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Background: Higher cytotoxic T lymphocyte (CTL) numbers in the tumor microenvironment (TME) predict pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) and positive long-term outcomes in triple-negative breast cancer (TNBC). pCR to NAC is achieved only in 30-40% of patients. The combination of NAC with pembrolizumab increases the pCR rate but at the cost of immune-related adverse events (irAEs). Based on these considerations, we tested if systemic infusion of the chemokine modulatory regimen (CKM; selective toll-like receptor 3 (TLR3) agonist rintatolimod, interferon (IFN)-α2b, and cyclooxygenase-2 (COX-2) inhibitor celecoxib) regimen can be safely combined with NAC to enhance intratumoral CTL numbers and NAC effectiveness., Methods: Phase I study NCT04081389 evaluated nine patients with early-stage TNBC who received 3 weeks of paclitaxel with CKM (dose-escalation of IFN-α2b), followed by 9 weeks of paclitaxel alone, dose-dense doxorubicin and cyclophosphamide, and surgery. Primary and secondary endpoints were safety and clinical efficacy, respectively., Results: The combination treatment was well-tolerated with no dose-limiting toxicities or irAEs. 5/9 patients achieved pCR and one patient had microinvasive disease (ypTmic). We observed elevated IFN signature and uniform decreases in CTL numbers (average 8.3-fold) in the blood of all treated patients. This was accompanied by reciprocal uniform increases in CD8β (overall 5.9-fold), CD8α/FoxP3 (2.11-fold), and CCL5 (4.73-fold) transcripts in TME, particularly pronounced in patients with pCR. Multiplex immunohistochemistry revealed selectively increased numbers of CTL (but not regulatory T cells) in both the epithelial and stromal tumor compartments and early decreases in the numbers of αSMA + vascular/stromal cells in the tumors of all pCR patients., Conclusions: Combined paclitaxel/CKM regimen was safe, with desirable TME changes and preliminary indications of promising pCR+ypTmic of 66%, comparable to the combination of NAC with pembrolizumab., Competing Interests: Competing interests: No, there are no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

This opinion consolidates regulatory frameworks, legal cases, workforce data, and research studies to advocate for the advancement of licensed practical nurses to registered nurses within correctional health care. By emphasizing adherence to nursing scope of practice and proposing a sustainable workforce development model, this article aims to enhance patient care and elevate standards in correctional facilities.

Introduction: Anticipating and addressing implementation challenges is critical to ensuring success of mobile healthcare programs. Mobile Prosthetic and Orthotic (O&P) Care (MoPOC) is a new U.S. Department of Veterans Affairs (VA) program that aims to improve access to VA-based O&P services through a national network of traveling O&P clinicians who deliver care in rural communities. We conducted an iterative evaluation guided by the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework to identify challenges and associated strategies for successful implementation of this mobile O&P program., Methods: MoPOC is delivered by an O&P clinician anchored at a VA medical center (VAMC). Clinicians travel to remote VA clinics and Veteran's homes with a custom vehicle which provides storage and a workshop to modify O&P devices. Each clinician is supported by a program support assistant. MoPOC was implemented in three phases. The qualitative evaluation of MoPOC implementation was conducted as part of a larger evaluation of MoPOC program outcomes. We conducted semi-structured interviews and regular check-ins with MoPOC clinicians, site managers, and stakeholders both prior to implementation and throughout the implementation process. Interviews were recorded and transcribed verbatim. Data was analyzed across sites and comparatively by phase using a rapid matrix analysis to identify themes related to adoption and implementation challenges and key strategies developed to address those challenges., Results: We identified four key themes related to successful program implementation, each with associated challenges and improvement strategies: (1) "Finding the right sites for MoPOC" through intentional recruitment and site selection; (2) Identifying the "sweet spot": Balancing program capacity, sustainability, and MoPOC clinician satisfaction; (3) Shifting from testing to standardizing; and (4) "Being strategic with hiring" to improve program adoption., Discussion: Implementation challenges were related to recruiting and selecting successful sites, ensuring timely program adoption, balancing site level adaptation and program standardization, and scaling programs to enhance efficiency, reach, and satisfaction. An iterative approach guided by the RE-AIM framework resulted in program improvement and more rapid implementation in each successive phase. The challenges described in MoPOC implementation may be common issues in implementing new mobile programs in rural areas., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Leonard, Young, McKown, Klassen, Kaufman and Abrahamson.)

Research has explored why people seek assisted dying (AD), families' bereavement, and AD providers' experiences, yet few studies have investigated decision-making of the time and date for AD. This article elucidates how cancer patients, families and AD providers decide on and experience living with a date and time for AD in New Zealand. We longitudinally interviewed 23 people. Using thematic analysis, we identified four decision-making phases: deciding how and when to draw a line in the sand, the final countdown, a date with death and the right time. Picking a date was an embodied, relational, situational decision that balanced time left, families' wishes, providers' needs, and AD regulations. Time is a silent factor in AD decision-making; choosing a date reorients time to clock, event and embodied time, and contrives the right time for death. We discuss the implications and recommend how AD providers and policymakers can support service users and providers.

