PKG1-modified TSC2 regulates mTORC1 activity to counter adverse cardiac stress.

The mechanistic target of rapamycin complex-1 (mTORC1) coordinates regulation of growth, metabolism, protein synthesis and autophagy1. Its hyperactivation contributes to disease in numerous organs, including the heart1,2, although broad inhibition of mTORC1 risks interference with its homeostatic roles. Tuberin (TSC2) is a GTPase-activating protein and prominent intrinsic regulator of mTORC1 that acts through modulation of RHEB (Ras homologue enriched in brain). TSC2 constitutively inhibits mTORC1; however, this activity is modified by phosphorylation from multiple signalling kinases that in turn inhibits (AMPK and GSK-3ß) or stimulates (AKT, ERK and RSK-1) mTORC1 activity3-9. Each kinase requires engagement of multiple serines, impeding analysis of their role in vivo. Here we show that phosphorylation or gain- or loss-of-function mutations at either of two adjacent serine residues in TSC2 (S1365 and S1366 in mice; S1364 and S1365 in humans) can bidirectionally control mTORC1 activity stimulated by growth factors or haemodynamic stress, and consequently modulate cell growth and autophagy. However, basal mTORC1 activity remains unchanged. In the heart, or in isolated cardiomyocytes or fibroblasts, protein kinase G1 (PKG1) phosphorylates these TSC2 sites. PKG1 is a primary effector of nitric oxide and natriuretic peptide signalling, and protects against heart disease10-13. Suppression of hypertrophy and stimulation of autophagy in cardiomyocytes by PKG1 requires TSC2 phosphorylation. Homozygous knock-in mice that express a phosphorylation-silencing mutation in TSC2 (TSC2(S1365A)) develop worse heart disease and have higher mortality after sustained pressure overload of the heart, owing to mTORC1 hyperactivity that cannot be rescued by PKG1 stimulation. However, cardiac disease is reduced and survival of heterozygote Tsc2S1365A knock-in mice subjected to the same stress is improved by PKG1 activation or expression of a phosphorylation-mimicking mutation (TSC2(S1365E)). Resting mTORC1 activity is not altered in either knock-in model. Therefore, TSC2 phosphorylation is both required and sufficient for PKG1-mediated cardiac protection against pressure overload. The serine residues identified here provide a genetic tool for bidirectional regulation of the amplitude of stress-stimulated mTORC1 activity.

Bridging the gap between academic research and industrial development in advanced all-solid-state lithium-sulfur batteries.

The energy storage and vehicle industries are heavily investing in advancing all-solid-state batteries to overcome critical limitations in existing liquid electrolyte-based lithium-ion batteries, specifically focusing on mitigating fire hazards and improving energy density. All-solid-state lithium-sulfur batteries (ASSLSBs), featuring earth-abundant sulfur cathodes, high-capacity metallic lithium anodes, and non-flammable solid electrolytes, hold significant promise. Despite these appealing advantages, persistent challenges like sluggish sulfur redox kinetics, lithium metal failure, solid electrolyte degradation, and manufacturing complexities hinder their practical use. To facilitate the transition of these technologies to an industrial scale, bridging the gap between fundamental scientific research and applied R&D activities is crucial. Our review will address the inherent challenges in cell chemistries within ASSLSBs, explore advanced characterization techniques, and delve into innovative cell structure designs. Furthermore, we will provide an overview of the recent trends in R&D and investment activities from both academia and industry. Building on the fundamental understandings and significant progress that has been made thus far, our objective is to motivate the battery community to advance ASSLSBs in a practical direction and propel the industrialized process.

Triple-tuned birdcage and single-tuned dipole array for quadri-nuclear head MRI at 7 T.

