Transgender and Nonbinary Individuals' Perceptions Regarding Gender-Affirming Hormone Therapy and Cardiovascular Health: A Qualitative Study.

BACKGROUND: Transgender and nonbinary individuals face substantial cardiovascular health uncertainties. The use of gender-affirming hormone therapy can be used to achieve one's gender-affirming goals. As self-rated health is an important predictor of health outcomes, an understanding of how this association is perceived by transgender and nonbinary individuals using gender-affirming hormone therapy is required. The objective of this research was to explore transgender and nonbinary individuals' perceptions of cardiovascular health in the context of using gender-affirming hormone therapy. METHODS: In this qualitative study, English-speaking transgender and nonbinary adults using gender-affirming hormone therapy for 3 months or more were recruited from across Canada using purposive and snowball sampling methods. Semistructured interviews were conducted through videoconference to explore transgender and nonbinary individuals' perceptions of the association between gender-affirming hormone therapy and cardiovascular health between May and August 2023. Data were transcribed verbatim, and transcripts were analyzed independently by 3 reviewers using thematic analysis. RESULTS: Twenty-one participants were interviewed (8 transgender women, 9 transgender men, and 3 nonbinary individuals; median [range] age, 27 [20-69] years; 80% White participants). Three main themes were identified: cardiovascular health was not a primary concern in the decision-making process with regard to gender-affirming hormone therapy, the improved well-being associated with gender-affirming hormone therapy was felt to contribute to improved cardiovascular health, and health care provider knowledge and attitude facilitate the transition process. CONCLUSIONS: Gender-affirming hormone therapy in transgender and nonbinary individuals is perceived to improve cardiovascular health. Given the positive associations between care aligned with patient priorities, self-rated health, and health outcomes, these findings should be considered as part of shared decision-making and person-centered care.

Robot-assisted partial nephrectomy in patients aged 75 years or older - comparing the risk of complications with their younger counterparts.

BACKGROUND & AIM: More elderly patients are diagnosed with kidney tumors where partial nephrectomy is technically possible. We investigated whether patients ≥ 75 years old had an increased risk of complications following robot-assisted partial nephrectomy (RAPN) compared to younger patients. METHODS: Retrospective, consecutive study including patients who underwent RAPN between May 2016 - April 2023. Preoperative data, operative data and complications within 90 days were recorded by patient record review. Complications were classified according to Clavien-Dindo (CD). RESULTS: 451 patients underwent RAPN and a postoperative complication was recorded in 131 (29%) patients of which 28 (6%) were CD ≥ III. Any postoperative complication was recorded in 24/113 patients (21%) < 55 years, 40/127 patients (31%) 55-64 years, 45/151 patients (42%) 65-74 years, and 22/60 patients (37%) ≥ 75 years. Comparable numbers for a CD ≥ III postoperative complication were 2/113 (2%) < 55 years, 6/127 (7%) 55-64 years, 12/151 (8%) 65-74 years, and 5/60 (8%) ≥ 75 years. In multivariate logistic regression analysis, patients ≥ 75 years had a non-significant increased risk of complications when controlling for preoperative variables (OR 1.82 [95% CI 0.80-4.13]) or perioperative variables (OR 1.98 [95% CI 0.86-4.58]) compared to patients < 55 years. Two patients died postoperatively. Both were ≥ 75 years (2/60, 3%). DISCUSSION AND CONCLUSIONS: Selected patients ≥ 75 years can undergo RAPN without a significantly increased risk of postoperative complications. However, a mortality rate of 3% in this age group indicates that these patients are frail when postoperative complications occur.

Level of Pain and Physical Function in Patient with Chronic Knee Pain Visiting Dhulikhel Hospital.

Background Chronic knee pain is a common and major health problem in ageing population which is also associated with high levels of disability. So early detection and treatment of pain related functional limitation is likely to have major influence on healthy ageing. Objective To quantify the level of pain and physical function in patient with chronic knee pain. Method Preliminary screening of population with chronic knee pain was taken and cross sectional descriptive study was done. Questionnaire with inclusion criteria was fulfilled with administration of Nepali version of Numerical Pain Rating Scale and Nepali version of Patient Specific Functional Scale on interview as well as self-report basis. Data was collected, recorded and analyzed using Statistical Package for the Social Sciences (SPSS) version 23. Result Chronic knee pain was found in 75.6% of female with the average pain level found to be 5 in Nepali version of Numerical pain rating scale. Sitting function was found to be affected in 82.1% of population with mean score of 2 in Nepali version of Patient specific functional Scale. Similarly 80.8% reported going downstairs to be difficult due to knee pain. Conclusion Pain and functional disability are the principle findings in patient with chronic knee pain for which they seek medical treatment. So the treatments should target on functional task with effective strategy to address disability. Focus on function is important for the development of optimal rehabilitation programs in patients with chronic knee pain.

The Heat Shock Protein 27 Immune Complex Enhances Exosomal Cholesterol Efflux.