Background: The use of rapid qualitative methods has increased substantially over the past decade in quality improvement and health services research. These methods have gained traction in implementation research and practice, wherein real-time adjustments are often made to optimize processes and outcomes. This brisk increase begs the questions: what does rigor entail in projects that use rapid qualitative analysis (RQA)? How do we define a pragmatic framework to help research teams design and conduct rigorous and valid rapid qualitative projects? How can authors articulate rigor in their methods descriptions? Lastly, how can reviewers evaluate the rigor of rapid qualitative projects?., Methods: A team of seven interdisciplinary qualitative methods experts developed a framework for ensuring rigor and validity in RQA and methods suitable for this analytic approach. We conducted a qualitative evidence synthesis to identify gaps in the literature and then drew upon literature, standard procedures within our teams, and a repository of rapid qualitative training materials to create a planning and reporting framework. We iteratively refined this framework through 11 group working meetings (60-90 minutes each) over the course of one year and invited feedback on items to ensure their completeness, clarity, and comprehensibility., Results: The Planning for and Assessing Rigor in Rapid Qualitative Analysis (PARRQA) framework is organized progressively across phases from design to dissemination, as follows: 1) rigorous design (rationale and staffing), 2) semi-structured data collection (pilot and planning), 3) RQA: summary template development (accuracy and calibration), 4) RQA: matrix analysis (matrices), and 5) rapid qualitative data synthesis. Eighteen recommendations across these sections specify best practices for rigor and validity., Conclusions: Rapid qualitative methods play a central role in implementation evaluations, with the potential to yield prompt information and insights about context, processes, and relationships. However, guidance on how to assess rigor is nascent. The PARRQA framework enhances the literature by offering criteria to ensure appropriate planning for and assessment of rigor in projects that involve RQA. This framework provides a consensus-based resource to support high-level qualitative methodological rigor in implementation science., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Introduction: Increasing numbers of jurisdictions are legalising assisted dying (AD). Developing research protocols to study the experiences and outcomes of legislation is imperative. AD is a topic that, by nature of its complexity and inherent ethical issues, lends itself to qualitative research. Using the objectives of the statutory framework, this qualitative study aims to provide a robust review of the newly formed AD service in New Zealand and the extent to which it is safe, people-centred, dignity-enhancing, accessible and available equitably to all eligible people., Methods and Analysis: The research uses an appreciative inquiry design to focus on what is working well, what could be improved, what constitutes the 'ideal' and how to enable people to achieve that ideal. We are using online semi-structured interviews and face-to-face focus groups to explore the experiences of key stakeholders: eligible/ineligible service users; eligible/ineligible service users with impairments; families of service users; AD providers; non-providers (providers who object to AD and others who are not directly involved in providing AD but are not opposed in principle); health service leaders; and Māori community members. An estimated 110 participants will be interviewed. We will conduct thematic and regulatory analyses of data., Ethics and Dissemination: The ethical aspects of this study have been approved by the Northern A Health and Disability Ethics Committee through the full review pathway (2023 EXP 18493). To disseminate the findings, we will draft resources to support interviewee groups, to be developed with feedback from stakeholder meetings. We will submit evidence-based recommendations to inform the government review of the End of Life Choice Act 2019. Findings will be disseminated in peer-reviewed publications, conferences, webinars, media, stakeholder feedback sessions and accessible research briefings., Competing Interests: Competing interests: Associate Professors THK-C and JR sit on an AD statutory committee and the research team, both of which have processes for managing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Zika virus (ZIKV) infection during pregnancy can lead to fetal brain infection and developmental anomalies collectively known as congenital Zika syndrome (CZS). To define the molecular features underlying CZS in a relevant human cell model, we evaluated ZIKV infection and neurodevelopment in primary fetal brain explants and induced pluripotent stem cell-derived mixed neural cultures at single cell resolution. We identified astrocytes as key innate immune sentinel cells detecting ZIKV and producing IFN-β. In contrast, neural progenitor cells displayed impaired innate immunity and supported high levels of viral replication. ZIKV infection of neurons suppressed differentiation and synaptic signaling networks and programmed a molecular switch from neurogenesis to astrogliogenesis. We identified a universal ZIKV-driven cellular stress response linked to intrinsic apoptosis and regulated by IFN-β. These findings reveal how innate immune signaling intersects with ZIKV-driven perturbations in cellular function to influence CZS outcomes including neuron developmental dysfunction and apoptotic cell death.

Grieving at a distance is a common and often challenging experience for migrants. As a result of travel restrictions and border closures, grieving at a distance became a focus of media reporting during the COVID-19 pandemic. This paper aimed to examine the representation of migrants' grief at a distance during the pandemic in online newspaper articles. We used a qualitative framing analysis to analyze nine articles published in online international newspapers. Three frames were identified: Grief as an impossible situation, migrants left with impossible choices, and grief as culturally mediated. These frames focused on how the psychological experience of grief was intertwined with migrants' broader societal and cultural contexts. They emphasized the complex choices migrants faced due to their personal situations and cross-cultural experiences. Findings offer insights into how the media depicts migrant experiences, thus shaping public perceptions of their grief and bereavement. They reveal the difficulties of transnational grief migrants experienced.

The inability to identify dates of death in insurance claims data is the United States is a major limitation to retrospective claims-based research. While deaths result in disenrollment, disenrollment can also occur due to changes in insurance providers. We created an algorithm to differentiate between disenrollment from health plans due to death and disenrollment for other reasons. We identified 5,259,735 adults who disenrolled from private insurance between 2007 and 2018. Using death dates ascertained from the Social Security Death Index, inpatient discharge status, and death indicators in the administrative data, 7.6% of all disenrollments were classified as resulting from death. We used elastic net regression to build an algorithm using claims data in the year prior to disenrollment; candidate predictors included medical conditions, individual demographic characteristics, treatment utilization, and structural factors related to health insurance eligibility and coding. Using a predicted probability threshold of 0.9 (selected to reflect the corresponding known prevalence of mortality), internal validation found that the algorithm classified death at disenrollment with a positive predictive value of 0.815, sensitivity of 0.721 and specificity of 0.986 (AUC=0.97). Independent data sources were used for external validation and for an applied example. Code for implementation is publicly available., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Antidepressants are among the most commonly prescribed medications, but evidence on comparative weight change for specific first-line treatments is limited., Objective: To compare weight change across common first-line antidepressant treatments by emulating a target trial., Design: Observational cohort study over 24 months., Setting: Electronic health record (EHR) data from 2010 to 2019 across 8 U.S. health systems., Participants: 183 118 patients., Measurements: Prescription data determined initiation of treatment with sertraline, citalopram, escitalopram, fluoxetine, paroxetine, bupropion, duloxetine, or venlafaxine. The investigators estimated the population-level effects of initiating each treatment, relative to sertraline, on mean weight change (primary) and the probability of gaining at least 5% of baseline weight (secondary) 6 months after initiation. Inverse probability weighting of repeated outcome marginal structural models was used to account for baseline confounding and informative outcome measurement. In secondary analyses, the effects of initiating and adhering to each treatment protocol were estimated., Results: Compared with that for sertraline, estimated 6-month weight gain was higher for escitalopram (difference, 0.41 kg [95% CI, 0.31 to 0.52 kg]), paroxetine (difference, 0.37 kg [CI, 0.20 to 0.54 kg]), duloxetine (difference, 0.34 kg [CI, 0.22 to 0.44 kg]), venlafaxine (difference, 0.17 kg [CI, 0.03 to 0.31 kg]), and citalopram (difference, 0.12 kg [CI, 0.02 to 0.23 kg]); similar for fluoxetine (difference, -0.07 kg [CI, -0.19 to 0.04 kg]); and lower for bupropion (difference, -0.22 kg [CI, -0.33 to -0.12 kg]). Escitalopram, paroxetine, and duloxetine were associated with 10% to 15% higher risk for gaining at least 5% of baseline weight, whereas bupropion was associated with 15% reduced risk. When the effects of initiation and adherence were estimated, associations were stronger but had wider CIs. Six-month adherence ranged from 28% (duloxetine) to 41% (bupropion)., Limitation: No data on medication dispensing, low medication adherence, incomplete data on adherence, and incomplete data on weight measures across time points., Conclusion: Small differences in mean weight change were found between 8 first-line antidepressants, with bupropion consistently showing the least weight gain, although adherence to medications over follow-up was low. Clinicians could consider potential weight gain when initiating antidepressant treatment., Primary Funding Source: National Institutes of Health., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M23-2742.

