TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A.

Variants of UNC13A, a critical gene for synapse function, increase the risk of amyotrophic lateral sclerosis and frontotemporal dementia1-3, two related neurodegenerative diseases defined by mislocalization of the RNA-binding protein TDP-434,5. Here we show that TDP-43 depletion induces robust inclusion of a cryptic exon in UNC13A, resulting in nonsense-mediated decay and loss of UNC13A protein. Two common intronic UNC13A polymorphisms strongly associated with amyotrophic lateral sclerosis and frontotemporal dementia risk overlap with TDP-43 binding sites. These polymorphisms potentiate cryptic exon inclusion, both in cultured cells and in brains and spinal cords from patients with these conditions. Our findings, which demonstrate a genetic link between loss of nuclear TDP-43 function and disease, reveal the mechanism by which UNC13A variants exacerbate the effects of decreased TDP-43 function. They further provide a promising therapeutic target for TDP-43 proteinopathies.

Neuronal enhancers are hotspots for DNA single-strand break repair.

Defects in DNA repair frequently lead to neurodevelopmental and neurodegenerative diseases, underscoring the particular importance of DNA repair in long-lived post-mitotic neurons1,2. The cellular genome is subjected to a constant barrage of endogenous DNA damage, but surprisingly little is known about the identity of the lesion(s) that accumulate in neurons and whether they accrue throughout the genome or at specific loci. Here we show that post-mitotic neurons accumulate unexpectedly high levels of DNA single-strand breaks (SSBs) at specific sites within the genome. Genome-wide mapping reveals that SSBs are located within enhancers at or near CpG dinucleotides and sites of DNA demethylation. These SSBs are repaired by PARP1 and XRCC1-dependent mechanisms. Notably, deficiencies in XRCC1-dependent short-patch repair increase DNA repair synthesis at neuronal enhancers, whereas defects in long-patch repair reduce synthesis. The high levels of SSB repair in neuronal enhancers are therefore likely to be sustained by both short-patch and long-patch processes. These data provide the first evidence of site- and cell-type-specific SSB repair, revealing unexpected levels of localized and continuous DNA breakage in neurons. In addition, they suggest an explanation for the neurodegenerative phenotypes that occur in patients with defective SSB repair.

The active zone protein Clarinet regulates synaptic sorting of ATG-9 and presynaptic autophagy.

Autophagy is essential for cellular homeostasis and function. In neurons, autophagosome biogenesis is temporally and spatially regulated to occur near presynaptic sites, in part via the trafficking of autophagy transmembrane protein ATG-9. The molecules that regulate autophagy by sorting ATG-9 at synapses remain largely unknown. Here, we conduct forward genetic screens at single synapses of C. elegans neurons and identify a role for the long isoform of the active zone protein Clarinet (CLA-1L) in regulating sorting of autophagy protein ATG-9 at synapses, and presynaptic autophagy. We determine that disrupting CLA-1L results in abnormal accumulation of ATG-9 containing vesicles enriched with clathrin. The ATG-9 phenotype in cla-1(L) mutants is not observed for other synaptic vesicle proteins, suggesting distinct mechanisms that regulate sorting of ATG-9-containing vesicles and synaptic vesicles. Through genetic analyses, we uncover the adaptor protein complexes that genetically interact with CLA-1 in ATG-9 sorting. We also determine that CLA-1L extends from the active zone to the periactive zone and genetically interacts with periactive zone proteins in ATG-9 sorting. Our findings reveal novel roles for active zone proteins in the sorting of ATG-9 and in presynaptic autophagy.

Moving beyond the mean: Promising research pathways to support a precision medicine approach to hormonal contraception.

Women's psychological and behavioral responses to hormonal contraceptive (HC) treatment can be highly variable. One of the great challenges to researchers seeking to improve the experiences of women who use HCs is to identify the sources of this variability to minimize unpleasant psychobehavioral side-effects. In the following, we provide recommendations for programs of research aimed at identifying sources of heterogeneity in women's experiences with HC. First, we review research demonstrating person- and prescription- based heterogeneity in women's psychobehavioral responses to HCs. Next, we identify several promising person- and prescription- based sources of this heterogeneity that warrant future research. We close with a discussion of research approaches that are particularly well-suited to address the research questions raised in article. Together, this review provides researchers with several promising research pathways to help support the development of a precision medicine approach to HC treatment.

