdirected thoracolumbar and sacroiliac screws can be performed using intraoperative CT and navigation as a means to detect and directly visualize appropriate placement.

BACKGROUND: Preventing progression to moderate or severe opioid use disorder (OUD) among people who exhibit risky opioid use behavior that does not meet criteria for treatment with opioid agonists or antagonists (subthreshold OUD) is poorly understood. The Subthreshold Opioid Use Disorder Prevention (STOP) Trial is designed to study the efficacy of a collaborative care intervention to reduce risky opioid use and to prevent progression to moderate or severe OUD in adult primary care patients with subthreshold OUD. METHODS: The STOP trial is a cluster randomized controlled trial, randomized at the PCP level, conducted in 5 distinct geographic sites. STOP tests the efficacy of the STOP intervention in comparison to enhanced usual care (EUC) in adult primary care patients with risky opioid use that does not meet criteria for moderate-severe OUD. The STOP intervention consists of (1) a practice-embedded nurse care manager (NCM) who provides patient participant education and supports primary care providers (PCPs) in engaging and monitoring patient-participants; (2) brief advice, delivered to patient participants by their PCP and/or prerecorded video message, about health risks of opioid misuse; and (3) up to 6 sessions of telephone health coaching to motivate and support behavior change. EUC consists of primary care treatment as usual, plus printed overdose prevention educational materials and an educational video on cancer screening. The primary outcome measure is self-reported number of days of risky (illicit or nonmedical) opioid use over 180 days, assessed monthly via text message using items from the Addiction Severity Index and the Current Opioid Misuse Measure. Secondary outcomes assess other substance use, mental health, quality of life, and healthcare utilization as well as PCP prescribing and monitoring behaviors. A mixed effects negative binomial model with a log link will be fit to estimate the difference in means between treatment and control groups using an intent-to-treat population. DISCUSSION: Given a growing interest in interventions for the management of patients with risky opioid use, and the need for primary care-based interventions, this study potentially offers a blueprint for a feasible and effective approach to improving outcomes in this population. TRIAL REGISTRATION: Clinicaltrials.gov, identifier NCT04218201, January 6, 2020.

An ethnoracial minority density (EMD) effect in studies of psychotic spectrum disorders has been observed, whereby the risk of psychosis in ethnoracial minority group individuals is inversely related to the proportion of minorities in their area of residence. The authors investigated the relationships among area-level EMD during childhood, cortical thickness (CT), and social engagement (SE) in clinical high risk for psychosis (CHR-P) youth. Data were collected as part of the North American Prodrome Longitudinal Study. Participants included 244 ethnoracial minoritized (predominantly Hispanic, Asian and Black) CHR-P youth and ethnoracial minoritized healthy controls. Among youth at CHR-P (n = 164), lower levels of EMD during childhood were associated with reduced CT in the right fusiform gyrus (adjusted β = 0.54; 95% CI 0.17 to 0.91) and right insula (adjusted β = 0.40; 95% CI 0.05 to 0.74). The associations between EMD and CT were significantly moderated by SE: among youth with lower SE (SE at or below the median, n = 122), lower levels of EMD were significantly associated with reduced right fusiform gyrus CT (adjusted β = 0.72; 95% CI 0.29 to 1.14) and reduced right insula CT (adjusted β = 0.57; 95% CI 0.18 to 0.97). However, among those with greater SE (n = 42), the associations between EMD and right insula and fusiform gyrus CT were not significant. We found evidence that lower levels of ethnic density during childhood were associated with reduced cortical thickness in regional brain regions, but this association may be buffered by greater levels of social engagement.

IntroductionRetrospective studies report that angiotensin-converting enzyme inhibitors (ACEIs) may reduce the severity of COVID-19, but prospective data on de novo treatment with ACEIs are limited. The RAMIC trial was a randomized, multicenter, placebo-controlled, double-blind, allocation-concealed clinical trial to examine the efficacy of de novo ramipril versus placebo for the treatment of COVID-19.MethodsEligible participants were aged 18 years and older with a confirmed diagnosis of SARS-CoV-2 infection, recruited from urgent care clinics, emergency departments, and hospital inpatient wards at eight sites in the USA. Participants were randomly assigned to daily ramipril 2.5 mg or placebo orally in a 2:1 ratio, using permuted block randomization. Analyses were conducted on an intention-to-treat basis. The primary outcome was a composite of mortality, intensive care unit (ICU) admission, or invasive mechanical ventilation by day 14.ResultsBetween 27 May 2020 and 19 April 2021, a total of 114 participants (51% female) were randomized to ramipril (n = 79) or placebo (n = 35). The overall mean (± SD) age and BMI were 45 (± 15) years and 33 (± 8) kg/m2. Two participants in the ramipril group required ICU admission and one died, compared with none in the placebo group. There were no significant differences between ramipril and placebo in the primary endpoint (ICU admission, mechanical ventilation, or death) (3% versus 0%, p = 1.00) or adverse events (27% versus 29%, p = 0.82). The study was terminated early because of a low event rate and subsequent Emergency Use Authorization of therapies for COVID-19.ConclusionDe novo ramipril was not different compared with placebo in improving or worsening clinical outcomes from COVID-19 but appeared safe in non-critically ill patients with COVID-19.Trial registrationClinicaltrials.gov NCT04366050.

IntroductionRemoval of tobacco industry branding from cigarette packs may reduce their appeal. Adding graphic warning labels (GWLs) should enhance this effect. We investigate whether willingness to pay for various packaging designs changes after 3 months' use of: (1) US branded packs without GWLs (US), (2) non-branded packs without GWLs (Blank), and (3) rotating non-branded packs with GWLs (gangrene; throat cancer; neonatal baby) covering >75% of pack (GWL).MethodsCalifornian adult daily smokers not planning to quit (n=287; 56% female; mean age=39.6) completed a discrete choice purchase task before and after 3 months' experience using one of three packaging options. Conjoint analysis and pre-post modelling evaluated the change in importance of pack attributes and willingness to pay for US, Blank or GWL (blindness; teeth; gangrene) pack designs.ResultsPrice determined ~70% of purchase choices, while pack design determined ~22%. Irrespective of intervention arm, US packaging generated appeal valuations compared with Blank packaging, while GWLs consistently provoked strong aversive valuations at baseline and follow-up. Compared with the US pack arm, using GWL packs for 3 months decreased willingness to pay for US packaging (β=-$0.38, 95% CI -0.76 to 0.00). Wear-out effects were detected in the discount needed to willingly purchase the gangrene-GWL pack (β=$0.49, 95% CI 0.16 to 0.82) and Blank pack (β=$0.42, 95% CI 0.09 to 0.74) but not for GWLs (blindness, teeth) not used in trial.ConclusionCompared with US branded packs, the negative valuation of non-branded GWL packs attenuates with even 3 months' use but does not generalise to non-used GWLs. This suggests that GWLs should be regularly refreshed. The appeal valuation of industry imagery suggests that the US plan to retain such imagery on packs may ameliorate the effect of GWLs.