Breast cancer is treated with a multidisciplinary approach involving surgical oncology, radiation oncology, and medical oncology. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer include recommendations for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget's disease, Phyllodes tumor, inflammatory breast cancer, and management of breast cancer during pregnancy. The content featured in this issue focuses on the recommendations for overall management of systemic therapy (preoperative and adjuvant) options for nonmetastatic breast cancer. For the full version of the NCCN Guidelines for Breast Cancer, visit NCCN.org.

The SORL1 gene encodes the sortilin related receptor protein SORLA, a sorting receptor that regulates endo-lysosomal trafficking of various substrates. Loss of function variants in SORL1 are causative for Alzheimer's disease (AD) and decreased expression of SORLA has been repeatedly observed in human AD brains. SORL1 is highly expressed by microglia, the tissue resident immune cells of the brain. Loss of SORLA leads to enlarged lysosomes in hiPSC-derived microglia like cells (hMGLs). However, whether SORLA deficiency contributes to microglia dysfunction and how this is relevant to AD is not known. In this study, we show that loss of SORLA results in decreased lysosomal degradation and lysosomal enzyme activity due to altered trafficking of lysosomal enzymes in hMGLs. Furthermore, lysosomal exocytosis, an important process involved in immune responses and cellular signaling, is also impaired in SORL1 deficient microglia. Phagocytic uptake of fibrillar amyloid beta 1-42 and synaptosomes is increased in SORLA deficient hMGLs, but due to reduced lysosomal degradation, these substrates aberrantly accumulate in lysosomes. Overall, these data highlight the microglial endo-lysosomal network as a potential novel pathway through which SORL1 may increase AD risk and contribute to development of AD. Additionally, our findings may inform development of novel lysosome and microglia associated drug targets for AD.

Introduction: Brain insulin resistance and deficiency is a consistent feature of Alzheimer's disease (AD). Insulin resistance can be mediated by the surface expression of the insulin receptor (IR). Cleavage of the IR generates the soluble IR (sIR)., Methods: We measured the levels of sIR present in cerebrospinal fluid (CSF) from individuals along the AD diagnostic spectrum from two cohorts: Seattle ( n  = 58) and the Consortium for the Early Identification of Alzheimer's Disease-Quebec (CIMA-Q; n  = 61). We further investigated the brain cellular contribution for sIR using human cell lines., Results: CSF sIR levels were not statistically different in AD. CSF sIR and amyloid beta (Aβ)42 and Aβ40 levels significantly correlated as well as CSF sIR and cognition in the CIMA-Q cohort. Human neurons expressing the amyloid precursor protein "Swedish" mutation generated significantly greater sIR and human astrocytes were also able to release sIR in response to both an inflammatory and insulin stimulus., Discussion: These data support further investigation into the generation and role of sIR in AD., Highlights: Cerebrospinal fluid (CSF) soluble insulin receptor (sIR) levels positively correlate with amyloid beta (Aβ)42 and Aβ40.CSF sIR levels negatively correlate with cognitive performance (Montreal Cognitive Assessment score).CSF sIR levels in humans remain similar across Alzheimer's disease diagnostic groups.Neurons derived from humans with the "Swedish" mutation in which Aβ42 is increased generate increased levels of sIR.Human astrocytes can also produce sIR and generation is stimulated by tumor necrosis factor α and insulin., Competing Interests: The authors declare no conflicts of interest. Author disclosures are available in the supporting information., (© 2024 The Author(s). Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Objective: Musculoskeletal pain complaints are common in the emergency department (ED). The objective of this study was to determine the impact of physical therapy (PT) in the ED on pain and ED return., Methods: A prospective cohort study was performed with those presenting to the ED or Urgent Care at a single academic center for musculoskeletal pain between November 2020 and December 2022. All patients were referred to outpatient PT. During business hours, PT was available to begin treatment in the ED. Long-term follow-up was performed using the electronic health records. Statistical analyses included descriptive and non-parametric pairwise comparisons, Fisher's exact test, and multiple logistic regression., Results: A total of 974 patients were included in the study with 553 completing optional surveys. Back pain was most common. Pain was reduced at ED discharge for all patients, but pain was significantly improved if patients saw PT in the ED. Patients in the ED were less likely to keep their outpatient PT appointments than others, but importantly, patients who saw PT in the ED were less likely to return to the ED for the same complaint up to 1 year later. Those who kept PT appointments were likely to establish or maintain healthcare outside emergency services later., Conclusions: Initiating PT in this ED reduces pain at ED discharge. However, patients who utilized PT were more likely to later utilize health care resources outside of emergency services. Those who saw PT in this ED were less likely to return to the ED for the same complaint up to 1 year later., Competing Interests: The authors declared they have no conflicts of interest., (© 2024 The Author(s). Journal of the American College of Emergency Physicians Open published by Wiley Periodicals, Inc. on behalf of American College of Emergency Physicians.)

The number of Americans with multiple jobs is increasing and multiple jobholders work more hours per week. However, the associations between multiple jobholding and hypertension are unknown. The aim of this study was to examine the associations of multiple jobholding with hypertension and determine whether weekly working hours moderated this association. Data from the 2015 National Health Interview Survey on adults (age ≥18 years) were used and included participants who self-identified as non-Hispanic Asian, non-Hispanic Black, Hispanic, or non-Hispanic White in the U.S. (n = 16,926), The associations of multiple jobholding with self-reported hypertension by sex were assessed using modified Poisson regressions. Both the number of working hours per week and race/ethnicity were assessed as moderators using multiplicative interaction terms. Multiple jobholding was not associated with hypertension among women. However, there was a significant three-way interaction such that multiple jobholding was associated with hypertension among non-Hispanic Black men who worked ≥55 hours per week (relative risk = 1.02, 95% confidence interval = 1.01-1.05). The results suggest that the associations between multiple jobholding, number of working hours, and hypertension should be examined at the intersection of race/ethnicity and sex. Future studies should further characterize multiple jobholding and hypertension among non-Hispanic Black men., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Bell et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Cancer risk factors are more common among sexual minority populations (e.g., lesbian, bisexual) than their heterosexual peers, yet little is known about cancer incidence across sexual orientation groups., Methods: The 1989-2017 data from the Nurses' Health Study II, a longitudinal cohort of female nurses across the United States, were analyzed (N = 101,543). Sexual orientation-related cancer disparities were quantified by comparing any cancer incidence among four sexual minority groups based on self-disclosure-(1) heterosexual with past same-sex attractions/partners/identity; (2) mostly heterosexual; (3) bisexual; and (4) lesbian women-to completely heterosexual women using age-adjusted incidence rate ratios (aIRR) calculated by the Mantel-Haenszel method. Additionally, subanalyses at 21 cancer disease sites (e.g., breast, colon/rectum) were conducted., Results: For all-cancer analyses, there were no statistically significant differences in cancer incidence at the 5% type I error cutoff among sexual minority groups when compared to completely heterosexual women; the aIRR was 1.17 (95% CI,0.99-1.38) among lesbian women and 0.80 (0.58-1.10) among bisexual women. For the site-specific analyses, incidences at multiple sites were significantly higher among lesbian women compared to completely heterosexual women: thyroid cancer (aIRR, 1.87 [1.03-3.41]), basal cell carcinoma (aIRR, 1.85 [1.09-3.14]), and non-Hodgkin lymphoma (aIRR, 2.13 [1.10-4.12])., Conclusion: Lesbian women may be disproportionately burdened by cancer relative to their heterosexual peers. Sexual minority populations must be explicitly included in cancer prevention efforts. Comprehensive and standardized sexual orientation data must be systematically collected so nuanced sexual orientation-related cancer disparities can be accurately assessed for both common and rare cancers., (© 2024 American Cancer Society.)