Previously, we demonstrated that Heat Shock Protein 27 (HSP27) reduces the inflammatory stages of experimental atherogenesis, is released by macrophage (MΦ) exosomes and lowers cholesterol levels in atherosclerotic plaques. Recently, we discovered that natural autoantibodies directed against HSP27 enhance its signaling effects, as HSP27 immune complexes (IC) interact at the cell membrane to modulate signaling. We now seek to evaluate the potential role of the HSP27 IC on MΦ exosomal release and cholesterol export. First, in human blood samples, we show that healthy control subjects have 86% more exosomes compared to patients with coronary artery disease (p < 0.0001). Treating human THP-1 MΦ with rHSP27 plus a validated anti-HPS27 IgG antibody increased the abundance of exosomes in the culture media (+98%; p < 0.0001) as well as expression of Flotillin-2, a marker reflective of exosomal release. Exosome cholesterol efflux was independent of Apo-A1. THP-1 MΦ loaded with NBD-labeled cholesterol and treated with the HSP27 IC showed a 22% increase in extracellular vesicles labeled with NBD and a 95% increase in mean fluorescent intensity. In conclusion, exosomal abundance and secretion of cholesterol content increases in response to HSP27 IC treatment, which may represent an important therapeutic option for diseases characterized by cholesterol accumulation.

Analysis of natural product regulation of opioid receptors in the treatment of human disease.

Opioid receptors (ORs), µOR, δOR, κOR and ORL1 mediate numerous signalling cascades, most importantly, through the modulation of ion channels. Research demonstrates the role of OR mediated signal transduction in treating pain, cancer, neurodegenerative disorders and cardiac insults. Yet, the primary application of drugs that modulate ORs is analgesia. Current opioids like morphine that are mainly µOR orthosteric agonists attract many undesirable side-effects (constipation, urinary retention, respiratory depression and hypotension) and the existing modus operandi against these is the inclusion of a µOR antagonist (for example, naloxone) which itself produces side-effects. As such, there is a current thrust to delineate the anti-nociceptive pathways mediated by ORs from the pathways involved in their induction of debilitating side-effects, in order to develop enhanced lead molecules. This review discusses the effects of natural products on the OR-induced signalling cascades and compares these to current synthetic leads and drugs. Important to these discussions is the complexity of OR signalling which involves OR trafficking, de- and re-sensitization, homo- and hetero-dimerization, the type of ligand binding (agonist, antagonist, reverse antagonist, orthosteric and allosteric agonist and antagonist in the context of biased agonism) and reasons for dysregulation that primarily occur because of inter-individual variations. Our current understanding of the different forms of ORs has expanded, thus introducing the concept of allosterism, which is also discussed. The authors present possible combination therapies to be explored towards developing the 'Holy Grail' of analgesics, for example, ignavine, the natural µOR positive allosteric modulator (PAM) with codeine and the natural fascaplysin, a balanced agonist with fentanyl. There remain many gaps in natural products research on ORs, more so on ORL1 and δ- and κ receptors. Furthermore, additional exploration of ORs' modulation is needed for ameliorating other associated disease conditions of global concern.

Analysis of natural product regulation of cannabinoid receptors in the treatment of human disease.

The organized, tightly regulated signaling relays engaged by the cannabinoid receptors (CBs) and their ligands, G proteins and other effectors, together constitute the endocannabinoid system (ECS). This system governs many biological functions including cell proliferation, regulation of ion transport and neuronal messaging. This review will firstly examine the physiology of the ECS, briefly discussing some anomalies in the relay of the ECS signaling as these are consequently linked to maladies of global concern including neurological disorders, cardiovascular disease and cancer. While endogenous ligands are crucial for dispatching messages through the ECS, there are also commonalities in binding affinities with copious exogenous ligands, both natural and synthetic. Therefore, this review provides a comparative analysis of both types of exogenous ligands with emphasis on natural products given their putative safer efficacy and the role of Δ9-tetrahydrocannabinol (Δ9-THC) in uncovering the ECS. Efficacy is congruent to both types of compounds but noteworthy is the effect of a combination therapy to achieve efficacy without unideal side-effects. An example is Sativex that displayed promise in treating Huntington's disease (HD) in preclinical models allowing for its transition to current clinical investigation. Despite the in vitro and preclinical efficacy of Δ9-THC to treat neurodegenerative ailments, its psychotropic effects limit its clinical applicability to treating feeding disorders. We therefore propose further investigation of other compounds and their combinations such as the triterpene, α,ß-amyrin that exhibited greater binding affinity to CB1 than CB2 and was more potent than Δ9-THC and the N-alkylamides that exhibited CB2 selective affinity; the latter can be explored towards peripherally exclusive ECS modulation. The synthetic CB1 antagonist, Rimonabant was pulled from commercial markets for the treatment of diabetes, however its analogue SR144528 maybe an ideal lead molecule towards this end and HU-210 and Org27569 are also promising synthetic small molecules.