PURPOSE: The purpose of this work was to design and build a coil for quadri-nuclear MRI of the human brain at 7 T. METHODS: We built a transmit/receive triple-tuned (45.6 MHz for 2 $$ {}^2 $$ H, 78.6 MHz for 23 $$ {}^{23} $$ Na, and 120.3 MHz for 31 $$ {}^{31} $$ P) quadrature four-rod birdcage that was geometrically interleaved with a transmit/receive four-channel dipole array (297.2 MHz for 1 $$ {}^1 $$ H). The birdcage rods contained passive, two-pole resonant circuits that emulated capacitors required for single-tuning at three frequencies. The birdcage assembly also included triple-tuned matching networks, baluns, and transmit/receive switches. We assessed the performance of the coil with quality factor (Q) and signal-to-noise ratio (SNR) measurements, and performed in vivo multinuclear MRI and MR spectroscopic imaging (MRSI). RESULTS: Q measurements showed that the triple-tuned birdcage efficiency was within 33% of that of single-tuned baseline birdcages at all three frequencies. The quadri-tuned coil SNR was 78%, 59%, 44%, and 48% lower than that of single or dual-tuned reference coils for 1 $$ {}^1 $$ H, 2 $$ {}^2 $$ H, 23 $$ {}^{23} $$ Na, and 31 $$ {}^{31} $$ P, respectively. Quadri-nuclear MRI and MRSI was demonstrated in brain in vivo in about 30 min. CONCLUSION: While the SNR of the quadruple tuned coil was significantly lower than dual- and single-tuned reference coils, it represents a step toward truly simultaneous quadri-nuclear measurements.

A multicenter real-world analysis of risk factors, therapeutics, and outcomes of patients with metastatic basal cell carcinoma.

BACKGROUND: Metastatic basal cell carcinoma (mBCC) is rare and there are limited data regarding patient and tumor risk factors, optimal treatments, and disease prognosis. OBJECTIVE: To assess patient and tumor characteristics, therapeutics, and outcomes of mBCC stratified by location of metastasis. METHODS: Retrospective cohort study of 53 patients with mBCC treated at 4 large academic centers in Boston, Massachusetts; Philadelphia, Pennsylvania; and Cleveland, Ohio between January 1, 2005 and December 31, 2021. RESULTS: A total of 53 patients with mBCC were identified across 4 centers, 22 (42%) of whom had mBCC with spread limited to lymph nodes and 31 (58%) patients with distant organ spread (with or without lymph node involvement). Overall, half (n = 11) of patients with nodal metastasis achieved complete remission of disease, compared with just 1 (3%) patient with distant metastasis. The 5-year survival for nodal and distant metastatic patients was 89.3% and 61.0%, respectively. LIMITATIONS: Small sample size due to disease rarity. CONCLUSIONS AND RELEVANCE: Patients with nodal disease are more likely to have disease remission whereas patients with distant metastasis are more likely to have persistent disease and die from their disease. However, 5-year survival rates exceed 50%, even for stage IV disease.

Mortality of older construction and craft workers employed at Department of Energy (DOE) nuclear sites: Follow-up through 2021.

BACKGROUND: To determine if construction and trades workers formerly employed at US Department of Energy (DOE) nuclear weapons sites are at significant risk for occupational diseases, we studied the mortality experience of participants in the Building Trades National Medical Screening Program (BTMed). METHODS: The cohort included 26,922 participants enrolled between 1998 and 2021 and 8367 deaths. Standardized mortality ratios were calculated based on US death rates. Cox models compared construction workers (n = 22,747; 7487 deaths) to two nonconstruction subpopulations: administrative, scientific and security workers (n = 1894; 330 deaths), and all other nonconstruction workers (n = 2218; 550 deaths). RESULTS: Mortality was elevated for all causes, all cancers, cancers of the trachea, bronchus, lung, kidneys, and lymphatic and hematopoietic system, mesothelioma, chronic obstructive pulmonary disease (COPD), asbestosis, transportation injuries, and other injuries, particularly accidental poisonings. There were 167 deaths from coronavirus disease 2019 (COVID-19), which was lower than expected using US death rates. Overall cause-specific mortality was significantly higher among construction workers than for internal comparison groups. CONCLUSIONS: Construction workers employed at DOE sites have a significantly increased risk for occupational illnesses. Apart from COVID-19 deaths, this update: (1) found that mortality among construction workers is significantly elevated compared to the US population and significantly higher than in the internal comparison populations, and (2) confirmed excess risk for these workers for first employment after 1990. Cancer mortality risks are similar to the cancers identified for DOE compensation from radiation exposures. The high lung cancer risk supports the value of early lung cancer detection. Continued medical surveillance is important.

