Subjective evaluation of home environment and levels of self-reported depression in middle to old age: Results from the HCHS study.

OBJECTIVES: The immediate living environment might, like other lifestyle factors, be significantly related to mental well-being. The current study addresses the question whether five relevant subjective home environment variables (i.e., protection from disturbing nightlight, daylight entering the home, safety at home, quality of window views, and noise disturbance) are associated with levels of self-reported depression over and above well-known sociodemographic and common lifestyle variables. METHODS: Data from the Hamburg City Health Study (HCHS) were analyzed. In N = 8757 with available PHQ-9 depression data, multiple linear regression models were computed, with demographic data, lifestyle variables, and variables describing the subjective evaluation of the home environment. RESULTS: The model explained 15% of variance in depression levels, with ratings for the subjective evaluation of home environment accounting for 6%. Better protection from disturbing light at night, more daylight entering the home, feeling safer, and perceived quality of the window views, were all significantly associated with lower, while more annoyance by noise was associated with higher levels of self-reported depression. Results did not differ if examining a sample of the youngest (middle-aged participants: 46-50 years) versus oldest (70-78 years) participants within HCHS. CONCLUSION: Beyond studying the role of lifestyle factors related to self-reported depression, people's homes may be important for subclinical levels of depression in middle and older age, albeit the direction of effects or causality cannot be inferred from the present study. The development of a consensus and tools for a standardized home environment assessment is needed.

Inactivation of SARS-CoV-2 on salt-coated surfaces: an in vitro study.

In the COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), face masks have become a very important safety measure against the main route of transmission of the virus: droplets and aerosols. Concerns that masks contaminated with SARS-CoV-2 infectious particles could be a risk for self-contamination have emerged early in the pandemic as well as solutions to mitigate this risk. The coating of masks with sodium chloride, an antiviral and non-hazardous to health chemical, could be an option for reusable masks. To assess the antiviral properties of salt coatings deposited onto common fabrics by spraying and dipping, the present study established an in vitro bioassay using three-dimensional airway epithelial cell cultures and SARS-CoV-2 virus. Virus particles were given directly on salt-coated material, collected, and added to the cell cultures. Infectious virus particles were measured by plaque forming unit assay and in parallel viral genome copies were quantified over time. Relative to noncoated material, the sodium chloride coating significantly reduced virus replication, confirming the effectiveness of the method to prevent fomite contamination with SARS-CoV-2. In addition, the lung epithelia bioassay proved to be suitable for future evaluation of novel antiviral coatings.

Protocol for Development of American Association of Clinical Endocrinology Clinical Practice Guidelines and Consensus Statements: Summary of Methodology, Process, and Policy - 2023 Update.

OBJECTIVE: This 2023 updated protocol summarizes the American Association of Clinical Endocrinology's (AACE's) new framework for the development of clinical practice guidelines and other guidance documents that includes changes to methodology, processes, and policies. METHODS: AACE has critically reviewed its development processes for guidance documents over the last several years against the National Academy of Medicine Standards for Developing Trustworthy Clinical Practice Guidelines and the Council of Medical Specialty Societies Principles for Development of Specialty Society Clinical Guidelines to determine areas for improvement. RESULTS: The new AACE framework for development of guidance documents incorporates many changes, including a revised conflicts of interest (COI) policy; strengthened commitment to collection of disclosures and management of relevant COI during development; open calls to membership for authors; new requirements for authors; new diversity, equity, and inclusion (DEI) policy; new empanelment process that incorporates consideration of DEI; and adoption of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology to increase the quality of evidence assessment and standardize recommendation grades and statements, among other improvements. CONCLUSIONS: AACE has revised its policies and adopted a completely new methodology for guideline development in support of the mission to elevate the practice of clinical endocrinology to improve patient care. With the use of an evidence-based medicine framework and by continually assessing and improving its processes for development of guidance, AACE strives to deliver trustworthy, unbiased, and up-to-date information that ensures clinician and patient confidence in AACE content. Further, AACE hopes that these enhancements foster a more collaborative approach to development and increase engagement with the worldwide medical community to improve global health.

Error quantification in multi-parameter mapping facilitates robust estimation and enhanced group level sensitivity.