OBJECTIVE: Plain packaging and graphic warning labels are two regulatory strategies that may impact cigarette risk beliefs and reduce consumption, but data are needed to better understand how smokers respond to such regulations. METHODS: Adult, daily, Marlboro non-menthol smokers (Red [n = 141] or Gold [n = 43]) completed a mixed factorial randomized trial. Participants smoked their usual cigarettes during baseline (5-days) and were randomized to receive cigarette packs with a warning label manipulation (graphic vs. text-only). Within each warning label condition, participants completed three within-subjects pack color manipulations (red, gold, plain), each lasting 15 days. Participants were blinded to the fact that all packs contained their usual cigarettes. Mixed-effects models examined between- and within-subject differences on risk beliefs, product perceptions, and smoking behavior. RESULTS: Warning type and package color did not impact cigarette consumption or subjective ratings. However, use increased in all conditions (2.59-3.59 cigarettes per day) relative to baseline. While smokers largely held correct risk beliefs at baseline (Mean = 6.02, SE = 0.17, Range:0-8), the cumulative number of incorrect or uncertain cigarette risk beliefs increased from baseline in all pack color manipulations in the text (IRR range = 1.70-2.16) and graphic (IRR range = 1.31-1.70) warning conditions. Across all pack color periods, those in the graphic (vs. text) warning condition had reduced odds of reporting their study cigarettes as safer than regular cigarettes (OR range = 0.22-0.32). CONCLUSIONS: Pack color modification may increase uncertainty about several key cigarette risk beliefs, though graphic warnings may attenuate these effects. Regulatory agencies could consider supporting policy changes with information campaigns to maximize public knowledge. TRIAL REGISTRATION: November 25, 2014; Registration number: NCT02301351.

BACKGROUND: Growing evidence suggests bidirectional links between gut microbiota and sleep quality as shared contributors to health. Little is known about the relationship between microbiota and sleep among older persons. METHODS: We used 16S rRNA sequencing to characterize stool microbiota among men (n = 606, mean [standard deviation] age = 83.9 [3.8]) enrolled in the Osteoporotic Fractures in Men (MrOS) study from 2014 to 2016. Sleep was assessed concurrently by a questionnaire (Pittsburgh Sleep Quality index [PSQI]), and activity monitor to examine timing (acrophase) and regularity of patterns (F-statistic). Alpha diversity was measured using Faiths phylogenetic diversity (PD). Beta diversity was calculated with robust Aitchison distance with matrix completion (RPCA) and phylogenetic-RPCA (PRPCA). Their association with sleep variables was tested with partial distance-based redundancy analysis (dbRDA). Predictive-ratio biomarkers associated with sleep measurements were identified with CoDaCoRe. RESULTS: In unadjusted analyses, men with poor sleep (PSQI >5) tended to have lower alpha diversity compared to men with normal sleep (Faiths PD, beta = -0.15; 95% confidence interval [CI]: -0.30 to 0.01, p = .06). Sleep regularity was significantly associated with RPCA and PRPCA, even after adjusting for site, batch, age, ethnicity, body mass index, diabetes, antidepressant and sleep medication use, and health behaviors (RPCA/PRPCA dbRDA; p = .033/.002). In taxonomic analysis, ratios of 7:6 bacteria for better regularity (p = .0004) and 4:7 for worse self-reported sleep (p = .005) were differentially abundant: some butyrate-producing bacteria were associated with better sleep characteristics. CONCLUSIONS: Subjective and objective indicators of sleep quality suggest that older men with better sleep patterns are more likely to harbor butyrate-producing bacteria associated with better health.

BACKGROUND: Individual risk assessment allows donors to be evaluated based on their own behaviors. Study objectives were to assess human immunodeficiency virus (HIV) risk behaviors in men who have sex with men (MSM) and estimate the proportion of the study population who would not be deferred for higher risk HIV sexual behaviors. STUDY DESIGN AND METHODS: Cross-sectional survey and biomarker assessment were conducted in eight U.S. cities. Participants were sexually active MSM interested in blood donation aged 18-39 years, assigned male sex at birth. Participants completed surveys during two study visits to define eligibility, and self-reported sexual and HIV prevention behaviors. Blood was drawn at study visit 1 and tested for HIV and the presence of tenofovir, one of the drugs in oral HIV pre-exposure prophylaxis (PrEP). Associations were assessed between HIV infection status or HIV PrEP use and behaviors, including sex partners, new partners, and anal sex. RESULTS: A total of 1566 MSM completed the visit 1 questionnaire and blood draw and 1197 completed the visit 2 questionnaire. Among 1562 persons without HIV, 789 (50.4%) were not taking PrEP. Of those not taking PrEP, 66.2% reported one sexual partner or no anal sex and 69% reported no new sexual partners or no anal sex with a new partner in the past 3 months. CONCLUSION: The study found that questions were able to identify sexually active, HIV-negative MSM who report lower risk sexual behaviors. About a quarter of enrolled study participants would be potentially eligible blood donors using individual risk assessment questions.

Human cognitive performance is a key function whose biological foundations have been partially revealed by genetic and brain imaging studies. The sleep electroencephalogram (EEG) is tightly linked to structural and functional features of the central nervous system and serves as another promising biomarker. We used data from MrOS, a large cohort of older men and cross-validated regularized regression to link sleep EEG features to cognitive performance in cross-sectional analyses. In independent validation samples 2.5-10% of variance in cognitive performance can be accounted for by sleep EEG features, depending on the covariates used. Demographic characteristics account for more covariance between sleep EEG and cognition than health variables, and consequently reduce this association by a greater degree, but even with the strictest covariate sets a statistically significant association is present. Sigma power in NREM and beta power in REM sleep were associated with better cognitive performance, while theta power in REM sleep was associated with worse performance, with no substantial effect of coherence and other sleep EEG metrics. Our findings show that cognitive performance is associated with the sleep EEG (r = 0.283), with the strongest effect ascribed to spindle-frequency activity. This association becomes weaker after adjusting for demographic (r = 0.186) and health variables (r = 0.155), but its resilience to covariate inclusion suggest that it also partially reflects trait-like differences in cognitive ability.