Capturing anatomy in computed tomography scans for genital pathology.

PURPOSE: In this cross-sectional study, we aimed to characterize how frequently the anatomy of interest (AOI) was excluded when evaluating genital pathology using the current CT pelvis protocol recommended by the American College of Radiology and evaluate how AOI exclusion affects patient management. METHODS: We retrospectively reviewed medical records, using diagnosis and CPT codes, of patients admitted with genital pathology who obtained a CT scan at our institution from July 1, 2020-April 30, 2023. Baseline patient demographics were included. Data about each index CT scan (scan obtained at our institution) were recorded and assessed for exclusion of the AOI. Statistical analysis was performed to determine the rate of AOI exclusion and to compare patient management between patients with AOI excluded versus those without AOI exclusion. RESULTS: 113 presentations for genital pathology included an index CT scan and were included for analysis. Patients were primarily men (98%) with a mean age of 53.1 years (SD 13.9). The most common diagnoses were Fournier's gangrene (35%), scrotal abscess (22%) and unspecified infection (19%). 26/113 scans (23%) did not capture the entire AOI. When the AOI was missed during the index scan, there was a higher rate of obtaining additional scans (38% vs. 21%), but a similar rate of intervention (77% vs. 63%) when compared to index scans that captured the entire AOI. 35 scans (31%) had protocol-extending instructions; index scans that captured the entire AOI were more likely to have specific protocol-extending instructions (38% vs. 8% p < 0.01). CONCLUSIONS: Creating a specific CT protocol for genital pathology could decrease the amount of inappropriate irradiation and improve AOI capture rates without relying on specific request for protocol deviation.

MTORC1-Regulated Metabolism Controlled by TSC2 Limits Cardiac Reperfusion Injury.

RATIONALE: The mTORC1 (mechanistic target of rapamycin complex-1) controls metabolism and protein homeostasis and is activated following ischemia reperfusion (IR) injury and by ischemic preconditioning (IPC). However, studies vary as to whether this activation is beneficial or detrimental, and its influence on metabolism after IR is little reported. A limitation of prior investigations is their use of broad gain/loss of mTORC1 function, mostly applied before ischemic stress. This can be circumvented by regulating one serine (S1365) on TSC2 (tuberous sclerosis complex) to achieve bidirectional mTORC1 modulation but only with TCS2-regulated costimulation. OBJECTIVE: We tested the hypothesis that reduced TSC2 S1365 phosphorylation protects the myocardium against IR and is required for IPC by amplifying mTORC1 activity to favor glycolytic metabolism. METHODS AND RESULTS: Mice with either S1365A (TSC2SA; phospho-null) or S1365E (TSC2SE; phosphomimetic) knockin mutations were studied ex vivo and in vivo. In response to IR, hearts from TSC2SA mice had amplified mTORC1 activation and improved heart function compared with wild-type and TSC2SE hearts. The magnitude of protection matched IPC. IPC requited less S1365 phosphorylation, as TSC2SE hearts gained no benefit and failed to activate mTORC1 with IPC. IR metabolism was altered in TSC2SA, with increased mitochondrial oxygen consumption rate and glycolytic capacity (stressed/maximal extracellular acidification) after myocyte hypoxia-reperfusion. In whole heart, lactate increased and long-chain acylcarnitine levels declined during ischemia. The relative IR protection in TSC2SA was lost by lowering glucose in the perfusate by 36%. Adding fatty acid (palmitate) compensated for reduced glucose in wild type and TSC2SE but not TSC2SA which had the worst post-IR function under these conditions. CONCLUSIONS: TSC2-S1365 phosphorylation status regulates myocardial substrate utilization, and its decline activates mTORC1 biasing metabolism away from fatty acid oxidation to glycolysis to confer protection against IR. This pathway is also engaged and reduced TSC2 S1365 phosphorylation required for effective IPC. Graphic Abstract: A graphic abstract is available for this article.