Hormonal contraceptive use is associated with differences in women's inflammatory and psychological reactivity to an acute social stressor.

Women using hormonal contraceptives (HCs) exhibit numerous signs of chronic inflammation, including elevated C-reactive protein levels and greater risk of developing mood and autoimmune disorders. However, users and non-users of HCs often have similar circulating proinflammatory cytokine levels, making the mechanism of association unclear. One possible explanation for this paradox is that HC users exhibit differences in their inflammatory responses to psychosocial stress that, over time, could contribute to chronic inflammation and its pathologies. Here, we tested this possibility by examining women's glucocorticoid, inflammatory, and psychological responses to the Trier Social Stress Test (TSST) in 67 naturally cycling (NC) and 60 oral HC-using women (Mage = 19.31, SDage = 1.95). As hypothesized, HC users and NC women exhibited different glucocorticoid and proinflammatory cytokine responses to the TSST. For NC women, TSST-induced increases in glucocorticoids were uncommon, and increases in glucocorticoids were accompanied by elevations in IL-6. In contrast, for women using HCs, increases in glucocorticoids in response to the TSST were common, and increases in glucocorticoids were accompanied by increases in TNF-α. HC users and NC women also differed in their psychological responses to the TSST, with HC users reporting elevated stress levels compared to NC women. Together, these results suggest that HC use impacts women's glucocorticoid, inflammatory, and psychological responses to psychosocial stress, potentially contributing to observed differences in these women's mental and physical health.

Longitudinal changes in sexual desire and attraction among women who started using the Natural Cycles app.

Many women experience sexual side effects, such as decreased libido, when taking hormonal contraceptives (HCs). However, little is known about the extent to which libido recovers after discontinuing HCs, nor about the timeframe in which recovery is expected to occur. Given that HCs suppress the activities of multiple endogenous hormones that regulate both the ovulatory cycle and women's sexual function, resumption of cycles should predict libido recovery. Here, using a combination of repeated and retrospective measures, we examined changes in sexual desire and partner attraction (among partnered women) across a three-month period in a sample of Natural Cycles users (Survey 1: n = 1596; Survey 2: n = 550) who recently discontinued HCs. We also tested whether changes in these outcomes coincided with resumption of the ovulatory cycle and whether they were associated with additional factors related to HC use (e.g., duration of HC use) or relationship characteristics (e.g., relationship length). Results revealed that both sexual desire and partner attraction, on average, increased across three months after beginning to use Natural Cycles. While the prediction that changes in sexual desire would co-occur with cycle resumption was supported, there was also evidence that libido continued to increase even after cycles resumed. Together, these results offer new insights into relationships between HC discontinuation and women's sexual psychology and lay the groundwork for future research exploring the mechanisms underlying these effects.

The Impact of a Digital Contraceptive Decision Aid on User Outcomes: Results of an Experimental, Clinical Trial.

BACKGROUND: Nearly 40% of unplanned pregnancies in the USA are the result of inconsistent or incorrect contraceptive use. Finding ways to increase women's comfort and satisfaction with contraceptive use is therefore critical to public health. One promising pathway for improving patient outcomes is through the use of digital decision aids that assist women and their physicians in choosing a contraceptive option that women are comfortable with. Testing the ability of these aids to improve patient outcomes is therefore a necessary first step toward incorporating this technology into traditional physician appointments. PURPOSE: To evaluate the effectiveness of a novel contraceptive decision aid at minimizing decisional conflict and increasing comfort with contraception among adult women. METHODS: In total, 310 adult women were assigned to use either the Tuune contraceptive decision aid or a control aid modeled after a leading online contraceptive prescriber's patient intake form. Participants then completed self-report measures of decisional conflict, contraceptive expectations, satisfaction, and contraceptive use intentions. Individual between-subjects analysis of variance (ANOVA) models were used to examine these outcomes. RESULTS: Women using the Tuune decision aid (vs. those using the control aid) reported lower decisional conflict, more positive contraceptive expectations, greater satisfaction with the decision aid and recommendation, and more positive contraceptive use intentions. CONCLUSIONS: Use of Tuune improved each of the predicted patient outcomes relative to a control decision aid. Online decision aids, particularly when used alongside physician consultations, may be an effective tool for increasing comfort with contraceptive use. CLINICAL TRIALS REGISTRATION #: NCT05177783, ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT05177783.