Multi-Parameter Mapping (MPM) is a comprehensive quantitative neuroimaging protocol that enables estimation of four physical parameters (longitudinal and effective transverse relaxation rates R1 and R2*, proton density PD, and magnetization transfer saturation MTsat) that are sensitive to microstructural tissue properties such as iron and myelin content. Their capability to reveal microstructural brain differences, however, is tightly bound to controlling random noise and artefacts (e.g. caused by head motion) in the signal. Here, we introduced a method to estimate the local error of PD, R1, and MTsat maps that captures both noise and artefacts on a routine basis without requiring additional data. To investigate the method's sensitivity to random noise, we calculated the model-based signal-to-noise ratio (mSNR) and showed in measurements and simulations that it correlated linearly with an experimental raw-image-based SNR map. We found that the mSNR varied with MPM protocols, magnetic field strength (3T vs. 7T) and MPM parameters: it halved from PD to R1 and decreased from PD to MTsat by a factor of 3-4. Exploring the artefact-sensitivity of the error maps, we generated robust MPM parameters using two successive acquisitions of each contrast and the acquisition-specific errors to down-weight erroneous regions. The resulting robust MPM parameters showed reduced variability at the group level as compared to their single-repeat or averaged counterparts. The error and mSNR maps may better inform power-calculations by accounting for local data quality variations across measurements. Code to compute the mSNR maps and robustly combined MPM maps is available in the open-source hMRI toolbox.

American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update.

OBJECTIVE: The objective of this clinical practice guideline is to provide updated and new evidence-based recommendations for the comprehensive care of persons with diabetes mellitus to clinicians, diabetes-care teams, other health care professionals and stakeholders, and individuals with diabetes and their caregivers. METHODS: The American Association of Clinical Endocrinology selected a task force of medical experts and staff who updated and assessed clinical questions and recommendations from the prior 2015 version of this guideline and conducted literature searches for relevant scientific papers published from January 1, 2015, through May 15, 2022. Selected studies from results of literature searches composed the evidence base to update 2015 recommendations as well as to develop new recommendations based on review of clinical evidence, current practice, expertise, and consensus, according to established American Association of Clinical Endocrinology protocol for guideline development. RESULTS: This guideline includes 170 updated and new evidence-based clinical practice recommendations for the comprehensive care of persons with diabetes. Recommendations are divided into four sections: (1) screening, diagnosis, glycemic targets, and glycemic monitoring; (2) comorbidities and complications, including obesity and management with lifestyle, nutrition, and bariatric surgery, hypertension, dyslipidemia, retinopathy, neuropathy, diabetic kidney disease, and cardiovascular disease; (3) management of prediabetes, type 2 diabetes with antihyperglycemic pharmacotherapy and glycemic targets, type 1 diabetes with insulin therapy, hypoglycemia, hospitalized persons, and women with diabetes in pregnancy; (4) education and new topics regarding diabetes and infertility, nutritional supplements, secondary diabetes, social determinants of health, and virtual care, as well as updated recommendations on cancer risk, nonpharmacologic components of pediatric care plans, depression, education and team approach, occupational risk, role of sleep medicine, and vaccinations in persons with diabetes. CONCLUSIONS: This updated clinical practice guideline provides evidence-based recommendations to assist with person-centered, team-based clinical decision-making to improve the care of persons with diabetes mellitus.

Fractionation and Extraction Optimization of Potentially Valuable Compounds and Their Profiling in Six Varieties of Two Nicotiana Species.

There is an increasingly urgent call to shift industrial processes from fossil fuel feedstock to sustainable bio-based resources. This change becomes of high importance considering new budget requirements for a carbon-neutral economy. Such a transformation can be driven by traditionally used plants that are able to produce large amounts of valuable biologically relevant secondary metabolites. Tobacco plants can play a leading role in providing value-added products in remote areas of the world. In this study, we propose a non-exhaustive list of compounds with potential economic interest that can be sourced from the tobacco plant. In order to optimize extraction methodologies, we first analyzed their physico-chemical properties using rapid solubility tests and high-resolution microfractionation techniques. Next, to identify an optimal extraction for a selected list of compounds, we compared 13 different extraction method-solvent combinations. We proceeded with profiling some of these compounds in a total of six varieties from Nicotiana tabacum and Nicotiana rustica species, identifying the optimal variety for each. The estimated expected yields for each of these compounds demonstrate that tobacco plants can be a superior source of valuable compounds with diverse applications beyond nicotine. Among the most interesting results, we found high variability of anatabine content between species and varieties, ranging from 287 to 1699 µg/g. In addition, we found that CGA (1305 µg/g) and rutin (7910 µg/g) content are orders of magnitude lower in the Burley variety as compared to all others.