Dynamic Source Distribution and Emission Inventory of a Persistent, Mobile, and Toxic (PMT) Substance, Melamine, in China.

Persistent, mobile, and toxic (PMT) substances are affecting the safety of drinking water and are threatening the environment and human health. Many PMT substances are used in industrial processing or consumer products, but their sources and emissions mostly remain unclear. This study presents a long-term source distribution and emission estimation of melamine, a high-production-volume PMT substance of emerging global concern. The results indicate that in China, approximately 1858.7 kilotonnes (kt) of melamine were released into the water (∼58.9%), air (∼27.0%), and soil systems (∼14.1%) between 1995 and 2020, mainly from its production and use in the decorative panels, textiles, and paper industries. The textile and paper industries have the highest emission-to-consumption ratios, with more than 90% emissions per unit consumption. Sewage treatment plants are the largest source of melamine in the environment for the time being, but in-use products and their wastes will serve as significant melamine sources in the future. The study prompts priority action to control the risk of PMT substances internationally.

Traction alopecia: assessing the presentation, management and outcomes in a diverse urban population.

Traction alopecia (TA) is a type of hair loss caused by repetitive tension placed on the hair follicle. An institutional review board-approved retrospective study was conducted at a single institution located in the Bronx, New York. The review identified 216 unique patients with TA and collected information on demographics, patient presentation, history, physical exam, treatment, follow-up and disease improvement. Almost all patients identified as female (98.6%), and most were Black or African American (72.7%). Mean (SD) age was 41.3 (17.1) years (median 40 years; range 1-88). Patients reported hair loss for a mean duration of 35 (51.1) months (median 18 months; range 1-264) prior to presentation. Most patients experienced asymptomatic hair loss. Around half (49.1%) of the patients attended a follow-up, with 42.5% of these patients noting improvement in hair loss or symptoms across all visits. Duration of hair loss was not associated with improvement in hair loss at follow-up visit (P = 0.23).

Providing culturally responsive care in a pediatric setting: are our trainees ready?

BACKGROUND: Extensive data consistently demonstrates inequities in access and delivery of healthcare for patients from historically marginalized populations, resulting in poorer health outcomes. To address this systemic oppression in healthcare, it is necessary to embed principles of equity, diversity, and inclusion (EDI) at an early stage within medical education. This study aimed to assess pediatric trainees' perceived interest in EDI curricula as well as their confidence in applying this knowledge to provide culturally responsive care. METHODS: An anonymous online survey was distributed to pediatric trainees at the University of Toronto. Closed-ended questions used a Likert scale to assess respondents' confidence and interest in providing culturally responsive care to patients. Open-ended questions explored trainees' perceptions of effective EDI learning modalities. A mixed methods approach was utilized, where quantitative data was summarized using descriptive statistics and descriptive content analysis was used to highlight themes within qualitative data. RESULTS: 116 pediatric trainees completed the survey, of which 72/116 (62%) were subspecialty residents/fellows and 44/116 (38%) were core residents. 97% of all responses agreed or strongly agreed that it was important to learn about providing culturally responsive care to patients from historically marginalized communities; however, many trainees lacked confidence in their knowledge of providing culturally responsive care (42%) and applying their knowledge in clinical practice (47%). Respondents identified direct clinical exposure through rotations, immersive experiences, and continuity clinics as effective EDI teaching modalities. Identified barriers included time constraints in the clinical environment, burnout, and lack of exposure to diverse patient populations. CONCLUSION: Most pediatric trainees want to provide culturally responsive care to patients from historically marginalized communities, but do not feel confident in their knowledge to do so. Trainees value learning about EDI through direct clinical exposure and immersive experiences, rather than didactic lectures or modules. These study findings will be utilized to develop and implement an enhanced EDI education curriculum for pediatric trainees at the University of Toronto and other postgraduate residency programs.