PURPOSE: ARF1 was previously implicated in periventricular nodular heterotopia (PVNH) in only five individuals and systematic clinical characterisation was not available. The aim of this study is to provide a comprehensive description of the phenotypic and genotypic spectrum of ARF1-related neurodevelopmental disorder. METHODS: We collected detailed phenotypes of an international cohort of individuals (n=17) with ARF1 variants assembled through the GeneMatcher platform. Missense variants were structurally modelled, and the impact of several were functionally validated. RESULTS: De novo variants (10 missense, 1 frameshift, 1 splice altering resulting in 9 residues insertion) in ARF1 were identified among 17 unrelated individuals. Detailed phenotypes included intellectual disability (ID), microcephaly, seizures and PVNH. No specific facial characteristics were consistent across all cases, however microretrognathia was common. Various hearing and visual defects were recurrent, and interestingly, some inflammatory features were reported. MRI of the brain frequently showed abnormalities consistent with a neuronal migration disorder. CONCLUSION: We confirm the role of ARF1 in an autosomal dominant syndrome with a phenotypic spectrum including severe ID, microcephaly, seizures and PVNH due to impaired neuronal migration.

BACKGROUND: Men who have sex with men who ever injected drugs (ever MSM-IDU) carry a high hepatitis C virus (HCV) burden. We estimated whether current HCV testing and treatment in San Francisco can achieve the 2030 World Health Organization (WHO) HCV elimination target on HCV incidence among ever MSM-IDU. METHODS: A dynamic HCV/HIV transmission model among MSM was calibrated to San Francisco data, including HCV antibody (15.5%, 2011) and HIV prevalence (32.8%, 2017) among ever MSM-IDU. MSM had high HCV testing (79%-86% ever tested, 2011-2019) and diagnosed MSM had high HCV treatment (65% ever treated, 2018). Following coronavirus disease 2019 (COVID-19)-related lockdowns, HCV testing and treatment decreased by 59%. RESULTS: Among all MSM, 43% of incident HCV infections in 2022 were IDU-related. Among ever MSM-IDU in 2015, HCV incidence was 1.2/100 person-years (95% credibility interval [CrI], 0.8-1.6). Assuming COVID-19-related declines in HCV testing/treatment persist until 2030, HCV incidence among ever MSM-IDU will decrease by 84.9% (95% CrI, 72.3%-90.8%) over 2015-2030. This decline is largely attributed to HCV testing and treatment (75.8%; 95% CrI, 66.7%-89.5%). Slightly greater decreases in HCV incidence (94%-95%) are projected if COVID-19 disruptions recover by 2025 or 2022. CONCLUSIONS: We estimate that HCV incidence will decline by >80% over 2015-2030 among ever MSM-IDU in San Francisco, achieving the WHO target.

Genomic stability in proliferating cells critically depends on telomere maintenance by telomerase reverse transcriptase. Here we report the development and proof-of-concept results of a single-molecule approach to monitor the catalytic activity of human telomerase in real time and with single-nucleotide resolution. Using zero-mode waveguides and multicolor FRET, we recorded the processive addition of multiple telomeric repeats to individual DNA primers. Unlike existing biophysical and biochemical tools, the novel approach enables the quantification of nucleotide-binding kinetics before nucleotide incorporation. Moreover, it provides a means to dissect the unique translocation dynamics that telomerase must undergo after synthesis of each hexameric DNA repeat. We observed an unexpectedly prolonged binding dwell time of dGTP in the enzyme active site at the start of each repeat synthesis cycle, suggesting that telomerase translocation is composed of multiple rate-contributing sub-steps that evade classical biochemical analysis.

IntroductionThis study examined trajectories of tobacco dependence (TD) in relationship to changes in tobacco product use, and explored the effects of product-specific adding, switching, or discontinued use on dependence over time.MethodsData were analyzed from the first three waves from the Population Assessment of Tobacco and Health (PATH) Study, a nationally representative, longitudinal study of adults and youth in the United States (U.S.). Data included 9556 Wave 1 (2013/2014) adult current established tobacco users aged 18 or older who completed all three interviews and had established use at ≥2 assessments. Mutually exclusive groups included: users of cigarettes only, e-cigarettes only, cigars only, hookah only, any smokeless only, cigarette + e-cigarette dual users, and other multiple product users. A validated 16-item scale assessed TD across product users.ResultsPeople who used e-cigarettes exclusively at Wave 1 had small increases in TD through Wave 3. Wave 1 multiple product users' TD decreased across waves. TD for all other Wave 1 user groups remained about the same. For Wave 1 cigarette only smokers, switching to another product was associated with lower levels of TD than smokers whose use stayed the same. Movement to no established use of any tobacco product was consistently associated with lower TD for all product users.ConclusionsExcept for Wave 1 e-cigarette only users (who experienced small increases in TD), TD among U.S. tobacco product users was stable over time, with daily users less likely to vary from baseline.ImplicationsThe level of TD among most U.S. tobacco users was stable over the first three waves of the PATH Study and trends in levels of TD were predominantly unrelated to changes in patterns of continued product use. Stable levels of TD suggest a population at persistent risk of health impacts from tobacco. Wave 1 e-cigarette users experienced small increases in levels of TD over time, perhaps due to increases in quantity or frequency of their e-cigarette use or increasing efficiency of nicotine delivery over time.

OBJECTIVE: This study examined whether social activity diversity, a novel concept indicating an active social lifestyle, is associated with lower subsequent loneliness, and decreased loneliness is further associated with less chronic pain over time. METHODS: 2528 adults from the Midlife in the United States Study (Mage = 54 yrs) provided data at baseline (2004-2009) and 9 years later. Social activity diversity was operationalized by Shannons entropy that captures the variety and evenness of engagement across 13 social activities (0-1). Participants reported feelings of loneliness (1-5), presence of any chronic pain (yes/no), the degree of chronic pain-related interference (0-10), and the number of chronic pain locations. Indirect associations of social activity diversity with chronic pain through loneliness were evaluated, adjusting for sociodemographics, living alone, and chronic conditions. RESULTS: Higher social activity diversity at baseline (B = -0.21, 95%CI = [-0.41, -0.02]) and an increase in social activity diversity over time (B = -0.24, 95%CI = [-0.42, -0.06]) were associated with lower loneliness 9 years later. An increase in loneliness was associated with 24% higher risk of any chronic pain (95%CI = [1.11, 1.38]), greater chronic pain-related interference (B = 0.36, 95%CI = [0.14, 0.58]), and 17% increase in the number of chronic pain locations (95%CI = [1.10, 1.25]) at the follow-up, after controlling for corresponding chronic pain at baseline and covariates. Social activity diversity was not directly was associated with chronic pain, but there were indirect associations through its association with loneliness. CONCLUSION: Diversity in social life may be associated with decreased loneliness, which in turn, may be associated with less chronic pain, two of the prevalent concerns in adulthood.