Hypoglycaemia and its management in primary care setting.

Hypoglycaemia is common in patients with type 1 diabetes and type 2 diabetes and constitutes a major limiting factor in achieving glycaemic control among people with diabetes. While hypoglycaemia is defined as a blood glucose level under 70 mg/dL (3.9 mmol/L), symptoms may occur at higher blood glucose levels in individuals with poor glycaemic control. Severe hypoglycaemia is defined as an episode requiring the assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions to assure neurologic recovery. Hypoglycaemia is the most important safety outcome in clinical studies of glucose lowering agents. The American Diabetes Association Standards of Medical Care recommends that a management protocol for hypoglycaemia should be designed and implemented by every hospital, along with a clear prevention and treatment plan. A tailored approach, using clinical and pathophysiologic disease stratification, can help individualize glycaemic goals and promote new therapies to improve quality of life of patients. Data from recent large clinical trials reported low risk of hypoglycaemic events with the use of newer anti-diabetic drugs. Increased hypoglycaemia risk is observed with the use of insulin and/or sulphonylureas. Vulnerable patients with T2D at dual risk of severe hypoglycaemia and cardiovascular outcomes show features of "frailty." Many of such patients may be better treated by the use of GLP-1 receptor agonists or SGLT2 inhibitors rather than insulin. Continuous glucose monitoring (CGM) should be considered for all individuals with increased risk for hypoglycaemia, impaired hypoglycaemia awareness, frequent nocturnal hypoglycaemia and with history of severe hypoglycaemia. Patients with impaired awareness of hypoglycaemia benefit from real-time CGM. The diabetes educator is an invaluable resource and can devote the time needed to thoroughly educate the individual to reduce the risk of hypoglycaemia and integrate the information within the entire construct of diabetes self-management. Conversations about hypoglycaemia facilitated by a healthcare professional may reduce the burden and fear of hypoglycaemia among patients with diabetes and their family members. Optimizing insulin doses and carbohydrate intake, in addition to a short warm up before or after the physical activity sessions may help avoiding hypoglycaemia. Several therapeutic considerations are important to reduce hypoglycaemia risk during pregnancy including administration of rapid-acting insulin analogues rather than human insulin, pre-conception initiation of insulin analogues, and immediate postpartum insulin dose reduction.

Global status of diabetes prevention and prospects for action: A consensus statement.

Primary prevention of type 2 diabetes (T2D) should be achievable through the implementation of early and sustainable measures. Several randomized control studies that found success in preventing the progression to T2D in high-risk populations have identified early and intensive intervention based on an individualized prevention model as the key factor for participant benefit. The global prevalence of both overweight and obesity has now been widely recognized as the major epidemic of the 21st century. Obesity is a major risk factor for the progression from normal glucose tolerance to prediabetes and then to T2D. However, not all obese individuals will develop prediabetes or progress to diabetes. Intensive, multicomponent behavioural interventions for overweight and obese adults can lead to weight loss. Diabetes medications, including metformin, GLP-1 agonists, glitazones, and acarbose, can be considered for selected high-risk patients with prediabetes when lifestyle-based programmes are proven unsuccessful. Nutrition education is the cornerstone of a healthy lifestyle. Also, physical activity is an integral part of the prediabetes management plan and one of the main pillars in the prevention of diabetes. Mobile phones, used extensively worldwide, can facilitate communication between health professionals and the general population, and have been shown to be helpful in the prevention of T2D. Universal screening is needed. Noninvasive risk scores should be used in all countries, but they should be locally validated in all ethnic populations focusing on cultural differences around the world. Lifestyle interventions reduce the progression to prediabetes and diabetes. Nevertheless, many questions still need to be answered.

Chromosome-wide histone deacetylation by sirtuins prevents hyperactivation of DNA damage-induced signaling upon replicative stress.