Sensitive, Highly Multiplexed Sequencing of Microhaplotypes From the Plasmodium falciparum Heterozygome.

BACKGROUND: Targeted next-generation sequencing offers the potential for consistent, deep coverage of information-rich genomic regions to characterize polyclonal Plasmodium falciparum infections. However, methods to identify and sequence these genomic regions are currently limited. METHODS: A bioinformatic pipeline and multiplex methods were developed to identify and simultaneously sequence 100 targets and applied to dried blood spot (DBS) controls and field isolates from Mozambique. For comparison, whole-genome sequencing data were generated for the same controls. RESULTS: Using publicly available genomes, 4465 high-diversity genomic regions suited for targeted sequencing were identified, representing the P. falciparum heterozygome. For this study, 93 microhaplotypes with high diversity (median expected heterozygosity = 0.7) were selected along with 7 drug resistance loci. The sequencing method achieved very high coverage (median 99%), specificity (99.8%), and sensitivity (90% for haplotypes with 5% within sample frequency in dried blood spots with 100 parasites/µL). In silico analyses revealed that microhaplotypes provided much higher resolution to discriminate related from unrelated polyclonal infections than biallelic single-nucleotide polymorphism barcodes. CONCLUSIONS: The bioinformatic and laboratory methods outlined here provide a flexible tool for efficient, low-cost, high-throughput interrogation of the P. falciparum genome, and can be tailored to simultaneously address multiple questions of interest in various epidemiological settings.

Stress hormone signalling inhibits Th1 polarization in a CD4 T-cell-intrinsic manner via mTORC1 and the circadian gene PER1.

Stress hormones are believed to skew the CD4 T-cell differentiation towards a Th2 response via a T-cell-extrinsic mechanism. Using isolated primary human naïve and memory CD4 T cells, here we show that both adrenergic- and glucocorticoid-mediated stress signalling pathways play a CD4 naïve T-cell-intrinsic role in regulating the Th1/Th2 differentiation balance. Both stress hormones reduced the Th1 programme and cytokine production by inhibiting mTORC1 signalling via two parallel mechanisms. Stress hormone signalling inhibited mTORC1 in naïve CD4 T cells (1) by affecting the PI3K/AKT pathway and (2) by regulating the expression of the circadian rhythm gene, period circadian regulator 1 (PER1). Both stress hormones induced the expression of PER1, which inhibited mTORC1 signalling, thus reducing Th1 differentiation. This previously unrecognized cell-autonomous mechanism connects stress hormone signalling with CD4 T-cell differentiation via mTORC1 and a specific circadian clock gene, namely PER1.

PKG1α Cysteine-42 Redox State Controls mTORC1 Activation in Pathological Cardiac Hypertrophy.

RATIONALE: Stimulated PKG1α (protein kinase G-1α) phosphorylates TSC2 (tuberous sclerosis complex 2) at serine 1365, potently suppressing mTORC1 (mechanistic [mammalian] target of rapamycin complex 1) activation by neurohormonal and hemodynamic stress. This reduces pathological hypertrophy and dysfunction and increases autophagy. PKG1α oxidation at cysteine-42 is also induced by these stressors, which blunts its cardioprotective effects. OBJECTIVE: We tested the dependence of mTORC1 activation on PKG1α C42 oxidation and its capacity to suppress such activation by soluble GC-1 (guanylyl cyclase 1) activation. METHODS AND RESULTS: Cardiomyocytes expressing wild-type (WT) PKG1α (PKG1αWT) or cysteine-42 to serine mutation redox-dead (PKG1αCS/CS) were exposed to ET-1 (endothelin 1). Cells expressing PKG1αWT exhibited substantial mTORC1 activation (p70 S6K [p70 S6 kinase], 4EBP1 [elF4E binding protein-1], and Ulk1 [Unc-51-like kinase 1] phosphorylation), reduced autophagy/autophagic flux, and abnormal protein aggregation; all were markedly reversed by PKG1αCS/CS expression. Mice with global knock-in of PKG1αCS/CS subjected to pressure overload (PO) also displayed markedly reduced mTORC1 activation, protein aggregation, hypertrophy, and ventricular dysfunction versus PO in PKG1αWT mice. Cardioprotection against PO was equalized between groups by co-treatment with the mTORC1 inhibitor everolimus. TSC2-S1365 phosphorylation increased in PKG1αCS/CS more than PKG1αWT myocardium following PO. TSC2S1365A/S1365A (TSC2 S1365 phospho-null, created by a serine to alanine mutation) knock-in mice lack TSC2 phosphorylation by PKG1α, and when genetically crossed with PKG1αCS/CS mice, protection against PO-induced mTORC1 activation, cardiodepression, and mortality in PKG1αCS/CS mice was lost. Direct stimulation of GC-1 (BAY-602770) offset disparate mTORC1 activation between PKG1αWT and PKG1αCS/CS after PO and blocked ET-1 stimulated mTORC1 in TSC2S1365A-expressing myocytes. CONCLUSIONS: Oxidation of PKG1α at C42 reduces its phosphorylation of TSC2, resulting in amplified PO-stimulated mTORC1 activity and associated hypertrophy, dysfunction, and depressed autophagy. This is ameliorated by direct GC-1 stimulation.