Leptospirosis, the most widespread zoonotic disease in the world, is broadly understudied in multi-host wildlife systems. Knowledge gaps regarding Leptospira circulation in wildlife, particularly in densely populated areas, contribute to frequent misdiagnoses in humans and domestic animals. We assessed Leptospira prevalence levels and risk factors in five target wildlife species across the greater Los Angeles region: striped skunks (Mephitis mephitis), raccoons (Procyon lotor), coyotes (Canis latrans), Virginia opossums (Didelphis virginiana), and fox squirrels (Sciurus niger). We sampled more than 960 individual animals, including over 700 from target species in the greater Los Angeles region, and an additional 266 sampled opportunistically from other California regions and species. In the five target species seroprevalences ranged from 5 to 60%, and infection prevalences ranged from 0.8 to 15.2% in all except fox squirrels (0%). Leptospira phylogenomics and patterns of serologic reactivity suggest that mainland terrestrial wildlife, particularly mesocarnivores, could be the source of repeated observed introductions of Leptospira into local marine and island ecosystems. Overall, we found evidence of widespread Leptospira exposure in wildlife across Los Angeles and surrounding regions. This indicates exposure risk for humans and domestic animals and highlights that this pathogen can circulate endemically in many wildlife species even in densely populated urban areas.

BACKGROUND: Falls occur annually in 25% of adults aged ≥65 years. Fall-related injuries are increasing, highlighting the need to identify modifiable risk factors. METHODS: Role of fatigability on prospective, recurrent, and injurious fall risk was examined in 1 740 men aged 77-101 years in the Osteoporotic Fractures in Men Study. The 10-item Pittsburgh Fatigability Scale measured perceived physical and mental fatigability (0-50/subscale) at Year 14 (2014-16); established cut-points identified men with more severe perceived physical (≥15, 55.7%), more severe mental (≥13, 23.7%) fatigability, or having both (22.8%). Prospective, recurrent (≥2), and injurious falls were captured by triannual questionnaires ≥1 year after fatigability assessment; risk of any fall was estimated with Poisson generalized estimating equations, and likelihood of recurrent/injurious falls with logistic regression. Models adjusted for age, health conditions, and other confounders. RESULTS: Men with more severe physical fatigability had a 20% (p = .03) increased fall risk compared with men with less physical fatigability, with increased odds of recurrent and injurious falls, 37% (p = .04) and 35% (p = .035), respectively. Men with both more severe physical and mental fatigability had a 24% increased risk of a prospective fall (p = .026), and 44% (p = .045) increased odds of recurrent falling compared with men with less severe physical and mental fatigability. Mental fatigability alone was not associated with fall risk. Additional adjustment for previous fall history attenuated associations. CONCLUSIONS: More severe fatigability may be an early indicator to identify men at high risk for falls. Our findings warrant replication in women, as they have higher rates of fatigability and prospective falls.

This guidance updates 2021 GRADE (Grading of Recommendations Assessment, Development and Evaluation) recommendations regarding immediate allergic reactions following coronavirus disease 2019 (COVID-19) vaccines and addresses revaccinating individuals with first-dose allergic reactions and allergy testing to determine revaccination outcomes. Recent meta-analyses assessed the incidence of severe allergic reactions to initial COVID-19 vaccination, risk of mRNA-COVID-19 revaccination after an initial reaction, and diagnostic accuracy of COVID-19 vaccine and vaccine excipient testing in predicting reactions. GRADE methods informed rating the certainty of evidence and strength of recommendations. A modified Delphi panel consisting of experts in allergy, anaphylaxis, vaccinology, infectious diseases, emergency medicine, and primary care from Australia, Canada, Europe, Japan, South Africa, the United Kingdom, and the United States formed the recommendations. We recommend vaccination for persons without COVID-19 vaccine excipient allergy and revaccination after a prior immediate allergic reaction. We suggest against >15-minute postvaccination observation. We recommend against mRNA vaccine or excipient skin testing to predict outcomes. We suggest revaccination of persons with an immediate allergic reaction to the mRNA vaccine or excipients be performed by a person with vaccine allergy expertise in a properly equipped setting. We suggest against premedication, split-dosing, or special precautions because of a comorbid allergic history.

ImportanceThe potential role of living alone in either facilitating or hampering access to and use of services for older adults with cognitive impairment is largely unknown. Specifically, it is critical to understand directly from health care and social services professionals how living alone creates barriers to the access and use of supportive health care and social services for racially and ethnically diverse patients with cognitive impairment.ObjectiveTo identify the potential role of living alone in the access and use of health care and social services for diverse patients with cognitive impairment by investigating professionals' perceptions of caring for such patients who live alone in comparison with counterparts living with others.Design, setting, and participantsThis qualitative study of 76 clinicians, social workers, and other professionals used semistructured interviews conducted between February 8, 2021, and June 8, 2022, with purposively sampled professionals providing services to diverse patients with cognitive impairment in Michigan, California, and Texas.Main outcomes and measuresClinicians, social workers, and other professionals compared serving patients with cognitive impairment and living alone vs counterparts living with others. An inductive content analysis was used to analyze the interview transcripts.ResultsA total of 76 professionals were interviewed (mean [SD] age, 49.3 [12.7] years); 59 were female (77.6%), 8 were Black or African American (11%), and 35 were White (46%). Participants included physicians, nurses, social workers, and home-care aides, for a total of 20 professions. Participants elucidated specific factors that made serving older adults living alone with cognitive impairment more challenging than serving counterparts living with others (eg, lacking an advocate, incomplete medical history, requiring difficult interventions), as well as factors associated with increased concerns when caring for older adults living alone with cognitive impairment, such as isolation and a crisis-dominated health care system. Participants also identified reasons for systematic unmet needs of older adults living alone with cognitive impairment for essential health care and social services, including policies limiting access and use to public home-care aides.Conclusions and relevanceIn this qualitative study of professionals' perspectives, findings suggest that living alone is a social determinant of health among patients with cognitive impairment owing to substantial barriers in access to services. Results raised considerable concerns about safety because the US health care system is not well equipped to address the unique needs of older adults living alone with cognitive impairment.

ObjectiveTo assess the effectiveness of e-cigarettes in smoking cessation in the USA from 2017 to 2019, given the 2017 increase in high nicotine e-cigarette sales.MethodsIn 2017, the PATH Cohort Study included data on 3578 previous year smokers with a recent quit attempt and 1323 recent former smokers. Respondents reported e-cigarettes or other products used to quit cigarettes and many covariates associated with e-cigarette use. Study outcomes were 12+ months of cigarette abstinence and tobacco abstinence in 2019. We report weighted unadjusted estimates and use propensity score matched analyses with 1500 bootstrap samples to estimate adjusted risk differences (aRD).ResultsIn 2017, 12.6% (95% CI 11.3% to 13.9%) of recent quit attempters used e-cigarettes to help with their quit attempt, a decline from previous years. Cigarette abstinence for e-cigarette users (9.9%, 95% CI 6.6% to 13.2%) was lower than for no product use (18.6%, 95% CI 16.0% to 21.2%), and the aRD for e-cigarettes versus pharmaceutical aids was -7.3% (95% CI -14.4 to -0.4) and for e-cigarettes versus any other method was -7.7% (95% CI -12.2 to -3.2). Only 2.2% (95% CI 0.0% to 4.4%) of recent former smokers switched to a high nicotine e-cigarette. Subjects who switched to e-cigarettes appeared to have a higher relapse rate than those who did not switch to e-cigarettes or other tobacco, although the difference was not statistically significant.ConclusionsSales increases in high nicotine e-cigarettes in 2017 did not translate to more smokers using these e-cigarettes to quit smoking. On average, using e-cigarettes for cessation in 2017 did not improve successful quitting or prevent relapse.

