Aims/hypothesis A type 2 diabetes-risk-increasing variant, MTNR1B (melatonin receptor 1B) rs10830963, regulates the circadian function and may influence the variability in metabolic responses to dietary carbohydrates. We investigated whether the effects of carbohydrate quantity and dietary glycaemic index (GI) on glycaemic response during OGTTs varied by the risk G allele of MTNR1B-rs10830963. Methods This study included participants (n=150) of a randomised crossover-controlled feeding trial of four diets with high/low GI levels and high/low carbohydrate content for 5 weeks. The MTNR1B-rs10830963 (C/G) variant was genotyped. Glucose response during 2 h OGTT was measured at baseline and the end of each diet intervention. Results Among the four study diets, carrying the risk G allele (CG/GG vs CC genotype) of MTNR1B-rs10830963 was associated with the largest AUC of glucose during 2 h OGTT after consuming a high-carbohydrate/high-GI diet (β 134.32 [SE 45.69] mmol/l × min; p=0.004). The risk G-allele carriers showed greater increment of glucose during 0–60 min (β 1.26 [0.47] mmol/l; p=0.008) or 0–90 min (β 1.10 [0.50] mmol/l; p=0.028) after the high-carbohydrate/high-GI diet intervention, but not after consuming the other three diets. At high carbohydrate content, reducing GI levels decreased 60 min post-OGTT glucose (mean –0.67 [95% CI: –1.18, –0.17] mmol/l) and the increment of glucose during 0–60 min (mean –1.00 [95% CI: –1.67, –0.33] mmol/l) and 0–90 min, particularly in the risk G-allele carriers (pinteraction <0.05 for all). Conclusions/interpretation Our study shows that carrying the risk G allele of MTNR1B-rs10830963 is associated with greater glycaemic responses after consuming a diet with high carbohydrates and high GI levels. Reducing GI in a high-carbohydrate diet may decrease post-OGTT glucose concentrations among the risk G-allele carriers. Graphical Abstract
Background Diabetes and diabetes complications are on the rise in US adults aged <65 years, while onset of menarche at a younger age is also increasing. We examined the associations of age at menarche with type 2 diabetes among women aged <65 years and with cardiovascular disease (CVD) complications among women with diabetes. Methods Using the nationally representative cross-sectional National Health and Nutrition Examination Survey 1999–2018, women aged 20–65 years free of cancer were included in the current analysis. Diabetes was defined as a self-reported diabetes diagnosis. CVD was defined as coronary heart disease or stroke. Age at menarche was self-reported age of first menstruation and categorised into ≤10, 11, 12, 13, 14 and ≥15 years. Results Of 17 377 women included in the analysis, 1773 (10.2%) reported having type 2 diabetes. Earlier age at menarche was associated with type 2 diabetes compared with median age at menarche of 13 years, after adjustment for age, race/ethnicity, education, parity, menopause status and family history of diabetes, smoking status, physical activity, alcohol consumption and body mass index (p for trend=0.02). Among women with diabetes, earlier age at menarche was associated with stroke with similar adjustment (p for trend=0.03), but not with total CVD. Extremely early age at menarche (≤10 years) was significantly associated with stroke (adjusted OR 2.66 (95% CI 1.07 to 6.64)) among women aged <65 years with diabetes with similar adjustment. Conclusions Earlier age at menarche was associated with type 2 diabetes among young and middle-aged women in the USA and with stroke complications among these women living with diabetes.
Objective Black/African American women with systemic lupus erythematosus (SLE) experience greater organ damage and at younger ages than white women. The objective of this study was to advance research on SLE inequities by identifying sociodemographic risk profiles associated with organ damage accrual specifically among Black/African American women. Methods Latent profile analysis was conducted among 438 Black/African American women with SLE living in Atlanta, GA and enrolled in the Black Women’s Experiences Living with Lupus (BeWELL) Study (May 2015 to April 2017). Proportional hazard and Poisson regression models examined prospective associations between sociodemographic profiles and the timing and degree of organ damage accrual over 2 years. Results Four profiles emerged: (1) “Younger/Lower SES with Uncontrolled SLE” (44.8%), (2) “Older/Lower SES with Uncontrolled SLE” (23.3%), (3) “Mid-SES with Controlled SLE” (19.6%), and (4) “Higher SES with Controlled SLE” (11.2%). Approximately 42% of participants experienced new organ damage during the follow-up period. Proportional hazard models indicated that “Older/Lower SES with Uncontrolled SLE” participants were at greatest risk of new organ damage (HR = 2.41; 95% CI = 1.39, 4.19), followed by “Younger/Lower SES with Uncontrolled SLE” participants (HR = 1.56; 95% CI = 0.92, 2.67), compared to those in the “Higher SES with Controlled SLE” profile. Poisson regression models revealed that these two groups also exhibited greater organ damage accrual (b = 0.98, SE = 0.24, 95% CI = 0.52, 1.44 and b = 0.72, SE = 0.23, 95% CI = 0.27, 1.17, respectively). Conclusions Black/African American women with fewer socioeconomic resources and uncontrolled SLE are at greatest risk for increasing disease severity over time. Social inequities likely contribute to racial inequities in SLE progression.