Background: Guidelines for the use of antihypertensives changed in 2014 and 2017. To understand the effect of these guidelines, we examined trends in antihypertensive prescriptions in the United States from 2010 to 2019 using a repeated cross-sectional design., Methods and Results: Using electronic health records from 15 health care institutions for adults (20-85 years old) who had ≥1 antihypertensive prescription, we assessed whether (1) prescriptions of beta blockers decreased after the 2014 Eighth Joint National Committee (JNC 8) report discouraged use for first-line treatment, (2) prescriptions for calcium channel blockers and thiazide diuretics increased among Black patients after the JNC 8 report encouraged use as first-line therapy, and (3) prescriptions for dual therapy and fixed-dose combination among patients with blood pressure ≥140/90 mm Hg increased after recommendations in the 2017 Hypertension Clinical Practice Guidelines. The study included 1 074 314 patients with 2 133 158 prescription episodes. After publication of the JNC 8 report, prescriptions for beta blockers decreased (3% lower in 2018-2019 compared to 2010-2014), and calcium channel blockers increased among Black patients (20% higher in 2015-2017 and 41% higher in 2018-2019, compared to 2010-2014), in accordance with guideline recommendations. However, contrary to guidelines, dual therapy and fixed-dose combination decreased after publication of the 2017 Hypertension Clinical Practice Guidelines (9% and 11% decrease in 2018-2019 for dual therapy and fixed-dose combination, respectively, compared to 2015-2017), and thiazide diuretics decreased among Black patients after the JNC 8 report (6% lower in 2018-2019 compared to 2010-2014)., Conclusions: Adherence to guidelines on prescribing antihypertensive medication was inconsistent, presenting an opportunity for interventions to achieve better blood pressure control in the US population.

Competing Interests: The authors report no conflicts of interest.

The endosomal gene SORL1 is a strong Alzheimer's disease (AD) risk gene that harbours loss-of-function variants causative for developing AD. The SORL1 protein SORL1/SORLA is an endosomal receptor that interacts with the multi-protein sorting complex retromer to traffic various cargo through the endo-lysosomal network (ELN). Impairments in endo-lysosomal trafficking are an early cellular symptom in AD and a novel therapeutic target. However, the cell types of the central nervous system are diverse and use the ELN differently. If this pathway is to be effectively therapeutically targeted, understanding how key molecules in the ELN function in various cell types and how manipulating them affects cell-type specific responses relative to AD is essential. Here, we discuss an example where deficiency of SORL1 expression in a human model leads to stress on early endosomes and recycling endosomes in neurons, but preferentially leads to stress on lysosomes in microglia. The differences observed in these organelles could relate to the unique roles of these cells in the brain as neurons are professional secretory cells and microglia are professional phagocytic cells. Experiments to untangle these differences are fundamental to advancing the understanding of cell biology in AD and elucidating important pathways for therapeutic development. Human-induced pluripotent stem cell models are a valuable platform for such experiments. This article is part of a discussion meeting issue 'Understanding the endo-lysosomal network in neurodegeneration'.

Purpose: The prevalent new user design extends the active comparator new user design to include patients switching to a treatment of interest from a comparator. We examined the impact of adding "switchers" to incident new users on the estimated hazard ratio (HR) of hospitalized heart failure., Methods: Using MarketScan claims data (2000-2014), we estimated HRs of hospitalized heart failure between patients initiating GLP-1 receptor agonists (GLP-1 RA) and sulfonylureas (SU). We considered three estimands: (1) the effect of incident new use; (2) the effect of switching; and (3) the effect of incident new use or switching, combining the two population. We used time-conditional propensity scores (TCPS) and time-stratified standardized morbidity ratio (SMR) weighting to adjust for confounding., Results: We identified 76 179 GLP-1 RA new users, of which 12% were direct switchers (within 30 days) from SU. Among incident new users, GLP-1 RA was protective against heart failure (adjHR SMR  = 0.74 [0.69, 0.80]). Among switchers, GLP-1 RA was not protective (adjHR SMR  = 0.99 [0.83, 1.18]). Results in the combined population were largely driven by the incident new users, with GLP-1 RA having a protective effect (adjHR SMR  = 0.77 [0.72, 0.83]). Results using TCPS were consistent with those estimated using SMR weighting., Conclusions: When analyses were conducted only among incident new users, GLP-1 RA had a protective effect. However, among switchers from SU to GLP-1 RA, the effect estimates substantially shifted toward the null. Combining patients with varying treatment histories can result in poor confounding control and camouflage important heterogeneity., (© 2024 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

This article is the written account of a discussion between a group of indigenous women (trained both in Western and Indigenous knowledge systems), on the relevance of diagnosis in their conceptualisations of health and illness., (© 2023 The Authors. Sociology of Health & Illness published by John Wiley & Sons Ltd on behalf of Foundation for the Sociology of Health & Illness.)

Objectives: Despite the growing rates of global obesity and the known positive associations between brown adipose tissue (BAT) and cardiovascular health, little is known about the metabolic effects of BAT activity in Samoans, a population at high risk of obesity and type II diabetes. Here we assessed the potential effects of inferred BAT activity on metabolic health markers in Samoan adults exposed to mild cold., Methods: Using point-of-care finger prick technology we measured fasting glucose, total cholesterol, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) levels before and after 30 min of cold exposure among 61 individuals (38 females, 23 males, ages 31-54) from 'Upolu Island, Samoa. Respiratory quotient was measured by indirect calorimetry to determine substrate metabolism at room temperature and cold exposure., Results: Fasting glucose levels decreased significantly (p < .001) after cold exposure while neither total cholesterol (p = .88), HDL (p = .312), nor LDL (p = .089) changed. Respiratory quotient decreased significantly (p = .009) between exposures, suggesting an increased preference for lipid metabolism as a response to cold., Conclusions: The observed effects of inferred BAT activity on biomarkers suggest BAT activity utilizes both glucose and lipid-derived fatty acids as fuel for thermogenesis. Our work provides evidence for the beneficial metabolic effects of BAT and emphasizes the need for the population-specific development of metabolic treatments involving BAT to ensure the successful and equitable minimization of extreme consequences of obesity and metabolic health., (© 2023 Wiley Periodicals LLC.)