The Saccharomyces cerevisiae genome encodes five sirtuins (Sir2 and Hst1-4), which constitute a conserved family of NAD-dependent histone deacetylases. Cells lacking any individual sirtuin display mild growth and gene silencing defects. However, hst3Δ hst4Δ double mutants are exquisitely sensitive to genotoxins, and hst3Δ hst4Δ sir2Δmutants are inviable. Our published data also indicate that pharmacological inhibition of sirtuins prevents growth of several fungal pathogens, although the biological basis is unclear. Here, we present genome-wide fitness assays conducted with nicotinamide (NAM), a pan-sirtuin inhibitor. Our data indicate that NAM treatment causes yeast to solicit specific DNA damage response pathways for survival, and that NAM-induced growth defects are mainly attributable to inhibition of Hst3 and Hst4 and consequent elevation of histone H3 lysine 56 acetylation (H3K56ac). Our results further reveal that in the presence of constitutive H3K56ac, the Slx4 scaffolding protein and PP4 phosphatase complex play essential roles in preventing hyperactivation of the DNA damage-response kinase Rad53 in response to spontaneous DNA damage caused by reactive oxygen species. Overall, our data support the concept that chromosome-wide histone deacetylation by sirtuins is critical to mitigate growth defects caused by endogenous genotoxins.

Characterization of three pyranose dehydrogenase isoforms from the litter-decomposing basidiomycete Leucoagaricus meleagris (syn. Agaricus meleagris).

Multigenicity is commonly found in fungal enzyme systems, with the purpose of functional compensation upon deficiency of one of its members or leading to enzyme isoforms with new functionalities through gene diversification. Three genes of the flavin-dependent glucose-methanol-choline (GMC) oxidoreductase pyranose dehydrogenase (AmPDH) were previously identified in the litter-degrading fungus Agaricus (Leucoagaricus) meleagris, of which only AmPDH1 was successfully expressed and characterized. The aim of this work was to study the biophysical and biochemical properties of AmPDH2 and AmPDH3 and compare them with those of AmPDH1. AmPDH1, AmPDH2 and AmPDH3 showed negligible oxygen reactivity and possess a covalently tethered FAD cofactor. All three isoforms can oxidise a range of different monosaccarides and oligosaccharides including glucose, mannose, galactose and xylose, which are the main constituent sugars of cellulose and hemicelluloses, and judging from the apparent steady-state kinetics determined for these sugars, the three isoforms do not show significant differences pertaining to their reaction with sugar substrates. They oxidize glucose both at C2 and C3 and upon prolonged reaction C2 and C3 double-oxidized glucose is obtained, confirming that the A. meleagris genes pdh2 (AY753308.1) and pdh3 (DQ117577.1) indeed encode CAZy class AA3_2 pyranose dehydrogenases. While reactivity with electron donor substrates was comparable for the three AmPDH isoforms, their kinetic properties differed significantly for the model electron acceptor substrates tested, a radical (the 2,2'-azino-bis[3-ethylbenzothiazoline-6-sulphonic acid] cation radical), a quinone (benzoquinone) and a complexed iron ion (the ferricenium ion). Thus, a possible explanation for this PDH multiplicity in A. meleagris could be that different isoforms react preferentially with structurally different electron acceptors in vivo.

The RTA3 Gene, Encoding a Putative Lipid Translocase, Influences the Susceptibility of Candida albicans to Fluconazole.

The RTA3 gene, coding for a member of the Rta1p-like lipid-translocating exporter family, is coordinately upregulated with the ATP-binding cassette transporter genes CDR1 and CDR2 in azole-resistant clinical isolates of Candida albicans that carry activating mutations in the transcription factor Tac1p. We show here that deleting RTA3 in an azole-resistant clinical isolate carrying a Tac1p-activating mutation lowered fluconazole resistance by 2-fold, while overexpressing RTA3 in an azole-susceptible clinical isolate resulted in enhanced fluconazole tolerance associated with trailing growth in a liquid microtiter plate assay. We also demonstrate that an Rta3p-green fluorescent protein (GFP) fusion protein localizes predominantly to the plasma membrane, consistent with a putative function for Rta3p as a lipid translocase.

Positive regulation of the Candida albicans multidrug efflux pump Cdr1p function by phosphorylation of its N-terminal extension.