In this paper, we challenge the standard interpretation of pain asymbolia (PA), a neuropsychiatric condition that causes unusual reactions to pain stimuli. The standard interpretation asserts that PA subjects experience pain but lack important features of the experience. However, the paper argues that the clinical evidence for PA does not support this interpretation and that the arguments put forward by the defenders of the standard interpretation end up making self-contradicting claims. Finally, we suggest that the best interpretation of the available evidence is to take a deflationist stance toward PA, at least until further evidence becomes available.
Outreach Training and Supportive Supervision (OTSS) of malaria services at health facilities has been adopted by numerous malaria-endemic countries. The OTSS model is characterized by a hands-on method to enhance national guidelines and supervision tools, train supervisors, and perform supervision visits. An independent evaluation was conducted to evaluate the effectiveness of OTSS on health worker competence in the clinical management of malaria, parasitological diagnosis, and prevention of malaria in pregnancy. From 2018 to 2021, health facilities in Cameroon, Ghana, Niger, and Zambia received OTSS visits during which health workers were observed directly during patient consultations, and supervisors completed standardized checklists to assess their performance. Mixed-effects logistic regression models were developed to assess the impact of increasing OTSS visit number on a set of eight program-generated outcome indicators, including overall competency and requesting a confirmatory malaria test appropriately. Seven of eight outcome indicators showed evidence of beneficial effects of increased OTSS visits. Odds of health workers reaching competency thresholds for the malaria-in-pregnancy checklist increased by more than four times for each additional OTSS visit (odds ratio [OR], 4.62; 95% CI, 3.62–5.88). Each additional OTSS visit was associated with almost four times the odds of the health worker foregoing antimalarial prescriptions for patients who tested negative for malaria (OR, 3.80; 95% CI, 2.35–6.16). This evaluation provides evidence that successive OTSS visits result in meaningful improvements in indicators linked to quality case management of patients attending facilities for malaria diagnosis and treatment, as well as quality malaria prevention services received by women attending antenatal services.
Measures of substance concentration in urine, serum or other biological matrices often have an assay limit of detection. When concentration levels fall below the limit, exact measures cannot be obtained, and thus are left censored. The problem becomes more challenging when the censored data come from heterogeneous populations consisting of exposed and non‐exposed subjects. If the censored data come from non‐exposed subjects, their measures are always zero and hence censored, forming a latent class governed by a distinct censoring mechanism compared with the exposed subjects. The exposed group's censored measurements are always greater than zero, but less than the detection limit. It is very often that the exposed and non‐exposed subjects may have different disease traits or different relationships with outcomes of interest, so we need to disentangle the two different populations for valid inference. In this article, we aim to fill the methodological gaps in the literature by developing a novel joint modeling approach to not only address the censoring issue in predictors, but also untangle different relationships of exposed and non‐exposed subjects with the outcome. Simulation studies are performed to assess the numerical performance of our proposed approach when the sample size is small to moderate. The joint modeling approach is also applied to examine associations between plasma metabolites and blood pressure in Bogalusa Heart Study, and identify new metabolites that are highly associated with blood pressure.
Background Cervical cancer is preventable with vaccination and early detection and treatment programs. However, for these programs to work as intended, stigma related to HPV and cervical cancer must be understood and addressed. We explored pre-existing stigma associated with HPV and cervical cancer in the public healthcare system and community of a low-resource setting prior to implementation of an HPV screen-and-treat program. Methods This study conducted thematic analysis of data collected during implementation of a novel HPV screen-and-treat system for cervical cancer early detection and treatment in Iquitos, Peru. We included 35 semi-structured interviews (19 health professionals, 16 women with cervical precancer or cancer), eight focus groups (70 community women), one workshop (14 health professionals), 210 counseling observations (with 20 nurse-midwives), and a document review. We used the Socio-Ecological Model to organize the analysis. Results We identified three main themes: 1. the implication that women are to blame for their HPV infection through characterizations of being easy or promiscuous, 2. the implication that men are to blame for women’s HPV infections through being considered careless or unfaithful, 3. HPV is shameful, embarrassing, and something that should be hidden from others. Consequently, in some cases, women refrained from getting screened for HPV. These themes were seen at the individual level among women, relationship level among women, men, and family members, community level among healthcare staff, and societal level within components of cervical cancer guidelines and male chauvinism. Conclusions Cervical cancer early detection and treatment programs in limited resource settings must address stigma entrenched throughout the entire healthcare system and community in order to sustainably and successfully implement and scale-up new programs. Interventions to tackle this stigma can incorporate messages about HPV infections and latency to lessen the focus on the influence of sexual behavior on HPV acquisition, and instead, promote screening and treatment as paramount preventative measures.