Digital decision aids that help women and their physicians choose contraceptive options that women are most comfortable with present one promising way to improve contraceptive use outcomes, such as avoiding unplanned pregnancies. However, current decision aids have been found to struggle in helping improve women's satisfaction with and confidence in their contraceptive choices. The aim of this study was to test the effectiveness of a new digital decision aid, named Tuune, at helping improve women's confidence and comfort with contraception. Three hundred and ten adult women were randomly assigned to use and then receive a contraceptive recommendation from either the Tuune decision aid or a control aid designed after leading traditional health intake forms. Women's confidence and satisfaction with the aids, as well as their contraceptive recommendation, were then compared between groups. We found good evidence to suggest that women using the Tuune contraceptive decision aid were more satisfied and positive about their contraceptive choices and reported greater intentions to use contraception with increased confidence compared to women who used the control decision aid. New online decision aids, like Tuune, may be an effective tool for increasing women's comfort and experiences using contraception.

Association Between Clinical Encounter Frequency and HIV-Related Stigma Among Newly-Diagnosed People Living with HIV in Rwanda.

HIV-related stigma in healthcare settings remains a key barrier to engaging people living with HIV (PLHIV) in care. This study investigated the association between clinical encounter frequency and HIV-related anticipated, enacted, and internalized stigma among newly-diagnosed PLHIV in Rwanda. From October 2020 to May 2022, we collected data from adult PLHIV on antiretroviral therapy (ART) in Kigali, Rwanda who were participating in a randomized, controlled trial testing early entry into differentiated care at 6 months after ART initiation. We measured anticipated HIV stigma with five-point Likert HIV Stigma Framework measures, enacted stigma with the four-point Likert HIV/AIDS Stigma Instrument, and internalized stigma with the four-point Likert HIV/AIDS Stigma Instrument. We used multivariable linear regression to test the associations between clinical encounter frequency (average inter-visit interval ≥ 50 days vs. < 50 days) and change in mean anticipated, enacted and internalized HIV stigma over the first 12 months in care. Among 93 individuals enrolled, 76 had complete data on encounter frequency and stigma measurements and were included in the present analysis. Mean internalized stigma scores of all participants decreased over the first 12 months in care. Anticipated and enacted stigma scores were low and did not change significantly over time. There was no association between encounter frequency and change in internalized stigma. In this pilot study of newly-diagnosed Rwandan PLHIV with relatively low levels of HIV-related stigma, clinical encounter frequency was not associated with change in stigma. Additional research in diverse settings and with larger samples is necessary to further explore this relationship.

Design of a Novel Orthodontic Appliance to Prevent Pedicle Trauma in Patients Undergoing Double-Opposing Buccal Flaps for Palatal Lengthening.

OBJECTIVE: To describe a novel orthodontic appliance to prevent pedicle trauma in patients undergoing double-opposing buccal flap surgery for secondary palatal lengthening. DESIGN: Case series. SETTING: Cleft and craniofacial clinic, Johns Hopkins Children's Center. PATIENTS, PARTICIPANTS: Four patients undergoing double-opposing buccal flap surgery for repair of velopharyngeal insufficiency. INTERVENTIONS: Patients were fitted with the device, which consists of a lower lingual holding arch with acrylic bite blocks. MAIN OUTCOME MEASURE: Presence of pedicle trauma postsurgery and tolerability of the device. RESULTS: The appliance was well tolerated in all 4 patients and no biting trauma to the pedicles was observed. CONCLUSIONS: A reliable appliance has been developed to prevent biting trauma to the pedicles in patients undergoing double-opposing buccal flap surgery in the permanent dentition stage.