OBJECTIVES: Overexpression of ATP-binding cassette (ABC) transporters is a frequent cause of multidrug resistance in cancer cells and pathogenic microorganisms. One example is the Cdr1p transporter from the human fungal pathogen Candida albicans that belongs to the pleiotropic drug resistance (PDR) subfamily of ABC transporters found in fungi and plants. Cdr1p is overexpressed in several azole-resistant clinical isolates, causing azole efflux and treatment failure. Cdr1p appears as a doublet band in western blot analyses, suggesting that the protein is post-translationally modified. We investigated whether Cdr1p is phosphorylated and the function of this modification. METHODS: Phosphorylated residues were identified by MS. Their function was investigated by site-directed mutagenesis and expression of the mutants in a C. albicans endogenous system that exploits a hyperactive allele of the Tac1p transcription factor to drive high levels of Cdr1p expression. Fluconazole resistance was measured by microtitre plate and spot assays and transport activity by Nile red accumulation. RESULTS: We identified a cluster of seven phosphorylated amino acids in the N-terminal extension (NTE) of Cdr1p. Mutating all seven sites to alanine dramatically diminished the ability of Cdr1p to confer fluconazole resistance and transport Nile red, without affecting Cdr1p localization. Conversely, a Cdr1p mutant in which the seven amino acids were replaced by glutamate was able to confer high levels of fluconazole resistance and to export Nile red. CONCLUSIONS: Our results demonstrate that the NTE of Cdr1p is phosphorylated and that NTE phosphorylation plays a major role in regulating Cdr1p and possibly other PDR transporter function.

A new class of anthelmintics effective against drug-resistant nematodes.

Anthelmintic resistance in human and animal pathogenic helminths has been spreading in prevalence and severity to a point where multidrug resistance against the three major classes of anthelmintics--the benzimidazoles, imidazothiazoles and macrocyclic lactones--has become a global phenomenon in gastrointestinal nematodes of farm animals. Hence, there is an urgent need for an anthelmintic with a new mode of action. Here we report the discovery of the amino-acetonitrile derivatives (AADs) as a new chemical class of synthetic anthelmintics and describe the development of drug candidates that are efficacious against various species of livestock-pathogenic nematodes. These drug candidates seem to have a novel mode of action involving a unique, nematode-specific clade of acetylcholine receptor subunits. The AADs are well tolerated and of low toxicity to mammals, and overcome existing resistances to the currently available anthelmintics.

Low-Level Visual Features of Window Views Contribute to Perceived Naturalness and Mental Health Outcomes.

Previous studies have shown that natural window views are beneficial for mental health, but it is still unclear which specific features constitute a 'natural' window view. On the other hand, studies on image analysis found that low-level visual features (LLVFs) are associated with perceived naturalness, but mainly conducted experiments with brief stimulus presentations. In this study, research on the effects of window views on mental health was combined with the detailed analysis of LLVFs. Healthy adults rated window views from their home and sent in photographs of those views for analysis. Content validity of the 'ecological' view assessment was evaluated by checking correlations of LLVFs with window view ratings. Afterwards, it was explored which of the LLVFs best explained variance in perceived percentage of nature and man-made elements, and in ratings of view quality. Criterion validity was tested by investigating which variables were associated with negative affect and impulsive decision-making. The objective and subjective assessments of nature/sky in the view were aligned but objective brightness was unreliable. The perceived percentage of nature was significantly explained by green pixel ratio, while view quality was associated with fractals, saturation, sky pixel ratio and straight edge density. The higher subjective brightness of rooms was associated with a lower negative affect, whereas results for impulsive decision-making were inconsistent. The research highlights the validity to apply LLVFs analysis to ecological window views. For affect, subjective brightness seemed to be more relevant than LLVFs. For impulsive decision-making, performance context needs to be controlled in future studies.

Design, synthesis and antiproliferative activity of raloxifene/histone deacetylase inhibitor hybrids in breast cancer.

Antiestrogen/histone deacetylase inhibitor (HDACi) hybrids were designed by merging structures of raloxifene with suberoylanilide hydroxamic acid, incorporating the HDACi unit into the phenolic ring of the antiestrogen. These hybrids were synthesized with a range of HDACi chain lengths and assessed for bifunctionality. Four hybrids, 21 (YW471), 22 (YW490), 27(YW486), and 28 (YW487) showed good potency both as antiestrogens in a BRET assay and in a fluorometric HDACi assay. The antiproliferative activity of the hybrids was demonstrated in both ER+ MCF7 and ER- MDA-MB-231 breast cancer cell lines.

Quantitative NMR Spectrometry of Phenylpropanoids, including Isoeugenol in Herbs, Spices, and Essential Oils.