Role of the modulation of CYP1A1 expression and activity in chemoprevention.

As one of the main extra-hepatic cytochrome P450 (CYP) enzymes, CYP1A1 has been comprehensively investigated for its ability to metabolize both exogenous and endogenous compounds into their carcinogenic derivatives. These derivatives are linked to cancer initiation and progression. The compound benzo-a-pyrene (BaP), a copious and noxious compound present in coal tar, automobile exhaust fumes, cigarette smoke and charbroiled food, is metabolised by CYP1A1 and has been studied in great detail. Other compounds reliant on the same enzyme for their activation include 7,12 dimethylbenz(a)anthracene (DMBA) and heterocyclic amine, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). This review takes an in-depth look at a number of phytochemicals, plant extracts and a few synthetic compounds that have been researched and deemed potential chemopreventives via their interaction with the activity and expression of CYP1A1. It will also review a useful active site model of CYP1A1. Based on inhibitors of CYP1A1 that have demonstrated in vivo use as chemopreventors, CYP1A1 is a useful initial target for screening compounds with such potential, with the use of rapid in vitro and/or in silico assessments. Chemoprevention is a means by which healthy tissues are protected via the prevention, inhibition or reversal of carcinogenesis. This review focuses on one important pathway of carcinogenesis and identifies the important role that CYP1A1 plays in that pathway. It is hoped that highlighting the importance of such a key target, will help revive further research into and application of inhibitors of CYP1A1 towards generating improved chemopreventors.

Cytochrome P450 1 enzyme inhibition and anticancer potential of chromene amides from Amyris plumieri.

Cytochrome P450 (CYP) enzyme inhibitory properties of six chromenylated amide compounds (CAs) from Amyris plumieri are described. Inhibition of CYP microsomes (CYP1A1, CYP1A2, CYP1B1, CYP2D6, CYP3A4 and CYP2C19) was monitored using a fluorescent assay. Potent inhibition was found against CYP1A1 with IC(50) and K(i) for CA1 (acetamide), being the lowest at 1.547 ± 1.0 µM and 0.37 µM respectively, displaying non-competitive kinetics. The selectivity for CYP1A1 was increased in CA3 (butanamide), which also exhibited cytotoxicity against breast cancer cells, MCF7 with an IC(50) of 47.46 ± 1.62 µM. Structure-activity relationship studies provide insight at a molecular level for CAs with implications in chemoprevention and chemotherapy.

Evaluation of anti-inflammatory and analgesic activity of a new class of biphenyl analogs in animal models of inflammation.

A new class of 4'-methylbiphenyl-2-(substituted phenyl)carboxamide derivatives had been previously evaluated in vivo for their anti-inflammatory activities in animal models of inflammation. In the present study, the most active compound of that series, compound 4e (4'-methylbiphenyl-2-(4-carboxy phenyl)carboxamide), was investigated in detail for its anti-inflammatory, analgesic and ulcerogenic potential. Pretreatment of rats with 4e (100 mg/kg) reduced carrageenan induced rat paw edema at 3 h compared to control group. Dose dependent percent inhibition of granuloma formation, exudate volume, total leukocyte count was observed in 4e (25, 50 and 100 mg/kg) and celecoxib (CAS 169590-42-5; 5 mg/kg) treated groups in the cotton pellet granuloma and granuloma pouch technique, respectively, in rats. C-reactive proteins were absent in the 4e treated group. Compound 4e inhibited acetic acid induced writhing dose dependently (10, 20 and 30 mg/kg). Compound 4e was inactive in the hot plate test. Gastric toxicity screening experiments showed that compound 4e, both after single and repeated oral administration, is devoid of any gastric irritation in rats. The LD50 was found to be more than 2000 mg/kg.

Men's violence against women in rural Bangladesh: undermined or exacerbated by microcredit programmes?

PIP: This ethnographic study examined the sociocultural context of domestic violence in 6 rural villages in Bangladesh, and the prevalence of wife-beating and its association with women's empowerment in income generation programs (IGPs). Data were obtained from interviews conducted during 1990-96. Four villages had IGPs, and 2 villages did not have credit programs. Over 66% of women reported having been beaten at one time or another. In one village 87% reported beatings. 38% reported beatings in the preceding year (a range of 14-60%). Men beat their wives over trivial matters or frustrations over problems for which wives were not responsible. Beatings were attributed to mens' desire to control behavior and reassert their authority when challenged or to exploit their wives for financial gain. Some of the most severe beatings were linked with dowry. Both husbands and wives considered the beatings legitimate. The highest level of violence was in villages that were experiencing the most changes in gender roles and that had the most women contributing to family support. The lowest levels of violence were in villages with the fewest contributing to family support. Interviews, case studies, and observations yielded ambivalent evidence about the influence of credit programs on domestic violence. Credit programs have the potential to increase women's status and to disseminate anti-violence messages among both men and women.^ieng