Research suggests consumers may misunderstand modified risk tobacco product (MRTP) claims. We examined the effects of nicotine content across four tobacco products with and without MRTP claims among a racially and ethnically diverse sample of adults who do and do not smoke. Adults (n = 1484) aged 21-65 completed an online experiment using a 2 × 2 × 4 mixed factorial design to examine the effects of tobacco product (Classic White Snus, IQOS, JUUL e-cigarette, and VLN cigarette) and nicotine content (high vs. low) stratified by MRTP claim (present vs. absent) across four outcomes: (1) likely to try (2) serious disease if used regularly, (3) least addictive, and (4) ease of quitting smoking. Not including an MRTP claim resulted in an increased likelihood of trying a product, decreased concern of serious disease, lower perceived addictiveness, and increased ease of quitting smoking. Participants selected low nicotine IQOS without a claim as the least likely to cause serious disease. Low nicotine JUUL, without a claim, was selected as least addictive and most likely to facilitate quitting. Intentions to try were highest for low nicotine JUUL. Participants selected low-nicotine products as less addictive than high nicotine products. Regulatory efforts should consider how MRTP claims interact with different product characteristics. Subtle differences exist across outcomes between racial and ethnic groups, which indicates that further research is warranted.

Information on fortifiable food consumption is essential to design, monitor and evaluate fortification programmes, yet detailed methods like 24-h recalls (24HRs) that provide such data are rarely conducted. Simplified questionnaire-based methods exist but their validity compared with 24HRs has not been shown. We compared two simplified methods (i.e., a household food acquisition and purchase questionnaire [FAPQ] and a 7-day semiquantitative food frequency questionnaire [SQ-FFQ]) against 24HRs for estimating fortifiable food consumption. We assessed the consumption of fortifiable wheat flour and oil using a FAPQ and, for wheat flour only, a 7-day SQ-FFQ and compared the results against 24HRs. The participants included children 12-18 months (n = 123) and their mothers 18-49 years selected for a study assessing child vitamin A intake and status in Mandaluyong City, Philippines. For fortifiable wheat flour, the FAPQ estimated considerably lower mean intakes compared to 24HRs for children and mothers (2.2 vs. 14.1 g/day and 5.1 vs. 42.3 g/day, respectively), while the SQ-FFQ estimated slightly higher mean intakes (15.7 vs. 14.1 g/day and 51.5 vs. 42.3 g/day, respectively). For fortifiable oil, the FAPQ estimated considerably higher mean intakes compared to 24HRs for children and mothers (4.6 vs. 1.8 g/day and 12.5 vs. 6.1 g/day, respectively). The SQ-FFQ, but not the FAPQ, generated useful information on fortifiable food consumption that can inform fortification programme design and monitoring decisions in the absence of more detailed individual-level data. Potential adaptations to improve the FAPQ, such as additional questions on foods prepared away from home and usage patterns, merit further research.

BackgroundMeasuring the incidence of HIV and hepatitis C virus (HCV) infection among people who inject drugs (PWID) is key to track progress towards elimination. We aimed to summarise global data on HIV and primary HCV incidence among PWID and associations with age and sex or gender.MethodsIn this systematic review and meta-analysis, we updated an existing database of HIV and HCV incidence studies among PWID by searching MEDLINE, Embase, and PsycINFO, capturing studies published between Jan 1, 2000, and Dec 12, 2022, with no language or study design restrictions. We contacted authors of identified studies for unpublished or updated data. We included studies that estimated incidence by longitudinally re-testing people at risk of infection or by using assays for recent infection. We pooled incidence and relative risk (RR; young [generally defined as ≤25 years] vs older PWID; women vs men) estimates using random-effects meta-analysis and assessed risk of bias with a modified Newcastle-Ottawa scale. This study is registered with PROSPERO, CRD42020220884.FindingsOur updated search identified 9493 publications, of which 211 were eligible for full-text review. An additional 377 full-text records from our existing database and five records identified through cross-referencing were assessed. Including 28 unpublished records, 125 records met the inclusion criteria. We identified 64 estimates of HIV incidence (30 from high-income countries [HICs] and 34 from low-income or middle-income countries [LMICs]) and 66 estimates of HCV incidence (52 from HICs and 14 from LMICs). 41 (64%) of 64 HIV and 42 (64%) of 66 HCV estimates were from single cities rather than being multi-city or nationwide. Estimates were measured over 1987-2021 for HIV and 1992-2021 for HCV. Pooled HIV incidence was 1·7 per 100 person-years (95% CI 1·3-2·3; I2=98·4%) and pooled HCV incidence was 12·1 per 100 person-years (10·0-14·6; I2=97·2%). Young PWID had a greater risk of HIV (RR 1·5, 95% CI 1·2-1·8; I2=66·9%) and HCV (1·5, 1·3-1·8; I2=70·6%) acquisition than older PWID. Women had a greater risk of HIV (RR 1·4, 95% CI 1·1-1·6; I2=55·3%) and HCV (1·2, 1·1-1·3; I2=43·3%) acquisition than men. For both HIV and HCV, the median risk-of-bias score was 6 (IQR 6-7), indicating moderate risk.InterpretationAlthough sparse, available HIV and HCV incidence estimates offer insights into global levels of HIV and HCV transmission among PWID. Intensified efforts are needed to keep track of the HIV and HCV epidemics among PWID and to expand access to age-appropriate and gender-appropriate prevention services that serve young PWID and women who inject drugs.FundingCanadian Institutes of Health Research, Fonds de recherche du Québec-Santé, Canadian Network on Hepatitis C, UK National Institute for Health and Care Research, and WHO.