Aims The aim of this study was to establish consensus statements on medial patellofemoral ligament (MPFL) reconstruction, anteromedialization tibial tubercle osteotomy, trochleoplasty, and rehabilitation and return to sporting activity in patients with patellar instability, using the modified Delphi process. Methods This was the second part of a study dealing with these aspects of management in these patients. As in part I, a total of 60 surgeons from 11 countries contributed to the development of consensus statements based on their expertise in this area. They were assigned to one of seven working groups defined by subtopics of interest. Consensus was defined as achieving between 80% and 89% agreement, strong consensus was defined as between 90% and 99% agreement, and 100% agreement was considered unanimous. Results Of 41 questions and statements on patellar instability, none achieved unanimous consensus, 19 achieved strong consensus, 15 achieved consensus, and seven did not achieve consensus. Conclusion Most statements reached some degree of consensus, without any achieving unanimous consensus. There was no consensus on the use of anchors in MPFL reconstruction, and the order of fixation of the graft (patella first versus femur first). There was also no consensus on the indications for trochleoplasty or its effect on the viability of the cartilage after elevation of the osteochondral flap. There was also no consensus on postoperative immobilization or weightbearing, or whether paediatric patients should avoid an early return to sport. Cite this article: Bone Joint J 2023;105-B(12):1265–1270.
I offer two objections to luck egalitarianism. The no-adequate-account objection takes note of the egalitarian insistence that the disvalue of inequality is only one of a plurality of values or disvalues that needs to be considered in arriving at a judgment about the ranking of alternative distributions of welfare. This turn to pluralism places a reasonable demand upon luck egalitarianism to provide an account of how the different sorts of values or disvalues that are supposed to attach to available distributions of welfare are to be aggregated or weighed against one another in that ranking procedure. I contend that the prospects for developing such an account are dim and that some salient responses to this objection misfire. The churlishness-envy objection against luck egalitarianism is that this doctrine countenances envy directed toward the faultless good fortune of others. This objection places a reasonable demand on luck egalitarians to formulate a version of their doctrine that does not underwrite envious responses toward those who gain through brute good luck. I contend that the most auspicious path toward satisfying the demand not to underwrite churlish envy advances a luck egalitarianism that asymmetrically affirms the badness of arbitrary disadvantage rather than the badness of both arbitrary disadvantage and arbitrary advantage. Since this is the strategy pursued in Shlomi Segall’s Why Inequality Matters, I offer critiques of Segall’s initial and revised versions of asymmetrical egalitarianism in support of my conclusion that luck egalitarianism seems unable to rebut or sidestep the churlishness-envy objection. I conclude that luck egalitarianism seems unable to satisfy either of the two reasonable demands upon it that I raise.
Erosional perturbations from changes in climate or tectonics are recorded in the profiles of bedrock rivers, but these signals can be challenging to unravel in settings with non-uniform lithology. In horizontally layered rocks, the surface lithology at a given location varies through time as different layers of rock are exposed. Recent modeling studies have used the Stream Power Model (SPM) to highlight complex variations in erosion rates that arise in bedrock rivers incising through layered rocks. However, these studies do not capture the effects of coarse sediment load on channel evolution. We use the “Stream Power with Alluvium Conservation and Entrainment” (SPACE) model to explore how sediment cover influences landscape evolution and modulates the topographic expression of erodibility contrasts in horizontally layered rocks. We simulate river evolution through alternating layers of hard and soft rock over million-year timescales, with a constant uplift rate of 1 mm/year. Compared to the SPM, model runs with sediment cover have systematically higher channel steepness values in soft rock layers and lower channel steepness values in hard rock layers. As sediment cover effects increase, the contrast in steepness between the two rock types decreases. Effective bedrock erodibilities back-calculated assuming the SPM are strongly influenced by sediment cover. We also find that sediment cover can significantly increase total relief and timescales of adjustment towards landscape-averaged steady-state topography and erosion rates.