Background: Barriers to accessing hospice and palliative care have been well studied. An important yet less researched area is why people approaching the end-of-life decline a referral when they are offered services. This review focused on synthesising literature on patients in the last months of life due to a cancer diagnosis who have declined a referral to end-of-life care., Methods: Six academic databases were systematically searched for qualitative literature published between 2007 and 2021. Two researchers independently reviewed and critically appraised the studies. Using meta-ethnographic methods of translation and synthesis, we set out to identify and develop a new overarching model of the reasons patients decline end-of-life care and the factors contributing to this decision., Results: The search yielded 2060 articles, and nine articles were identified that met the review inclusion criteria. The included studies can be reconceptualised with the key concept of 'embodied decisions unfolding over time'. It emphasises the iterative, dynamic, situational, contextual and relational nature of decisions about end-of-life care that are grounded in people's physical experiences. The primary influences on how that decision unfolded for patients were (1) the communication they received about end-of-life care; (2) uncertainty around their prognosis, and (3) the evolving situations in which the patient and family found themselves. Our review identified contextual, person and medical factors that helped to shape the decision-making process., Conclusions: Decisions about when (and for some, whether at all) to accept end-of-life care are made in a complex system with preferences shifting over time, in relation to the embodied experience of life-limiting cancer. Time is central to patients' end-of-life care decision-making, in particular estimating how much time one has left and patients' embodied knowing about when the right time for end-of-life care is. The multiple and intersecting domains of health that inform decision-making, namely physical, mental, social, and existential/spiritual as well as emotions/affect need further exploration. The integration of palliative care across the cancer care trajectory and earlier introduction of end-of-life care highlight the importance of these findings for improving access whilst recognising that accessing end-of-life care will not be desired by all patients., (© 2024. The Author(s).)

RNA sequencing and genetic data support spleen tyrosine kinase (SYK) and high affinity immunoglobulin epsilon receptor subunit gamma (FCER1G) as putative targets to be modulated for Alzheimer's disease (AD) therapy. FCER1G is a component of Fc receptor complexes that contain an immunoreceptor tyrosine-based activation motif (ITAM). SYK interacts with the Fc receptor by binding to doubly phosphorylated ITAM (p-ITAM) via its two tandem SH2 domains (SYK-tSH2). Interaction of the FCER1G p-ITAM with SYK-tSH2 enables SYK activation via phosphorylation. Since SYK activation is reported to exacerbate AD pathology, we hypothesized that disruption of this interaction would be beneficial for AD patients. Herein, we developed biochemical and biophysical assays to enable the discovery of small molecules that perturb the interaction between the FCER1G p-ITAM and SYK-tSH2. We identified two distinct chemotypes using a high-throughput screen (HTS) and orthogonally assessed their binding. Both chemotypes covalently modify SYK-tSH2 and inhibit its interaction with FCER1G p-ITAM, however, these compounds lack selectivity and this limits their utility as chemical tools., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Bashore et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Aims: Little is known about the exposure of young people in Aotearoa New Zealand to marketing of vape products on social media. This study investigated vaping behaviour and the extent of vape marketing exposure and engagement that young people (14-20 years) report on social media and examined differences across socio-demographic groups., Methods: An online survey was conducted with 3,698 participants aged between 14-20 years (M=17.1; SD=1.8). A range of genders (55.7% females, 38.3% males and 6% another gender), ethnicities (25.6% Māori, 46.7% Pākehā or NZ European, 6.5% Pasifika and 21.2% another ethnicity) and social classes took part., Results: Half (50.8%; n=1,110) of the respondents (N=2,185) reported that they had vaped at least once; vaping history was positively related to exposure to and engagement with digital vape marketing. Half (50.3%; n=1,119) of the respondents (N=2,224) reported seeing vape marketing on at least one social media platform. Binary logistic regressions showed that younger respondents were more likely to report seeing vape marketing than older respondents, and Māori and Pasifika more likely than other ethnicities. Over a quarter (26%; n=563) of respondents (N=2,148) reported engaging with vape marketing online, with Māori and Pasifika respondents more likely to engage than other ethnicity groups, and similarly for respondents of lower compared to higher socio-economic status. No interaction effects were found., Conclusions: Many young people, including a subset under the legal age for purchase, reported seeing vape product marketing on social media platforms. Patterns of exposure to vape product marketing on social media mirror the inequitable marketing exposure of harmful commodities in physical environments. Improved transparency and regulation of social media marketing is required., Competing Interests: Nil., (© PMA.)

Background: Professional caregiving relationships are central to quality healthcare but are not always developed to a consistently high standard in clinical practice. Existing literature on what constitutes high-quality relationships and how they should be developed is plagued by dyadic conceptualisations; discipline, context and condition-specific research; and the absence of healthcare recipient and informal carer voices. This study aimed to address these issues by exploring how healthcare recipients and carers conceptualise good professional caregiving relationships regardless of discipline, care setting and clinical condition., Design: A qualitative story completion approach was used. Participants completed a story in response to a hypothetical stem that described a healthcare recipient (and, in some instances, carer) developing a good relationship with a new healthcare provider. Stories were analysed using reflexive thematic analysis., Participants: Participants were 35 healthcare recipients and 37 carers (n = 72 total)., Results: Participants' stories were shaped by an overarching discourse that seeking help from new providers can elicit a range of unwanted emotions for both recipients and carers (e.g., anxiety, fear, dread). These unwanted emotions were experienced in relation to recipients' presenting health problems as well as their anticipated interactions with providers. Specifically, recipient and carer characters were fearful that providers would dismiss their concerns and judge them for deciding to seek help. Good relationships were seen to develop when healthcare providers worked to relieve or minimise these unwanted emotions, ensuring healthcare recipients and carers felt comfortable and at ease with the provider and the encounter. Participants positioned healthcare providers as primarily responsible for relieving recipients' and carers' unwanted emotions, which was achieved via four approaches: (1) easing into the encounter, (2) demonstrating interest in and understanding of recipients' presenting problems, (3) validating recipients' presenting problems and (4) enabling and respecting recipient choice. Participants' stories also routinely oriented to temporality, positioning relationships within recipients' and carers' wider care networks and biographical and temporal contexts., Conclusion: The findings expand our understanding of professional caregiving relationships beyond dyadic, static conceptualisations. Specifically, the findings suggest that high-quality relationships might be achieved via a set of core healthcare provider behaviours that can be employed across disciplinary, context and condition-specific boundaries. In turn, this provides a basis to support interprofessional education and multidisciplinary healthcare delivery, enabling different healthcare disciplines, specialties, and teams to work from the same understanding of what is required to develop high-quality relationships., Patient or Public Contribution: The findings are based on stories from 72 healthcare recipient and carer participants, providing rich insight into their conceptualisations of high-quality professional caregiving relationships., (© 2023 The Authors. Health Expectations published by John Wiley & Sons Ltd.)