Isoeugenol (2-methoxy-4-(1-propenyl)phenol) has been recently classified as possibly carcinogenic to humans (Group 2B) by the International Agency for Research on Cancer (IARC). This study conducted an analysis of isoeugenol in common herbs and spices, including basil, cinnamon, ginger, and nutmeg, using 1H nuclear magnetic resonance (NMR) spectrometry. Additionally, over 1300 coffee samples were analysed by 1H-NMR for isoeugenol, but it was not detected in any of the analysed samples. Various essential oils, including nutmeg, basil, clove, sweet flag, and ylang-ylang oils, were examined for isoeugenol content. Out of the twelve nutmeg oils tested, four contained isoeugenol, with concentrations ranging from 3.68 ± 0.09 g/kg to 11.2 ± 0.10 g/kg. However, isoeugenol was not detected in the essential oils of calamus, basil, ylang-ylang, and clove using NMR spectrometry. These findings warrant critical evaluation of the previous literature, given reports of high isoeugenol levels in some of these matrices. A toxicological assessment has determined that there is no risk to human health by exposure to isoeugenol via nutmeg essential oils.

Functional and Radiologic Outcomes of Degenerative Versus Traumatic Full-Thickness Rotator Cuff Tears Involving the Supraspinatus Tendon.

BACKGROUND: Arthroscopic rotator cuff repair (ARCR) is among the most commonly performed orthopaedic procedures. Several factors-including age, sex, and tear severity-have been identified as predictors for outcome after repair. The influence of the tear etiology on functional and structural outcome remains controversial. PURPOSE: To investigate the influence of tear etiology (degenerative vs traumatic) on functional and structural outcomes in patients with supraspinatus tendon tears. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Patients undergoing ARCR from 19 centers were prospectively enrolled between June 2020 and November 2021. Full-thickness, nonmassive tears involving the supraspinatus tendon were included. Tears were classified as degenerative (chronic shoulder pain, no history of trauma) or traumatic (acute, traumatic onset, no previous shoulder pain). Range of motion, strength, the Subjective Shoulder Value, the Oxford Shoulder Score (OSS), and the Constant-Murley Score (CMS) were assessed before (baseline) and 6 and 12 months after ARCR. The Subjective Shoulder Value and the OSS were also determined at the 24-month follow-up. Repair integrity after 12 months was documented, as well as additional surgeries up to the 24-month follow-up. Tear groups were compared using mixed models adjusted for potential confounding effects. RESULTS: From a cohort of 973 consecutive patients, 421 patients (degenerative tear, n = 230; traumatic tear, n = 191) met the inclusion criteria. The traumatic tear group had lower mean baseline OSS and CMS scores but significantly greater score changes 12 months after ARCR (OSS, 18 [SD, 8]; CMS, 34 [SD,18] vs degenerative: OSS, 15 [SD, 8]; CMS, 22 [SD, 15]) (P < .001) and significantly higher 12-month overall scores (OSS, 44 [SD, 5]; CMS, 79 [SD, 9] vs degenerative: OSS, 42 [SD, 7]; CMS, 76 [SD, 12]) (P≤ .006). At the 24-month follow-up, neither the OSS (degenerative, 44 [SD, 6]; traumatic, 45 [SD, 6]; P = .346) nor the rates of repair failure (degenerative, 14 [6.1%]; traumatic 12 [6.3%]; P = .934) and additional surgeries (7 [3%]; 7 [3.7%]; P = .723) differed between groups. CONCLUSION: Patients with degenerative and traumatic full-thickness supraspinatus tendon tears who had ARCR show satisfactory short-term functional results. Although patients with traumatic tears have lower baseline functional scores, they rehabilitate over time and show comparable clinical results 1 year after ARCR. Similarly, degenerative and traumatic rotator cuff tears show comparable structural outcomes, which suggests that degenerated tendons retain healing potential.

My home-my castle? Self-reported anxiety varies in relation to the subjective evaluation of home environment.