IntroductionUnderstanding the reasons young adults use e-cigarettes (ie, vape)-and whether these motivations vary across groups-is essential for informing tobacco regulatory efforts.Aims and methodsAn online panel of young adults who vape (n = 230; age = 18-30 years) completed a maximum difference discrete choice task for 15 reasons for vaping. Over 9 choice sets, participants were presented a subset of 5 reasons and selected the most and least important. Hierarchical bayesian analysis estimated the relative importance of each reason. Latent class analysis (LCA) identified groups with similarly ranked reasons for use. Multinomial regression evaluated the association between sample characteristics and class membership.ResultsOverall, relaxation had the highest probability of being the most important reason for use (14.8%), followed by harm reduction (13.2%), and flavors (10.3%). LCA identified five distinct classes, based on top reasons for use: 1. cessation (cigarette cessation [20.2%]; n = 80); 2. dependence (relaxation [20.5%] and unable to quit [19.2%]; n = 21); 3. relaxation (relaxation [20.6%]; n = 66); 4. socializing (socializing [22.2%]; n = 27); and 5. variable (boredom [10.5%] and acceptability [10.2%]; n = 36). Participants who were older, smoked cigarettes, or vaped more frequently were more likely to belong to the cessation class while those who were younger or more e-cigarette dependent were more likely to belong to the dependence class.ConclusionsPerceived reasons why young adults vape are highly heterogeneous and dependent on the type of user. Tobacco regulatory efforts targeting distinct types of vapers are needed to minimize the adverse public health impact of vaping without compromising appeal for smoking cessation.ImplicationsE-cigarette use remains high among young adults, with flavors, cost, and harm reduction (vs. combustible cigarettes) among the mostly commonly reported reasons for use. Yet, little is known about how relatively important these reasons are to the individual. Leveraging a maximum difference task, young adults' reasons for use were evaluated on a common interval scale and groups sharing similar reasons identified. Smoking cessation, dependence, relaxation, socialization, and boredom were respectively the most important reasons for use among five classes of vapers. E-cigarette regulatory policies should consider the distinct reasons for use as to not compromise their appeal for smoking cessation.

OBJECTIVE: Major obstacles to data harmonization in neuropsychology include lack of consensus about what constructs and tests are most important and invariant across healthy and clinical populations. This study addressed these challenges using data from the National Neuropsychology Network (NNN). METHOD: Data were obtained from 5,000 NNN participants and Pearson standardization samples. Analyses included variables from four instruments: Wechsler Adult Intelligence Scale, 4th Edition (WAIS-IV); Wechsler Memory Scale, 4th Edition (WMS-IV); California Verbal Learning Test, 3rd Edition (CVLT3); and Delis-Kaplan Executive Function System (D-KEFS). We used confirmatory factor analysis to evaluate models suggested by prior work and examined fit statistics and measurement invariance across samples. We examined relations of factor scores to demographic and clinical characteristics. RESULTS: For each instrument, we identified four first-order and one second-order factor. Optimal models in patients generally paralleled the best-fitting models in the standardization samples, including task-specific factors. Analysis of the NNN data prompted specification of a Recognition-Familiarity factor on the WMS-IV and an Inhibition-Switching factor on the D-KEFS. Analyses showed strong to strict factorial invariance across samples with expected differences in factor means and variances. The Recognition-Familiarity factor correlated with age more strongly in NNN than in the standardization sample. CONCLUSIONS: Factor models derived from healthy groups generally fit well in patients. NNN data helped identify novel Recognition-Familiarity and Inhibition-Switching factors that were also invariant across samples and may be clinically useful. The findings support efforts to identify evidence-based and optimally efficient measurements of neuropsychological constructs that are valid across groups. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

ObjectiveTo identify whether three types of cigarette pack designs, including three versions of graphic warning label (GWL) plain packs, one GWL absent and branding absent pack (blank) and the smoker's own GWL absent and branding present pack (US), elicit different valence, type and levels of affect.DesignUS daily smokers (n=324) were asked to handle each of the five pack types and 'think aloud' their reactions. To avoid a muted familiarity response, exposure to their own US pack followed exposure to at least one GWL plain pack. Reactions were scored on a reactivity scale (-3 to +3) and the text was coded for speech polarity (-1 to +1) and emotive word frequency.ResultsReactivity scores had excellent inter-rater reliability (agreement ≥86%; intraclass correlation coefficient ≥0.89) and were correlated with speech polarity (r=0.21-0.37, p

Blood storage promotes the rapid depletion of red blood cell (RBC) high-energy adenosine triphosphate (ATP) and 2,3-diphosphoglycerate (DPG), which are critical regulators of erythrocyte physiology and function, as well as oxygen kinetics and posttransfusion survival. Sphingosine-1-phosphate (S1P) promotes fluxes through glycolysis. We hypothesized that S1P supplementation to stored RBC units would improve energy metabolism and posttransfusion recovery. We quantified S1P in 1929 samples (n = 643, storage days 10, 23, and 42) from the REDS RBC Omics study. We then supplemented human and murine RBCs from good storer (C57BL6/J) and poor storer strains (FVB) with S1P (1, 5, and 10 μM) before measurements of metabolism and posttransfusion recovery. Similar experiments were repeated for mice with genetic ablation of the S1P biosynthetic pathway (sphingosine kinase 1 [Sphk1] knockout [KO]). Sample analyses included metabolomics at steady state, tracing experiments with 1,2,3-13C3-glucose, proteomics, and analysis of end-of-storage posttransfusion recovery, under normoxic and hypoxic storage conditions. Storage promoted decreases in S1P levels, which were the highest in units donated by female or older donors. Supplementation of S1P to human and murine RBCs boosted the steady-state levels of glycolytic metabolites and glycolytic fluxes, ie the generation of ATP and DPG, at the expense of the pentose phosphate pathway. Lower posttransfusion recovery was observed upon S1P supplementation. All these phenomena were reversed in Sphk1 KO mice or with hypoxic storage. S1P is a positive regulator of energy metabolism and a negative regulator of antioxidant metabolism in stored RBCs, resulting in lower posttransfusion recoveries in murine models.

Multiple randomized, controlled clinical trials have yielded discordant results regarding the efficacy of convalescent plasma in outpatients, with some showing an approximately 2-fold reduction in risk and others showing no effect. We quantified binding and neutralizing antibody levels in 492 of the 511 participants from the Clinical Trial of COVID-19 Convalescent Plasma in Outpatients (C3PO) of a single unit of COVID-19 convalescent plasma (CCP) versus saline infusion. In a subset of 70 participants, peripheral blood mononuclear cells were obtained to define the evolution of B and T cell responses through day 30. Binding and neutralizing antibody responses were approximately 2-fold higher 1 hour after infusion in recipients of CCP compared with saline plus multivitamin, but levels achieved by the native immune system by day 15 were almost 10-fold higher than those seen immediately after CCP administration. Infusion of CCP did not block generation of the host antibody response or skew B or T cell phenotype or maturation. Activated CD4+ and CD8+ T cells were associated with more severe disease outcome. These data show that CCP leads to a measurable boost in anti-SARS-CoV-2 antibodies but that the boost is modest and may not be sufficient to alter disease course.