Researchers are often interested in estimating the effect of sustained use of a treatment on a health outcome. However, adherence to strict treatment protocols can be challenging for individuals in practice and, when non-adherence is expected, estimates of the effect of sustained use may not be useful for decision making. As an alternative, more relaxed treatment protocols which allow for periods of time off treatment (i.e. grace periods) have been considered in pragmatic randomized trials and observational studies. In this article, we consider the interpretation, identification, and estimation of treatment strategies which include grace periods. We contrast natural grace period strategies which allow individuals the flexibility to take treatment as they would naturally do, with stochastic grace period strategies in which the investigator specifies the distribution of treatment utilization. We estimate the effect of initiation of a thiazide diuretic or an angiotensin-converting enzyme inhibitor in hypertensive individuals under various strategies which include grace periods., Competing Interests: Conflict of interest: The authors have no conflicts of interest to declare., (© The Royal Statistical Society 2024. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The SORL1 gene has recently emerged as a strong Alzheimer's Disease (AD) risk gene. Over 500 different variants have been identified in the gene and the contribution of individual variants to AD development and progression is still largely unknown. Here, we describe a family consisting of 2 parents and 5 offspring. Both parents were affected with dementia and one had confirmed AD pathology with an age of onset > 75 years. All offspring were affected with AD with ages at onset ranging from 53 years to 74 years. DNA was available from the parent with confirmed AD and 5 offspring. We identified a coding variant, p.(Arg953Cys), in SORL1 in 5 of 6 individuals affected by AD. Notably, variant carriers had severe AD pathology, and the SORL1 variant segregated with TDP-43 pathology (LATE-NC). We further characterized this variant and show that this Arginine substitution occurs at a critical position in the YWTD-domain of the SORL1 translation product, SORL1. Functional studies further show that the p.R953C variant leads to retention of the SORL1 protein in the endoplasmic reticulum which leads to decreased maturation and shedding of the receptor and prevents its normal endosomal trafficking. Together, our analysis suggests that p.R953C is a pathogenic variant of SORL1 and sheds light on mechanisms of how missense SORL1 variants may lead to AD., (© 2024. The Author(s).)

Abnormal endo-lysosomal morphology is an early cytopathological feature of Alzheimer's disease (AD) and genome-wide association studies (GWAS) have implicated genes involved in the endo-lysosomal network (ELN) as conferring increased risk for developing sporadic, late-onset AD (LOAD). Characterization of ELN pathology and the underlying pathophysiology is a promising area of translational AD research and drug development. However, rigorous study of ELN vesicles in AD and aged control brains poses a unique constellation of methodological challenges due in part to the small size of these structures and subsequent requirements for high-resolution imaging. Here we provide a detailed protocol for high-resolution 3D morphological quantification of neuronal endosomes in postmortem AD brain tissue, using immunofluorescent staining, confocal imaging with image deconvolution, and Imaris software analysis pipelines. To demonstrate these methods, we present neuronal endosome morphology data from 23 sporadic LOAD donors and one aged non-AD control donor. The techniques described here were developed across a range of AD neuropathology to best optimize these methods for future studies with large cohorts. Application of these methods in research cohorts will help advance understanding of ELN dysfunction and cytopathology in sporadic AD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Rose, Williams, Hailey, Mishra, Kirkland, Keene, Garden, Jayadev and Young.)

Antiretroviral preexposure prophylaxis (PrEP) is highly effective in preventing human immunodeficiency virus (HIV) infection, but uptake has been limited and inequitable. Although interventions to increase PrEP uptake are being evaluated in clinical trials among men who have sex with men (MSM), those trials cannot evaluate effects on HIV incidence. Estimates from observational studies of the causal effects of PrEP-uptake interventions on HIV incidence can inform decisions about intervention scale-up. We used longitudinal electronic health record data from HIV-negative MSM accessing care at Fenway Health, a community health center in Boston, Massachusetts, from January 2012 through February 2018, with 2 years of follow-up. We considered stochastic interventions that increased the chance of initiating PrEP in several high-priority subgroups. We estimated the effects of these interventions on population-level HIV incidence using a novel inverse-probability weighted estimator of the generalized g-formula, adjusting for baseline and time-varying confounders. Our results suggest that even modest increases in PrEP initiation in high-priority subgroups of MSM could meaningfully reduce HIV incidence in the overall population of MSM. Interventions tailored to Black and Latino MSM should be prioritized to maximize equity and impact., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

Importance: Fertility status is a marker for future health, and infertility has been associated with risk for later cancer and diabetes, but associations with midlife cardiovascular health (CVH) in female individuals remain understudied., Objective: To evaluate the association of infertility history with CVH at midlife (approximately age 50 years) among parous individuals., Design, Setting, and Participants: Project Viva is a prospective cohort study of pregnant participants enrolled between 1999 and 2002 who delivered a singleton live birth in the greater Boston, Massachusetts, area. Infertility history was collected at a midlife visit between 2017 and 2021, approximately 18 years after enrollment. Data analysis was performed from January to June 2023., Exposures: The primary exposure was any lifetime history of infertility identified by self-report, medical record, diagnosis, or claims for infertility treatment., Main Outcomes and Measures: The American Heart Association's Life's Essential 8 (LE8) is a construct for ranking CVH that includes scores from 0 to 100 (higher scores denote better health status) in 4 behavioral (diet, physical activity, sleep, and smoking status) and 4 biomedical (body mass index, blood pressure, blood lipids, and glycemia) domains to form an overall assessment of CVH. Associations of a history of infertility (yes or no) with mean LE8 total, behavioral, biomedical, and blood biomarker (lipids and glycemia) scores were examined, adjusting for age at outcome (midlife visit), race and ethnicity, education, household income, age at menarche, and perceived body size at age 10 years., Results: Of 468 included participants (mean [SD] age at the midlife visit, 50.6 [5.3] years) with exposure and outcome data, 160 (34.2%) experienced any infertility. Mean (SD) LE8 scores were 76.3 (12.2) overall, 76.5 (13.4) for the behavioral domain, 76.0 (17.5) for the biomedical domain, and 78.9 (19.2) for the blood biomarkers subdomain. In adjusted models, the estimated overall LE8 score at midlife was 2.94 points lower (95% CI, -5.13 to -0.74 points), the biomedical score was 4.07 points lower (95% CI, -7.33 to -0.78 points), and the blood subdomain score was 5.98 points lower (95% CI, -9.71 to -2.26 points) among those with vs without history of infertility. The point estimate also was lower for the behavioral domain score (β = -1.81; 95% CI, -4.28 to 0.66), although the result was not statistically significant., Conclusions and Relevance: This cohort study of parous individuals found evidence for an association between a history of infertility and lower overall and biomedical CVH scores. Future study of enhanced cardiovascular preventive strategies among those who experience infertility is warranted.