T1 and T2 quantification using magnetic resonance fingerprinting in mild traumatic brain injury.

OBJECTIVES: To assess whether MR fingerprinting (MRF)-based relaxation properties exhibit cross-sectional and prospective correlations with patient outcome and compare the results with those from DTI. METHODS: Clinical imaging, MRF, and DTI were acquired in patients (24 ± 10 days after injury (timepoint 1) and 90 ± 17 days after injury (timepoint 2)) and once in controls. Patient outcome was assessed with global functioning, symptom profile, and neuropsychological testing. ADC and fractional anisotropy (FA) from DTI and T1 and T2 from MRF were compared in 12 gray and white matter regions with Mann-Whitney tests. Bivariate associations between MR measures and outcome were assessed using the Spearman correlation and logistic regression. RESULTS: Data from 22 patients (38 ± 12 years; 17 women) and 18 controls (32 ± 8 years; 12 women) were analyzed. Fourteen patients (37 ± 12 years; 11 women) returned for timepoint 2, while two patients provided only timepoint 2 clinical outcome data. At timepoint 1, there were no differences between patients and controls in T1, T2, and ADC, while FA was lower in mTBI frontal white matter. T1 at timepoint 1 and the change in T1 exhibited more (n = 18) moderate to strong correlations (|r|= 0.6-0.85) with clinical outcome at timepoint 2 than T2 (n = 3), FA (n = 7), and ADC (n = 2). High T1 at timepoint 1, and serially increasing T1, accounted for five of the six MR measures with the highest utility for identification of non-recovered patients at timepoint 2 (AUC > 0.80). CONCLUSION: T1 derived from MRF was found to have higher utility than T2, FA, and ADC for predicting 3-month outcome after mTBI. KEY POINTS: • In a region-of-interest approach, FA, ADC, and T1 and T2 all showed limited utility in differentiating patients from controls at an average of 24 and 90 days post-mild traumatic brain injury. • T1 at 24 days, and the serial change in T1, revealed more and stronger predictive correlations with clinical outcome at 90 days than did T2, ADC, or FA. • T1 showed better prospective identification of non-recovered patients at 90 days than ADC, T2, and FA.

Global Historical Production, Use, In-Use Stocks, and Emissions of Short-, Medium-, and Long-Chain Chlorinated Paraffins.