Introduction: Although people spend most of the day in their home environment, the focus of research in environmental psychology to date has been on factors outside the home. However, it stands to reason that indoor quality likewise has an impact on psychological well-being. Therefore, the present study addresses the question of whether the subjective evaluation of home environmental parameters are related to self-reported anxiety and whether they can additionally explain variance beyond the usual sociodemographic and general lifestyle variables. Methods: Data from the Hamburg City Health Study (first 10,000 participants) was analyzed. A subsample of N = 8,886 with available GAD-7 anxiety data was selected, and hierarchical regression models were computed, with demographic data entered first, followed by variables concerning lifestyle/habits and finally variables of the subjective evaluation of home environment. Results: Using the integrated model, we were able to explain about 13% of the variance in self-reported anxiety scores. This included both the demographic, lifestyle, and subjective evaluation of home environment variables. Protection from disturbing night lights, a greater sense of security, less disturbing noises, brighter accommodations, and a satisfactory window view explained almost 6% of the variance and was significantly associated with lower anxiety scores. Conclusion: The home as a place of refuge plays an increasingly important role as home office hours rise. It is therefore crucial to identify domestic factors contributing to people's mental well-being. The subjective evaluation of one's home environment has proven influential over and above modifiable lifestyle variables.

Use of Capillary Aerosol Generator in Continuous Production of Controlled Aerosol for Non-Clinical Studies.

The capillary aerosol generator (CAG) is operated with the principal of thermal liquid evaporation through heating of e-liquid in the initial phase, followed by nucleation and condensation regulated through a mixture of airflow to generate aerosols, such as in an electronic cigarette (EC). The CAG is particularly useful in generating aerosols of large volumes in a continuous manner, for instances such as in vivo inhalation toxicology studies, where usage of ECs is not feasible. The thermal effects of generating aerosol from the CAG are similar in terms of temperature applied in an EC, thus allowing investigators to assess the vapors of e-liquids at scale and reproducibility. As the operation of the CAG allows users to control critical parameters such as the flow rate of e-liquid, heating temperatures and dilution air flows, it allows investigators to test various e-liquid formulations in a well-controlled device. Properties, such as aerosol particle size, are demonstrated to be regulated with the air flow rate with respect to the e-liquid flow and e-liquid composition. The CAG, however, is limited in assessing common EC-related issues, such as overheating of its elements. We seek to demonstrate that the CAG can generate aerosol that is reproducible and continuous, by assessing the chemical and physical aerosol characteristics with a chosen e-liquid formulation. The protocol describes the operating parameters of liquid flow rate, dilution air-flow rates and operating procedures needing to optimize the aerosol concentration and particle size required for an in vivo toxicology study. Presenting the representative results from the protocol and discussing the challenges and applications of working with a CAG, we demonstrate that CAG can be used in a reproducible fashion. The technology and protocol, that has been developed from prior work, serve as a foundation for future innovations for laboratory-controlled aerosol generation investigations.

Stereospecific lasofoxifene derivatives reveal the interplay between estrogen receptor alpha stability and antagonistic activity in ESR1 mutant breast cancer cells.

Chemical manipulation of estrogen receptor alpha ligand binding domain structural mobility tunes receptor lifetime and influences breast cancer therapeutic activities. Selective estrogen receptor modulators (SERMs) extend estrogen receptor alpha (ERα) cellular lifetime/accumulation. They are antagonists in the breast but agonists in the uterine epithelium and/or in bone. Selective estrogen receptor degraders/downregulators (SERDs) reduce ERα cellular lifetime/accumulation and are pure antagonists. Activating somatic ESR1 mutations Y537S and D538G enable resistance to first-line endocrine therapies. SERDs have shown significant activities in ESR1 mutant setting while few SERMs have been studied. To understand whether chemical manipulation of ERα cellular lifetime and accumulation influences antagonistic activity, we studied a series of methylpyrollidine lasofoxifene (Laso) derivatives that maintained the drug's antagonistic activities while uniquely tuning ERα cellular accumulation. These molecules were examined alongside a panel of antiestrogens in live cell assays of ERα cellular accumulation, lifetime, SUMOylation, and transcriptional antagonism. High-resolution x-ray crystal structures of WT and Y537S ERα ligand binding domain in complex with the methylated Laso derivatives or representative SERMs and SERDs show that molecules that favor a highly buried helix 12 antagonist conformation achieve the greatest transcriptional suppression activities in breast cancer cells harboring WT/Y537S ESR1. Together these results show that chemical reduction of ERα cellular lifetime is not necessarily the most crucial parameter for transcriptional antagonism in ESR1 mutated breast cancer cells. Importantly, our studies show how small chemical differences within a scaffold series can provide compounds with similar antagonistic activities, but with greatly different effects of the cellular lifetime of the ERα, which is crucial for achieving desired SERM or SERD profiles.