More than just a pretty face? The relationship between immune function and perceived facial attractiveness.

It has long been hypothesized that attractiveness provides a cue to a target's health and immunocompetence. However, much of the research testing this hypothesis has relied on a small number of indirect proxies of immune function, and the results of this research have been mixed. Here, we build on this past research, examining the relationship between target attractiveness and (i) self-reported health, (ii) in vivo measures of inflammation and white blood cell count/composition, and (iii) in vitro tests of targets' immune function, including (c1) leucocyte proliferation in response to immunological stimulants, (c2) phagocytosis of Escherichia coli bioparticles, (c3) NK cell-mediated lysis of target tumour cells, and (c4) Staphylococcus aureus growth in isolated plasma. Results revealed multiple, sometimes sex-differentiated, relationships between targets' immune function and others' perceptions of their attractiveness. Together, this work suggests complex, often sex-differentiated relationships between immune function, health, and attractiveness.

Development of an Open-Access Webinar Series on Pathways for Global Surgery Engagement for Applicants to US Residency Programs.

BACKGROUND: Global surgery (GS) training pathways in residency are unclear and vary by specialty and program. Furthermore, information on these pathways is not always accessible. To address this gap, we produced a collection of open-access webinars for senior medical students focused on identifying GS training pathways during residency. METHODS: The Global Surgery Student Alliance (GSSA) is a national nonprofit that engages US students and trainees in GS education, research, and advocacy. GSSA organized nine one-hour, specialty-specific webinars featuring residents of surgical specialties, anesthesia, and OBGYN programs. Live webinars were produced via Zoom from August to October 2020, and all recordings were posted to the GSSA YouTube channel. Medical students moderated webinars with predetermined standardized questions and live questions submitted by attendees. Participant data were collected in mandatory registration forms. RESULTS: A total of 539 people were registered for 9 webinars. Among registrants, 189 institutions and 36 countries were represented. Registrants reported education/training levels from less than undergraduate education to attending physicians, while medical students represented the majority of registrants. Following the live webinars, YouTube recordings of the events were viewed 839 times. Webinars featuring otolaryngology and general surgery residents accrued the greatest number of registrations, while anesthesia accrued the least. CONCLUSIONS: Medical students at all levels demonstrated interest in both the live and recorded specialty-specific webinars on GS in residency. To address the gap in developing global surgery practitioners, additional online, open-access education materials and mentorship opportunities are needed for students applying to US residencies.

From silos to policy coherence: tobacco control, unhealthy commodity industries and the commercial determinants of health.

Tobacco control has achieved remarkable successes, underpinned by the distinctive norms codified in Article 5.3 of the WHO Framework Convention on Tobacco Control. Tobacco control's experience in managing conflicts of interest is increasingly recognised as relevant for addressing other non-communicable disease epidemics. At the same time, the wider environmental and social harms of tobacco-and other unhealthy commodity industries-underline the potential for enhanced strategic collaboration across health, development and environmental agendas. Such collaboration is increasingly necessary to address key challenges shared across tobacco control and related policy spheres, including the extent to which the harms of tobacco (and other unhealthy commodities) are underpinned by economic and social inequities. Here we demonstrate the relevance of a commercial determinants of health perspective, both for advancing tobacco control and for linking it with health and development more broadly. This perspective is already evident in many areas of research, policy and advocacy, where innovative approaches support the development of closer links with actors in related fields. We draw on the concepts of policy coordination, coherence and integration to show how tobacco control can advance key strategic goals via information sharing, complementary approaches to common problems and collective action with other related movements. Embrace of a commercial determinants perspective will help in building on tobacco control's successes and reorienting strategies in other sectors to more effectively manage health risks and promote sustainable development.

Challenges of conflict of interest, coordination and collaboration in small island contexts: towards effective tobacco control governance in UK Overseas Territories.