Study objectivesPeriodic limb movement in sleep is a common sleep phenotype characterized by repetitive leg movements that occur during or before sleep. We conducted a genome-wide association study (GWAS) of periodic limb movements in sleep (PLMS) using a joint analysis (i.e., discovery, replication, and joint meta-analysis) of four cohorts (MrOS, the Wisconsin Sleep Cohort Study, HypnoLaus, and MESA), comprised of 6843 total subjects.MethodsThe MrOS study and Wisconsin Sleep Cohort Study (N = 1745 cases) were used for discovery. Replication in the HypnoLaus and MESA cohorts (1002 cases) preceded joint meta-analysis. We also performed LD score regression, estimated heritability, and computed genetic correlations between potentially associated traits such as restless leg syndrome (RLS) and insomnia. The causality and direction of the relationships between PLMS and RLS was evaluated using Mendelian randomization.ResultsWe found 2 independent loci were significantly associated with PLMS: rs113851554 (p = 3.51 × 10-12, β = 0.486), an SNP located in a putative regulatory element of intron eight of MEIS1 (2p14); and rs9369062 (p = 3.06 × 10-22, β = 0.2093), a SNP located in the intron region of BTBD9 (6p12); both of which were also lead signals in RLS GWAS. PLMS is genetically correlated with insomnia, risk of stroke, and RLS, but not with iron deficiency. Pleiotropy adjusted Mendelian randomization analysis identified a causal effect of RLS on PLMS.ConclusionsBecause PLMS is more common than RLS, PLMS may have multiple causes and additional studies are needed to further validate these findings.

BACKGROUND: As the largest conduit vessel, the aorta is responsible for the conversion of phasic systolic inflow from ventricular ejection into more continuous peripheral blood delivery. Systolic distention and diastolic recoil conserve energy and are enabled by the specialized composition of the aortic extracellular matrix. Aortic distensibility decreases with age and vascular disease. OBJECTIVES: In this study, we sought to discover epidemiologic correlates and genetic determinants of aortic distensibility and strain. METHODS: We trained a deep learning model to quantify thoracic aortic area throughout the cardiac cycle from cardiac magnetic resonance images and calculated aortic distensibility and strain in 42,342 UK Biobank participants. RESULTS: Descending aortic distensibility was inversely associated with future incidence of cardiovascular diseases, such as stroke (HR: 0.59 per SD; P = 0.00031). The heritabilities of aortic distensibility and strain were 22% to 25% and 30% to 33%, respectively. Common variant analyses identified 12 and 26 loci for ascending and 11 and 21 loci for descending aortic distensibility and strain, respectively. Of the newly identified loci, 22 were not significantly associated with thoracic aortic diameter. Nearby genes were involved in elastogenesis and atherosclerosis. Aortic strain and distensibility polygenic scores had modest effect sizes for predicting cardiovascular outcomes (delaying or accelerating disease onset by 2%-18% per SD change in scores) and remained statistically significant predictors after accounting for aortic diameter polygenic scores. CONCLUSIONS: Genetic determinants of aortic function influence risk for stroke and coronary artery disease and may lead to novel targets for medical intervention.

BACKGROUND AND HYPOTHESIS: While individuals at clinical high-risk (CHR) for psychosis experience higher levels of discrimination than healthy controls, it is unclear how these experiences contribute to the etiology of attenuated positive symptoms. The present study examined the association of perceived discrimination with positive symptoms in a cohort from the North American Prodrome Longitudinal Study (NAPLS2). It predicted that CHR individuals will report higher levels of lifetime and past year perceived discrimination related to their race and ethnicity (ethnoracial discrimination) and that this form of discrimination will be significantly associated with baseline positive symptoms. STUDY DESIGN: Participants included 686 CHR and 252 healthy controls. The present study examined data from the perceived discrimination (PD) scale, the Brief Core Schema Scale, and the Scale for the Psychosis-Risk Symptoms. Structural equation modeling was employed to examine whether negative schema of self and others mediated the relation of past year ethnoracial PD to baseline suspiciousness symptoms. RESULTS: CHR individuals report higher levels of past year and lifetime PD compared to healthy controls. Lifetime ethnoracial PD was associated with suspiciousness and total positive symptoms. Negative schema of self and others scores partially mediated the relation of past year ethnoracial PD to suspiciousness, one of five positive symptom criteria for CHR. CONCLUSIONS: For CHR individuals, past year ethnoracial discrimination was associated with negative beliefs about themselves and others, which was associated with suspiciousness. These findings contribute to an emerging literature characterizing the mechanisms by which discrimination contributes to the positive symptoms characterizing the CHR syndrome.

Novel treatment strategies are needed for the treatment of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) in older patients. This trial evaluated the feasibility and outcomes with the anti-CD19 bispecific T-cell-engaging antibody, blinatumomab, in combination with dasatinib and steroids. Patients 65 years of age or older with Ph+ or Ph-like ALL (with dasatinib-sensitive fusions/mutations) were eligible and could be newly diagnosed or relapsed/refractory. Induction therapy consisted of dasatinib/prednisone. Patients not achieving response by day 56 proceeded to blinatumomab reinduction therapy. Patients achieving response with induction or reinduction therapy proceeded to blinatumomab/dasatinib postremission therapy for 3 cycles followed by dasatinib/prednisone maintenance. All patients received central nervous system prophylaxis with intrathecal methotrexate for a total of 8 doses. Response was assessed at days 28, 56, and 84 and at additional time points based on response parameters. Measurable residual disease was assessed centrally by 8-color flow cytometry at day 28. A total of 24 eligible patients with newly diagnosed Ph+ ALL were enrolled with a median age of 73 years (range, 65-87 years). This combination was safe and feasible. With a median of 2.7 years of follow-up, 3-year overall survival and disease-free survival were 87% (95% confidence interval [CI], 64-96) and 77% (95% CI, 54-90), respectively. Although longer follow-up is needed, these results are encouraging, and future trials are building on this backbone regimen. This trial was registered at www.clinicaltrials.gov as #NCT02143414.

BACKGROUND: The clinical high-risk (CHR) period offers a temporal window into neurobiological deviations preceding psychosis onset, but little attention has been given to regions outside the cerebrum in large-scale studies of CHR. Recently, the North American Prodrome Longitudinal Study (NAPLS)-2 revealed altered functional connectivity of the cerebello-thalamo-cortical circuitry among individuals at CHR; however, cerebellar morphology remains underinvestigated in this at-risk population, despite growing evidence of its involvement in psychosis. STUDY DESIGN: In this multisite study, we analyzed T1-weighted magnetic resonance imaging scans obtained from N = 469 CHR individuals (61% male, ages = 12-36 years) and N = 212 healthy controls (52% male, ages = 12-34 years) from NAPLS-2, with a focus on cerebellar cortex and white matter volumes separately. Symptoms were rated by the Structured Interview for Psychosis-Risk Syndromes (SIPS). The outcome by two-year follow-up was categorized as in-remission, symptomatic, prodromal-progression, or psychotic. General linear models were used for case-control comparisons and tests for volumetric associations with baseline SIPS ratings and clinical outcomes. STUDY RESULTS: Cerebellar cortex and white matter volumes differed between the CHR and healthy control groups at baseline, with sex moderating the difference in cortical volumes, and both sex and age moderating the difference in white matter volumes. Baseline ratings for major psychosis-risk dimensions as well as a clinical outcome at follow-up had tissue-specific associations with cerebellar volumes. CONCLUSIONS: These findings point to clinically relevant deviations in cerebellar cortex and white matter structures among CHR individuals and highlight the importance of considering the complex interplay between sex and age when studying the neuromaturational substrates of psychosis risk.