The last few decades have seen ubiquitous and increasing contamination of chlorinated paraffins (CPs) worldwide. Here, we develop the first global inventories of production, use, in-use stocks, and emissions of total CPs, including the short-, medium- and long-chain components (SCCPs, MCCPs, and LCCPs) during 1930-2020 using a dynamic substance flow analysis model named Chemical in Products Comprehensive Anthroposhpheric Fate Estimation. The model estimates that a total of ∼33 million metric tons of CPs have been produced and used globally, ∼40% of which still resided in in-use products by 2020 and is available for long-term emissions in the next decades. Global cumulative emissions of CPs have increased to ∼5.2 million metric tons by 2020, with SCCPs, MCCPs, and LCCPs accounting for ∼30, 40, and 30%, respectively. While the production, use, and emissions of CPs started declining in regions such as Western Europe, they remain high in China. The model also suggests that homologues with 10, 14, and 22-23 carbons were predominant in the cumulatively produced and emitted SCCPs, MCCPs, and LCCPs, respectively. The emission estimates were evaluated by generating environmental concentrations that are comparable to literature-reported environmental monitoring data. Our estimates provide opportunities to link the environmental fate and occurrence of CPs to emission sources and lay the basis for future risk-reduction strategies of CPs around the world.

The role conflict-burnout-depression link among Chinese female health care and social service providers: the moderating effect of marriage and motherhood.

BACKGROUND: Women with depression disorder outnumber men, and health care and social service providers are mostly female. Drawing on conservation of resources (COR) theory, this study aims to examine the association between role conflicts and depression among health care and social service providers, and further investigate the mediating effect of burnout, as well as the moderating effect of marital status and motherhood. METHODS: The data come from the baseline of the 'China Social Work Longitudinal Study' conducted in 2019, which contains 1,219 female social workers who reported work-family conflict. The five items of the scale in our model were extracted from the existing literature to ensure the construct validity of potential variables, and confirmatory factor analyses (CFAs) were also conducted to ensure the validity and reliability of the scale. Descriptive analyses and correlation analyses were performed with SPSS 24, while the path analysis was conducted using Amos 24. The moderating effects of marital status and motherhood were further tested using multiple-group analyses. RESULTS: Female health care and social service providers experienced a high level of depression. Work-to-family conflict (WFC), family-to-work conflict (FWC), and organizational role conflict (ORC) were significantly and positively associated with female social workers' depression. Exhaustion and cynicism fully mediated the effects of ORC on depression and partially mediated the effects of WFC on depression. In addition, FWC had only a direct effect on depression. A multiple-group analysis further indicated that both marital status and motherhood status may have played a moderating role in the conflict-burnout-depression link and that being unmarried and having no child were risk factors for depression in female health care and social service providers. CONCLUSIONS: Marriage and motherhood have both negative and positive effects on the depression of female health care and social service providers. This suggests that marriage and motherhood may act as a form of "family clientelism" for female health care and social service providers who marry and have children.

Narcolepsy Treatment: Voices of Adolescents.

INTRODUCTION: Narcolepsy, characterized by excessive daytime sleepiness, is a debilitating lifelong sleep disorder for which there is no cure. Current pharmacological and nonpharmacological treatments directed toward symptom management may be suboptimal. This qualitative study explores the perspective of adolescents on therapeutic interventions for narcolepsy. METHODS: Semi-structured interviews with adolescents with narcolepsy were conducted from May to August 2019 at The Hospital for Sick Children in Toronto, Canada. Qualitative thematic analysis was utilized to generate themes emerging from the data. RESULTS: Eighteen adolescents with narcolepsy (age range = 10-17, mean age = 14.4 ± 2.0 years, 72% male) participated and 56% had cataplexy. Four prominent themes arose regarding therapeutic interventions for narcolepsy. Firstly, participants described that pharmacotherapy was moderately effective but did not fully relieve symptoms associated with narcolepsy. Secondly, while medications are the first line treatment for narcolepsy, many participants reported frustration regarding medication dependence and side effects. Thirdly, nonpharmacological strategies including scheduled sleep times and exercise were accepted and often employed. Lastly, adolescents desired more psychosocial support to address mental health sequelae of narcolepsy that were not fully managed by current treatment modalities. CONCLUSIONS: Medications were perceived as moderately effective for managing narcolepsy but almost all participants expressed concerns with taking medications due to side effects. Adolescents valued the importance of more holistic care for their narcolepsy treatment such as psychosocial support and nonpharmacological modalities. Further anticipatory guidance regarding pharmacological side effect profiles and better integration with nonpharmacological modalities are needed to improve disease control in adolescent patients.