INTRODUCTION: The UK Overseas Territories (UKOTs) are semi-autonomous jurisdictions that face distinctive challenges in implementing tobacco control and protecting policy from industry influence. They are not eligible to become independent parties of the WHO Framework Convention on Tobacco Control (FCTC), although they can apply for treaty extension under the UK's ratification. This study explores the relevance of the FCTC-particularly Article 5.3-for tobacco control governance across a sample of UKOTs. METHODS: From March to May 2019, we interviewed 32 stakeholders across four territories (Anguilla, Bermuda, Cayman Islands, St Helena) at diverse stages in implementing key FCTC measures. Thematic qualitative analysis explored awareness and perceptions in relation to tobacco control. RESULTS: Interviewees' accounts highlight the complexity of protecting health policy from industry influence in a context where the 'tobacco industry' covers a diverse range of actors. Despite not being formally covered by the FCTC, several health officials spoke about the strategic value of invoking Article 5.3 in the context of tensions with economic priorities. Nevertheless, effective tobacco control governance is complicated by territories' reliance on local businesses-including tourism-and close social connections that occasionally blur the lines between private and public spheres. CONCLUSIONS: The UKOTs share many characteristics with other small island jurisdictions, creating distinctive challenges for advancing tobacco control and protecting policy from industry interference. Despite their complex status in relation to WHO and its architecture, these territories benefit from the norms embedded in the FCTC and the systems that support its implementation.

'Choice should be made through educated decisions not regressive dictates': discursive framings of a proposed 'sugar tax' in Bermuda: analysis of submissions to a government consultation.

BACKGROUND: Several governments have introduced taxes on products with high sugar content as part of their obesity prevention strategies. Bermuda is the first jurisdiction to apply such measures in the Caribbean - a region of small island developing states and territories with high obesity prevalence and substantial reliance on imported food products. This study examines how commercial and health actors framed the proposed introduction of a 75% import tariff on high-sugar products, based on written submissions to the Bermudan government. METHODS: Eleven submissions containing written comments were analysed with reference to their framing of the proposed import tariff, the 'problem' of obesity, and the relationship between the two (including alternative policy approaches for tackling obesity). RESULTS: Key emergent frames were complexity, partnership, products, personal responsibility, affordability and evidence. Respondents favoured different framings, depending on whether they supported or opposed the proposed import duty. Commercial actors were universally opposed, presenting obesity as a 'complex' problem that would be better addressed through government-industry partnerships (a framing particularly favoured by international and regional business associations). Increased product range and an emphasis on personal responsibility were also positioned as policy alternatives. Health actors expressed partial support for the proposed sugar tax, although this was tempered by a perceived lack of evidence where the proposal differed from sugar taxes introduced elsewhere. Like commercial respondents, health actors framed obesity as a 'complex' problem and emphasised the need for other measures, including efforts to address the affordability of fruits and vegetables. CONCLUSION: In responding to a proposed 'sugar tax' in Bermuda, commercial actors opposed the proposal and stated a clear preference for 'partnership' approaches to tackling obesity. Commercial responses were dominated by local businesses (with only two responses received from international or regional business associations), perhaps reflecting Bermuda's reliance on tourism and hospitality and the specificity of the proposed intervention (that is, an import tariff rather than an excise tax). The much smaller number of responses from health actors suggests limited civil society capacity. Nevertheless, the Bermudan government successfully introduced a 75% tariff on high-sugar imports, demonstrating the potential for policy innovation to address obesity in small-island jurisdictions.

Early life adversity, inflammation, and immune function: An initial test of adaptive response models of immunological programming.

Much research indicates that exposure to early life adversity (ELA) predicts chronic inflammatory activity, increasing one's risk of developing diseases of aging later in life. Despite its costs, researchers have proposed that chronic inflammation may be favored in this context because it would help promote immunological vigilance in environments with an elevated risk of infection and injury. Although intuitively appealing, the assumption that exaggerated inflammatory activity predicts favorable immunological outcomes among those exposed to ELA has not been tested. Here, we seek to address this gap, examining the links between exposure to ELA, inflammation, and immune function. Consistent with others' work, results revealed that those from low socioeconomic status (SES) childhood environments exhibited exaggerated unstimulated inflammatory activity relative to what was observed among those from higher SES childhood environments. Further, results revealed that - although levels of inflammation predicted the magnitude of immunological responses in those from higher SES backgrounds - for those who grew up in low SES environments, higher levels of inflammation were unrelated to the magnitude of immunological responses. Results suggest that exaggerated inflammatory activity in the context of ELA may not predict improved ability to manage acute immunological threats.