BACKGROUND: Zika virus (ZIKV) epidemics with infections in pregnant women are associated with severe neurological disease in newborns. Although an arbovirus, ZIKV is also blood transfusion-transmitted (TT). Greater knowledge of the efficiency of ZIKV TT would aid decisions on testing and pathogen reduction technologies (PRT). STUDY DESIGN AND METHODS: Plasma units from ZIKV RNA-reactive blood donors were used to study infectivity in vitro, in mice, and in macaques. Furthermore, plasma units were subjected to PRT using amotosalen/ultraviolet light A (A/UVA) before transfusion. RESULTS: In vitro infectivity of ZIKV RNA-reactive plasma varied between 100 and 1000 international units (IU) of ZIKV RNA. Immunodeficient mice were more sensitive with as low as 32 IU sufficient to infect 50% of mice. 50-5500 IU of RNA led to TT in macaques using dose escalation of three different RNA-positive, seronegative plasma units. In contrast, RNA-reactive units collected postseroconversion were not infectious in macaques, even at a dose of 9 million IU RNA. After A/UVA PRT, transfusion of plasma containing up to 18 million IU was no longer infectious in vitro and did not result in ZIKV TT in macaques. CONCLUSION: Significant risks of ZIKV TT are likely confined to a relatively short viremic window before seroconversion, and that sensitive nucleic acid amplification testing likely identifies the majority of infectious plasma. PRT was demonstrated to be effective at preventing ZIKV TT. Considering that there is no approved ZIKV vaccine, these data are relevant to mitigate the risk of TT during the future ZIKV outbreaks.

BACKGROUND: Except for public health case reports, the incidence of Zika virus (ZIKV), chikungunya virus (CHIKV), and dengue virus (DENV) infection are not available to assess the potential blood transfusion safety threat in Brazil. METHODS: Pools of 6 donation samples (MP6) left over from human immunodeficiency virus, hepatitis B virus, and hepatitis C virus nucleic acid testing were combined to create MP18 pools (3 MP6 pools). Samples were tested using the Grifols triplex ZIKV, CHIKV, and DENV real-time transcription mediated amplification assay to estimate prevalence of RNAemia and incidence, and to compare these results to case reports in São Paulo, Belo Horizonte, Recife, and Rio de Janeiro, from April 2016 through June 2019. RESULTS: ZIKV, CHIKV, and DENV RNAemia were found from donors who donated without overt symptoms of infection that would have led to deferral. The highest RNAemic donation prevalence was 1.2% (95% CI, .8%-1.9%) for DENV in Belo Horizonte in May 2019. Arbovirus infections varied by location and time of year, and were not always aligned with annual arbovirus outbreak seasons in different regions of the country. CONCLUSIONS: Testing donations for arboviruses in Brazil can contribute to public health. Transfusion recipients were likely exposed to ZIKV, CHIKV, and DENV viremic blood components during the study period.

Progressive grey matter loss has been demonstrated among clinical high-risk (CHR) individuals who convert to psychosis, but it is unknown whether these changes occur prior to psychosis onset. Identifying illness-related neurobiological mechanisms that occur prior to conversion is essential for targeted early intervention. Among participants in the third wave of the North American Prodrome Longitudinal Study (NAPLS3), this report investigated if steeper cortical thinning was observable prior to psychosis onset among CHR individuals who ultimately converted (CHR-C) and assessed the shortest possible time interval in which rates of cortical thinning differ between CHR-C, CHR non-converters (CHR-NC), and health controls (HC). 338 CHR-NC, 42 CHR-C, and 62 HC participants (age 19.3±4.2, 44.8% female, 52.5% racial/ethnic minority) completed up to 5 MRI scans across 8 months. Accelerated thinning among CHR-C compared to CHR-NC and HC was observed in multiple prefrontal, temporal, and parietal cortical regions. CHR-NC also exhibited accelerated cortical thinning compared to HC in several of these areas. Greater percent decrease in cortical thickness was observed among CHR-C compared to other groups across 2.9±1.8 months, on average, in several cortical areas. ROC analyses discriminating CHR-C from CHR-NC by percent thickness change in a left hemisphere region of interest, scanner, age, age2, and sex had an AUC of 0.74, with model predictive power driven primarily by percent thickness change. Findings indicate that accelerated cortical thinning precedes psychosis onset and differentiates CHR-C from CHR-NC and HC across short time intervals. Mechanisms underlying cortical thinning may provide novel treatment targets prior to psychosis onset.

ObjectivePrior genomewide association studies have identified variation in major histocompatibility complex (MHC) class I alleles and C-C chemokine receptor type 5 gene (CCR5Δ32) as genetic predictors of viral control, especially in 'elite' controllers, individuals who remain virally suppressed in the absence of therapy.DesignCross-sectional genomewide association study.MethodsWe analyzed custom whole exome sequencing and direct human leukocyte antigen (HLA) typing from 202 antiretroviral therapy (ART)-suppressed HIV+ noncontrollers in relation to four measures of the peripheral CD4+ T-cell reservoir: HIV intact DNA, total (t)DNA, unspliced (us)RNA, and RNA/DNA. Linear mixed models were adjusted for potential covariates including age, sex, nadir CD4+ T-cell count, pre-ART HIV RNA, timing of ART initiation, and duration of ART suppression.ResultsPreviously reported 'protective' host genetic mutations related to viral setpoint (e.g. among elite controllers) were found to predict smaller HIV reservoir size. The HLA 'protective' B∗57:01 was associated with significantly lower HIV usRNA (q = 3.3 × 10-3), and among the largest subgroup, European ancestry individuals, the CCR5Δ32 deletion was associated with smaller HIV tDNA (P = 4.3 × 10-3) and usRNA (P = 8.7 × 10-3). In addition, genomewide analysis identified several single nucleotide polymorphisms in MX1 (an interferon stimulated gene) that were significantly associated with HIV tDNA (q = 0.02), and the direction of these associations paralleled MX1 gene eQTL expression.ConclusionsWe observed a significant association between previously reported 'protective' MHC class I alleles and CCR5Δ32 with the HIV reservoir size in noncontrollers. We also found a novel association between MX1 and HIV total DNA (in addition to other interferon signaling relevant genes, PPP1CB, DDX3X). These findings warrant further investigation in future validation studies.