Many research questions concern treatment effects on outcomes that can recur several times in the same individual. For example, medical researchers are interested in treatment effects on hospitalizations in heart failure patients and sports injuries in athletes. Competing events, such as death, complicate causal inference in studies of recurrent events because once a competing event occurs, an individual cannot have more recurrent events. Several statistical estimands have been studied in recurrent event settings, with and without competing events. However, the causal interpretations of these estimands, and the conditions that are required to identify these estimands from observed data, have yet to be formalized. Here we use a formal framework for causal inference to formulate several causal estimands in recurrent event settings, with and without competing events. When competing events exist, we clarify when commonly used classical statistical estimands can be interpreted as causal quantities from the causal mediation literature, such as (controlled) direct effects and total effects. Furthermore, we show that recent results on interventionist mediation estimands allow us to define new causal estimands with recurrent and competing events that may be of particular clinical relevance in many subject matter settings. We use causal directed acyclic graphs and single world intervention graphs to illustrate how to reason about identification conditions for the various causal estimands based on subject matter knowledge. Furthermore, using results on counting processes, we show that our causal estimands and their identification conditions, which are articulated in discrete time, converge to classical continuous time counterparts in the limit of fine discretizations of time. We propose estimators and establish their consistency for the various identifying functionals. Finally, we use the proposed estimators to compute the effect of blood pressure lowering treatment on the recurrence of acute kidney injury using data from the Systolic Blood Pressure Intervention Trial., (© 2023. The Author(s).)

The SORL1 gene (SORLA) is strongly associated with risk of developing Alzheimer's disease (AD). SORLA is a regulator of endosomal trafficking in neurons and interacts with retromer, a complex that is a "master conductor" of endosomal trafficking. Small molecules can increase retromer expression in vitro, enhancing its function. We treated hiPSC-derived cortical neurons that are either fully deficient, haploinsufficient, or that harbor one copy of SORL1 variants linked to AD with TPT-260, a retromer-enhancing molecule. We show significant increases in retromer subunit VPS26B expression. We tested whether endosomal, amyloid, and TAU pathologies were corrected. We observed that the degree of rescue by TPT-260 treatment depended on the number of copies of functional SORL1 and which SORL1 variant was expressed. Using a disease-relevant preclinical model, our work illuminates how the SORL1-retromer pathway can be therapeutically harnessed., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Declaration of competing interest A.A.M. receives funds from the Strategic Research Program in Epidemiology at Karolinska Institutet, Forte (2020-00029), and Swedish Research Council (2021-02236). J.C.Y. receives funds from Cancerfonden (CAN 2018/703) and Forte (2021-00905). Outside of the work presented in this paper, T.K. reports having received research grants from the Gemeinsamer Bundesausschuss (G-BA–Federal Joint Committee, Germany), and the Bundesministerium für Gesundheit (BMG–Federal Ministry of Health, Germany). He further has received personal compensation from Eli Lilly and Company, the BMJ, and Frontiers.

Weekly and monthly CAM2038 (Brixadi ® ) extended-release subcutaneous buprenorphine (XR bup) has been available in Europe and Australia for several years and was approved by the Food and Drug Administration in May 2023. Little is known about the clinical experience of patients and providers using this new medication during prenatal care. Two cases of pregnant persons with opioid use disorder receiving weekly XR bup in an ongoing randomized multi-site outpatient clinical trial are presented along with a brief review of the pharmacology and literature on XR bup formulations. The cases in pregnancy illustrate how treatment with the weekly formulation is initiated including how to make dose adjustments, which may be necessary given the longer half-life; it takes 1 month to achieve steady state. Injection site pain with medication administration was time limited and managed readily. Other injection site reactions experienced included subcutaneous erythema and induration that was delayed in onset and typically mild, resolving with minimal intervention. Delivery management and breastfeeding recommendations while on weekly XR bup were not different compared to sublingual buprenorphine (SL bup). Weekly XR bup is a new treatment for opioid use disorder that may be used in the obstetric population. Obstetric and addiction medicine clinicians should be aware of this new formulation as its use is expected to increase., Competing Interests: Conflict of Interest Lofwall: research consultant for treatments in development for substance use disorder for Titan Pharmaceuticals, Journey Colab, Berkshire Biomedical and Braeburn. Wilder: none. Young: none. Gray: none. Guille: Visiting Scientist and Research Consultant for Maven Clinic. Leeman: none. Charles: serves as a medical consultant for Gilead Science Inc for hepatitis C treatment in pregnancy and RH Capital. Winhusen: none. Hansen: none. Wachman: none.

Many real-life treatments are of limited supply and cannot be provided to all individuals in the population. For example, patients on the liver transplant waiting list usually cannot be assigned a liver transplant immediately at the time they reach highest priority because a suitable organ is not immediately available. In settings with limited supply, investigators are often interested in the effects of treatment strategies in which a limited proportion of patients receive an organ at a given time, that is, treatment regimes satisfying resource constraints. Here, we describe an estimand that allows us to define causal effects of treatment strategies that satisfy resource constraints: incremental propensity score interventions (IPSIs) for limited resources. IPSIs flexibly constrain time-varying resource utilization through proportional scaling of patients' natural propensities for treatment, thereby preserving existing propensity rank ordering compared to the status quo. We derive a simple class of inverse-probability-weighted estimators, and we apply one such estimator to evaluate the effect of restricting or expanding utilization of "increased risk" liver organs to treat patients with end-stage liver disease., (© 2023 The Authors. Biometrics published by Wiley Periodicals LLC on behalf of International Biometric Society.)