Accumulation of the Toxic Metal Mercury in Multiple Tissues of Marine-Associated Birds from South Florida.

One of the best studied global "hot spots" for ecological mercury (Hg) contamination is south Florida (USA), where elevated Hg concentrations in environmental media and regional wildlife were first described over thirty years ago. While Hg contamination has lessened in this region, it is still critical to monitor Hg uptake and potential risks in south Florida wildlife, especially in marine-associated birds, which are known to accumulate potentially toxic Hg levels. In this study, total Hg (THg) concentrations were measured in liver, kidney, muscle, and feathers of 101 individuals from seven species of south Florida birds: brown pelican Pelecanus occidentalis, double-crested cormorant Phalacrocorax auratus, herring gull Larus argentatus, laughing gull Leucophaeus atricilla, northern gannet Morus bassanus, royal tern Thalasseus maximus, and osprey Pandion halietus. A sizeable proportion of individuals (> 40%) were found to contain THg concentrations in internal tissues that exceeded estimated toxicity thresholds for Hg-related effects. Certain species, especially osprey, were found to exhibit a higher rate of threshold exceedances than others and should continue to be monitored for Hg-related effects in future studies. Feather THg concentrations exhibited a lower rate of toxicity threshold exceedances (12%) and were not significantly correlated with those in internal tissues in most cases, suggesting that they may not be well suited for monitoring Hg exposure in these species unless sources of data variation can be better understood. The results of the present study contribute significantly to our understanding of trends in Hg accumulation and Hg-related health risks in south Florida marine-associated birds.

Exploring the Links between Personality and Immune Function.

Decades of research finds associations between personality traits and health. In recent years, it has become clear that the activities of the immune system play a key role in linking these variables. In the current work, we add to this research by exploring the relationship between Big Five personality traits and (Study 1) polymorphisms known to impact cytokine release and (Study 2) immunological parameters measured in vivo (differential white blood cell counts, plasma proinflammatory cytokine levels) and in vitro (proinflammatory cytokine release by peripheral blood mononuclear cells, Staphylococcus aureus growth in plasma). Results provide insights into potential mechanistic drivers of the link between personality and immune function and the possibility that, in some cases, relationships between personality and immune function may be sex differentiated.

The Nature and Evolution of the Mentoring Relationship in Academic Health Centers.

Mentoring has a long tradition in academic health centers, and from an institutional perspective can positively impact retention, wellness, promotion success, work satisfaction, and more. On the individual level, mentorship can provide professional growth and personal satisfaction for both participants. However, mentors may struggle with how to build their mentorship skills, navigating challenges with mentees over time, or if/how/when to conclude a mentor-mentee relationship. Mentees may not understand how to find a mentor, what the nature of that relationship is, or what their role is (what characterizes a "good" mentee). As important as mentorship is, it can be challenging for both to find and maintain a high-quality mentor-mentee relationship. This article reviews the qualities that are most critical in developing a successful mentoring relationship, the longitudinal nature of this relationship, common problems that arise, and the potential rewards that exist for each person involved in the relationship.

Effects of Fathers on Adolescent Daughters' Frequency of Substance Use and Risky Sexual Behavior.

This research: (1) implements a genetically informed design to examine the effects of fathers' presence-absence and quality of behavior during childhood/adolescence on daughters' frequency of substance use during adolescence; and (2) tests substance use frequency as mediating the relation between paternal behavior and daughters' sexual risk taking. Participants were 223 sister dyads from divorced/separated biological families. Sisters' developmental exposure to socially deviant paternal behavior predicted their frequency of tobacco, alcohol, and cannabis (TAC) use. Older sisters who co-resided with fathers who were more (vs. less) socially deviant reported more frequent TAC use during adolescence. More frequent TAC use predicted more risky sexual behavior for these daughters. No effects were found for younger sisters, who spent less time living with their fathers.