Background In 2020, the Zambia National Malaria Elimination Centre targeted the distribution of long-lasting insecticidal nets (LLINs) and indoor-residual spraying (IRS) campaigns based on sub-district micro-planning, where specified geographical areas at the health facility catchment level were assigned to receive either LLINs or IRS. Using data from the 2021 Malaria Indicator Survey (MIS), the objectives of this analysis were to (1) assess how well the micro-planning was followed in distributing LLINs and IRS, (2) investigate factors that contributed to whether households received what was planned, and (3) investigate how overall coverage observed in the 2021 MIS compared to the 2018 MIS conducted prior to micro-planning. Methods Households’ receipt of ≥ 1 LLIN, and/or IRS within the past 12 months in the 2021 MIS, was compared against the micro-planning area under which the households fell. GPS points for 3,550 households were overlayed onto digitized micro-planning maps in order to determine what micro-plan the households fell under, and thus whether they received their planned intervention. Mixed-effects regression models were conducted to investigate what factors affected whether these households: (1) received their planned intervention, and (2) received any intervention. Finally, coverage indicators between the 2021 and 2018 MIS were compared. Results Overall, 60.0% (95%CI 55.4, 64.4) of households under a micro-plan received their assigned intervention, with significantly higher coverage of the planned intervention in LLIN-assigned areas (75.7% [95%CI 69.5, 80.9]) compared to IRS-assigned areas (49.4% [95%CI: 44.4, 54.4]). Regression analysis indicated that households falling under the IRS micro-plan had significantly reduced odds of receiving their planned intervention (OR: 0.34 [95%CI 0.24, 0.48]), and significantly reduced odds of receiving any intervention (OR: 0.51 [95%CI 0.37, 0.72] ), compared to households under the LLIN micro-plan. Comparison between the 2021 and 2018 MIS indicated a 27% reduction in LLIN coverage nationally in 2021, while IRS coverage was similar. Additionally, between 2018 and 2021, there was a 13% increase in households that received neither intervention. Conclusions This analysis shows that although the micro-planning strategy adopted in 2020 worked much better for LLIN-assigned areas compared to IRS-assigned areas, there was reduced overall vector control coverage in 2021 compared to 2018 before micro-planning.
Background The occurrence of behavioral health emergencies (BHEs) in children is increasing in the United States, with patient presentations to Emergency Medical Services (EMS) behaving similarly. However, detailed evaluations of EMS encounters for pediatric BHEs at the national level have not been reported. Methods This was a secondary analysis of a national convenience sample of EMS electronic patient care records (ePCRs) collected from January 1, 2018 through December 31, 2021. Inclusion criteria were all EMS activations documented as 9-1-1 responses involving patients < 18 years of age with a primary or secondary provider impression of a BHE. Patient demographics, incident characteristics, and clinical variables including administration of sedation medications, use of physical restraint, and transport status were examined overall and by calendar year. Results A total of 1,079,406 pediatric EMS encounters were present in the dataset, of which 102,014 (9.5%) had behavioral health provider impressions. Just over one-half of BHEs occurred in females (56.2%), and 68.1% occurred in patients aged 14-17 years. Telecommunicators managing the 9-1-1 calls for these events reported non-BHE patient complaints in 34.7%. Patients were transported by EMS 68.9% of the time, while treatment and/or transport by EMS was refused in 12.5%. Prehospital clinicians administered sedation medications in 1.9% of encounters and applied physical restraints in 1.7%. Naloxone was administered for overdose rescue in 1.5% of encounters. Conclusion Approximately one in ten pediatric EMS encounters occurring in the United States involve a BHE, and the majority of pediatric BHEs attended by EMS result in transport of the child. Use of sedation medications and physical restraints by prehospital clinicians in these events is rare. National EMS data from a variety of sources should continue to be examined to monitor trends in EMS encounters for BHEs in children.
RNA-binding motif protein 10 (RBM10) is a frequently mutated tumor suppressor in lung adenocarcinoma (LUAD). Yet, it remains unknown whether cancer-derived mutant RBM10 compromises its tumor suppression function and, if so, the molecular insight of the underlying mechanisms. Here, we show that wild-type RBM10 suppresses lung cancer cell growth and proliferation by inactivating c-Myc that is essential for cancer cell survival. RBM10 directly binds to c-Myc and promotes c-Myc’s ubiquitin-dependent degradation, while RBM10 knockdown leads to the induction of c-Myc level and activity. This negative action on c-Myc is further boosted by ribosomal proteins (RPs) uL18 (RPL5) and uL5 (RPL11) via their direct binding to RBM10. Cancer-derived mutant RBM10-I316F fails to bind to uL18 and uL5 and to inactivate c-Myc, thus incapable of suppressing tumorigenesis. Our findings uncover RBM10 as a pivotal c-Myc repressor by cooperating with uL18 and uL5 in lung cancer cells, as its failure to do so upon mutation favors tumorigenesis.
A bstract We study the entanglement transition in monitored Brownian SYK chains in the large- N limit. Without measurement the steady state n -th Rényi entropy is obtained by summing over a class of solutions, and is found to saturate to the Page value in the n → 1 limit. In the presence of measurements, the analytical continuation n → 1 is performed using the cyclic symmetric solution. The result shows that as the monitoring rate increases, a continuous von Neumann entanglement entropy transition from volume-law to area-law occurs at the point of replica symmetry unbreaking.
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