Hearing impairment and tinnitus among older construction workers employed at DOE facilities.

BACKGROUND: Few studies have defined the risk of hearing impairment and tinnitus after retirement. This report measures hearing impairment and tinnitus prevalence among older construction trades workers. METHODS: The study cohort included 21,340 participants in a national medical screening program (www.btmed.org). Audiometric hearing impairment was classified according to the Global Burden of Disease Study. Tinnitus was determined by self-report. An internal subcohort of nonconstruction trades workers served as a reference group. Stratified analyses and multivariate analyses were used to measure the prevalence of hearing impairment and tinnitus by age, sex, and job category. RESULTS: Prevalence of any hearing impairment was 55.2% (males, 57.7%; females, 26.8%) and increased rapidly with age. Construction trades workers were 40% more likely to have hearing impairment than the reference group. The overall prevalence of tinnitus was 46.52% and followed patterns similar to hearing impairment. Workers with hearing impairment were more likely to also have tinnitus, but tinnitus was frequently reported in the absence of measured hearing impairment. CONCLUSIONS: Hearing impairment and tinnitus prevalence were much higher in this study than in previous research. A significant reason for the difference is that BTMed follows participants after they have retired. To draw conclusions about the risk for work-related chronic diseases and disorders it is important to monitor workers through their lifetimes. Also, tinnitus by itself should be given greater significance. These findings reinforce the need to promote noise reduction and hearing conservation in construction.

Role of Structural, Metabolic, and Functional MRI in Monitoring Visual System Impairment and Recovery.

The visual system, consisting of the eyes and the visual pathways of the brain, receives and interprets light from the environment so that we can perceive the world around us. A wide variety of disorders can affect human vision, ranging from ocular to neurologic to systemic in nature. While other noninvasive imaging techniques such as optical coherence tomography and ultrasound can image particular sections of the visual system, magnetic resonance imaging (MRI) offers high resolution without depth limitations. MRI also gives superior soft-tissue contrast throughout the entire pathway compared to computed tomography. By leveraging different imaging sequences, MRI is uniquely capable of unveiling the intricate processes of ocular anatomy, tissue physiology, and neurological function in the human visual system from the microscopic to macroscopic levels. In this review we discuss how structural, metabolic, and functional MRI can be used in the clinical assessment of normal and pathologic states in the anatomic structures of the visual system, including the eyes, optic nerves, optic chiasm, optic tracts, visual brain nuclei, optic radiations, and visual cortical areas. We detail a selection of recent clinical applications of MRI at each position along the visual pathways, including the evaluation of pathology, plasticity, and the potential for restoration, as well as its limitations and key areas of ongoing exploration. Our discussion of the current and future developments in MR ocular and neuroimaging highlights its potential impact on our ability to understand visual function in new detail and to improve our protection and treatment of anatomic structures that are integral to this fundamental sensory system. LEVEL OF EVIDENCE 3: TECHNICAL EFFICACY STAGE 3: .

A dual-specific macrophage colony-stimulating factor antagonist of c-FMS and αvß3 integrin for osteoporosis therapy.

There is currently a demand for new highly efficient and specific drugs to treat osteoporosis, a chronic bone disease affecting millions of people worldwide. We have developed a combinatorial strategy for engineering bispecific inhibitors that simultaneously target the unique combination of c-FMS and αvß3 integrin, which act in concert to facilitate bone resorption by osteoclasts. Using functional fluorescence-activated cell sorting (FACS)-based screening assays of random mutagenesis macrophage colony-stimulating factor (M-CSF) libraries against c-FMS and αvß3 integrin, we engineered dual-specific M-CSF mutants with high affinity to both receptors. These bispecific mutants act as functional antagonists of c-FMS and αvß3 integrin activation and hence of osteoclast differentiation in vitro and osteoclast activity in vivo. This study thus introduces a versatile platform for the creation of new-generation therapeutics with high efficacy and specificity for osteoporosis and other bone diseases. It also provides new tools for studying molecular mechanisms and the cell signaling pathways that mediate osteoclast differentiation and function.