Background: Influential studies conclude that each hour until antibiotics increases mortality in sepsis. However, these analyses often (1) adjusted for limited covariates, (2) included patients with long delays until antibiotics, (3) combined sepsis and septic shock, and (4) used linear models presuming each hour delay has equal impact. We evaluated the effect of these analytic choices on associations between time-to-antibiotics and mortality., Methods: We retrospectively identified 104 248 adults admitted to 5 hospitals from 2015-2022 with suspected infection (blood culture collection and intravenous antibiotics ≤24 h of arrival), including 25 990 with suspected septic shock and 23 619 with sepsis without shock. We used multivariable regression to calculate associations between time-to-antibiotics and in-hospital mortality under successively broader confounding-adjustment, shorter maximum time-to-antibiotic intervals, stratification by illness severity, and removing assumptions of linear hourly associations., Results: Changing covariates, maximum time-to-antibiotics, and severity stratification altered the magnitude, direction, and significance of observed associations between time-to-antibiotics and mortality. In a fully adjusted model of patients treated ≤6 hours, each hour was associated with higher mortality for septic shock (adjusted odds ratio [aOR]: 1.07; 95% CI: 1.04-1.11) but not sepsis without shock (aOR: 1.03; .98-1.09) or suspected infection alone (aOR: .99; .94-1.05). Modeling each hour separately confirmed that every hour of delay was associated with increased mortality for septic shock, but only delays >6 hours were associated with higher mortality for sepsis without shock., Conclusions: Associations between time-to-antibiotics and mortality in sepsis are highly sensitive to analytic choices. Failure to adequately address these issues can generate misleading conclusions., Competing Interests: Potential conflicts of interest. C. R. reports royalties from UpToDate, Inc, for chapters related to procalcitonin use; payments for an Associate Editor role at Clinical Infectious Diseases from the Infectious Diseases Society of America; and consulting fees from Cytovale related to sepsis diagnostics. M. K. reports royalties from UpToDate, Inc, for chapters related to hospital-acquired pneumonia and an institutional funding grant from the Massachusetts Department of Public Health. S. D. reports grants or contract payments from the CRICO Risk Management Foundation, the Eleanor Shore Award, and from Ce Symmetry for a CME (continuing medical education) course. J. Y. reports grants or contracts from the National Institutes of Health (NIH). All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Whether intubation should be initiated early in the clinical course of critically ill patients remains a matter of debate. Results from prior observational studies are difficult to interpret because of avoidable flaws including immortal time bias, inappropriate eligibility criteria, and unrealistic treatment strategies., Research Question: Do treatment strategies that intubate patients early in the critical care admission improve 30-day survival compared with strategies that delay intubation?, Study Design and Methods: We estimated the effect of strategies that require early intubation of critically ill patients compared with those that delay intubation. With data extracted from the Medical Information Mart for Intensive Care-IV database, we emulated three target trials, varying the flexibility of the treatment strategies and the baseline eligibility criteria., Results: Under unrealistically strict treatment strategies with broad eligibility criteria, the 30-day mortality risk was 7.1 percentage points higher for intubating early compared with delaying intubation (95% CI, 6.2-7.9). Risk differences were 0.4 (95% CI, -0.1 to 0.9) and -0.9 (95% CI, -2.5 to 0.7) percentage points in subsequent target trial emulations that included more realistic treatment strategies and eligibility criteria., Interpretation: When realistic treatment strategies and eligibility criteria are used, strategies that delay intubation result in similar 30-day mortality risks compared with those that intubate early. Delaying intubation ultimately avoids intubation in most patients., (Copyright © 2023 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

There is a large literature on work-related characteristics and hypertension, but studies on self-employment, longer working hours, and hypertension are mixed. Assessments of self-employment should be extended to account for people with part-time self-employment (i.e., employees also earning income from self-employment). The aim of this study was to determine the association of different types of self-employment with hypertension among adults by race/ethnicity and to assess whether longer working hours moderated these associations. Using data from the 2007-2018 National Health and Nutrition Examination Survey, measured hypertension (blood pressure ≥ 140/90 mm Hg) was assessed and employment categories included employees, part-time self-employment (i.e., employee with self-employment income), or full-time self-employment. Modified Poisson regressions and multiplicative interaction terms were used. Having full-time self-employment was associated with lower relative risk (RR) of hypertension compared to employees among Black (RR = 0.77, 95% confidence interval (CI) = 0.61-0.96) and White men (RR = 0.77, 0.65-0.93) compared to employees. Full-time self-employment was associated with higher risk of hypertension (RR = 1.36, 95% CI = 1.01-1.82) compared to employees among Hispanic women, while part-time self-employment was associated with lower risk (RR = 0.69, 95% CI = 0.48-0.98). Among White women, part-time self-employment was associated with higher relative risk of hypertension (RR = 1.27, 95% CI = 1.05-1.53) compared to employees. There were significant interactions between employment categories and longer working hours among Hispanic women as well as Black women and men. The results suggest that self-employment categories and longer working hours impact hypertension by race/ethnicity and sex. Because the number of full-time and part-time self-employed adults has increased, the health of this particular subgroup of workers should be further addressed., (© 2022. W. Montague Cobb-NMA Health Institute.)

Background: Per- and polyfluoroalkyl substances (PFAS) may disrupt mammary gland development and function; thereby inhibiting milk supply and breastfeeding duration. However, conclusions on the potential effects of PFAS and breastfeeding duration are limited by prior epidemiologic studies that inconsistently adjusted for past cumulative breastfeeding duration and by a lack of examination of the joint effects of PFAS mixtures., Methods: In Project Viva, a longitudinal cohort that enrolled pregnant participants from 1999 to 2002 in the greater Boston, MA area, we studied 1079 women who ever attempted to lactate. We investigated associations of plasma concentrations of select PFAS in early pregnancy (mean: 10.1 weeks gestation) with breastfeeding termination by 9 months, after which women typically cite self-weaning as the reason for terminating breastfeeding. We used Cox regression for single-PFAS models and quantile g-computation for mixture models, adjusting for sociodemographics, prior breastfeeding duration, and weeks of gestation at the time of blood draw., Results: We detected 6 PFAS [perfluorooctane sulfonate; perfluorooctanoate (PFOA); perfluorohexane sulfonate; perfluorononanoate; 2-(N-ethyl-perfluorooctane sulfonamido) acetate (EtFOSAA); 2-(N-methyl-perfluorooctane sulfonamide) acetate (MeFOSAA)] in >98 % of samples. Sixty percent of lactating women terminated breastfeeding by 9 months postpartum. Women with higher plasma concentrations of PFOA, EtFOSAA, and MeFOSAA had a greater hazard of terminating breastfeeding in the first 9 months postpartum [HR (95 % CI) per doubling concentration: 1.20 (1.04, 1.38) for PFOA; 1.10 (1.01, 1.20) for EtFOSAA; 1.18 (1.08, 1.30) for MeFOSAA]. In the quantile g-computation model, simultaneously increasing all PFAS in the mixture by one quartile was associated with 1.17 (95 % CI: 1.05, 1.31) greater hazard of terminating breastfeeding in the first 9 months., Conclusion: Our findings suggest that exposure to PFAS may be associated with reduced breastfeeding duration and draw further attention to environmental chemicals that may dysregulate human lactation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)