N6-Deoxyadenosine Methylation in Mammalian Mitochondrial DNA.

N6-Methyldeoxyadenosine (6mA) has recently been shown to exist and play regulatory roles in eukaryotic genomic DNA (gDNA). However, the biological functions of 6mA in mammals have yet to be adequately explored, largely due to its low abundance in most mammalian genomes. Here, we report that mammalian mitochondrial DNA (mtDNA) is enriched for 6mA. The level of 6mA in HepG2 mtDNA is at least 1,300-fold higher than that in gDNA under normal growth conditions, corresponding to approximately four 6mA modifications on each mtDNA molecule. METTL4, a putative mammalian methyltransferase, can mediate mtDNA 6mA methylation, which contributes to attenuated mtDNA transcription and a reduced mtDNA copy number. Mechanistically, the presence of 6mA could repress DNA binding and bending by mitochondrial transcription factor (TFAM). Under hypoxia, the 6mA level in mtDNA could be further elevated, suggesting regulatory roles for 6mA in mitochondrial stress response. Our study reveals DNA 6mA as a regulatory mark in mammalian mtDNA.

Heterogeneity of cancer stem cell-related marker expression is associated with three-dimensional structures in malignant pleural effusion produced by lung adenocarcinoma.

INTRODUCTION: Cancer stem cells have been described in lung adenocarcinoma-associated malignant pleural effusion. They show clinically important features, including the ability to initiate new tumours and resistance to treatments. However, their correlation with the three-dimensional tumour structures in the effusion is not well understood. METHODS: Cell blocks produced from lung adenocarcinoma patients' pleural effusion were examined for cancer stem cell-related markers Nanog and CD133 using immunocytochemistry. The three-dimensional cancer cell structures and CD133 expression patterns were visualized with tissue-clearing technology. The expression patterns were correlated with tumour cell structures, genetic variants and clinical outcomes. RESULTS: Thirty-nine patients were analysed. Moderate-to-strong Nanog expression was detected in 27 cases (69%), while CD133 was expressed by more than 1% of cancer cells in 11 cases (28%). Nanog expression was more homogenous within individual specimens, while CD133 expression was detected in single tumour cells or cells within small clusters instead of larger structures in 8 of the 11 positive cases (73%). Although no statistically significant correlation between the markers and tumour genetic variants or patient survival was observed, we recorded seven cases with follow-up specimens after cancer treatment, and four (57%) showed a change in stem cell-related marker expression corresponding to treatment response. CONCLUSIONS: Lung adenocarcinoma cells in the pleural effusion show variable expression of cancer stem cell-related markers, some showing a correlation with the size of cell clusters. Their expression level is potentially correlated with cancer treatment effects.

Platycodi radix aqueous extract salvages doxorubicin-induced senescence by mitochondrial reactive oxygen species reduction in umbilical cord matrix stem cells.

Platycodi radix is a widely used herbal medicine that contains numerous phytochemicals beneficial to health. The health and biological benefits of P. radix have been found across various diseases. The utilization of umbilical cord stromal stem cells, derived from Wharton's jelly of the human umbilical cord, has emerged as a promising approach for treating degenerative diseases. Nevertheless, growing evidence indicates that the function of stem cells declines with age, thereby limiting their regenerative capacity. The primary objective in this study is to investigate the beneficial effects of P. radix in senescent stem cells. We conducted experiments to showcase that diminished levels of Lamin B1 and Sox-2, along with an elevation in p21, which serve as indicative markers for the senescent stem cells. Our findings revealed the loss of Lamin B1 and Sox-2, coupled with an increase in p21, in umbilical cord stromal stem cells subjected to a low-dose (0.1 µM) doxorubicin (Dox) stimulation. However, P. radix restored the Dox-damage in the umbilical cord stromal stem cells. P. radix reversed the senescent conditions when the umbilical cord stromal stem cells exposed to Dox-induced reactive oxygen species (ROS) and mitochondrial membrane potential are significantly changed. In Dox-challenged aged umbilical cord stromal stem cells, P. radix reduced senescence, increased longevity, prevented mitochondrial dysfunction and ROS and protected against senescence-associated apoptosis. This study suggests that P. radix might be as a therapeutic and rescue agent for the aging effect in stem cells. Inhibition of cell death, mitochondrial dysfunction and aging-associated ROS with P. radix provides additional insights into the underlying molecular mechanisms.

Telemental Health Services Usage and Association with Health Care Utilization and Expenditures Among Vulnerable Medicare Beneficiaries in 2019: A Comparative Study Using Propensity Score Matching.

Background: Telemental health (TMH) offers a promising approach to managing major depressive disorder (MDD). The objective of our work was to evaluate TMH usage among a vulnerable population of MDD Medicare beneficiaries and its association with health care utilization and expenditures. Methods: This cohort study analyzed 2019 Mississippi Medicare fee-for-service data for adult beneficiaries with MDD. Subjects were matched by the use of TMH following 1:1 propensity score matching. Comparisons between TMH and non-TMH cohorts were made on health care utilization and expenditure outcomes, adjusting for provider types postmatching. Results: Among 7,673 identified beneficiaries, 551 used TMH and 7,122 did not. Prematching, TMH cohort showed greater proportions of dual beneficiaries, rural residents, subjects with income below $40,000, those with disability entitlement, and higher Charlson comorbidity index scores, compared to the non-TMH cohort (all p < 0.001). Moreover, the TMH cohort had fewer outpatient visits, but more inpatient admissions, emergency department (ED) visits, and higher medical, pharmacy, and total expenditures (all p < 0.001). Postmatching, TMH was associated with a 25% reduction in outpatient visits (p < 0.001) and a 20% reduction in pharmacy expenditures (p = 0.01), with no significant effect on inpatient admissions, ED visits, medical expenditures, or total expenditures. Conclusions: These results underscore the potential of TMH in enhancing accessible health care services for vulnerable populations and affordable services for Medicare. Our results provide a robust baseline for future policy discussions concerning TMH. Future studies should consider identifying barriers to TMH use among vulnerable populations and ensuring equitable and high-quality patient care.

Feasibility of Remote Blood Pressure Monitoring for Detection and Management of Maternal Hypertension in a predominantly Black, Rural and Medicaid Population in Mississippi.

Background: Remote patient monitoring (RPM) has potential in hypertension management, but limited studies have focused on maternal hypertension, especially among vulnerable populations. The objective of this study was to integrate RPM into perinatal care for pregnant patients at elevated risk of hypertensive disorders to show feasibility, acceptability, and safety. Methods: A prospective pilot cohort study was conducted at the University of Mississippi Medical Center 2021-2023. Participants' blood pressure readings were remotely captured and monitored until 8-week postpartum, with timely assessment and intervention. Results: Out of 98 enrollees, 77 utilized RPM, and no maternal or neonatal deaths occurred within 60-day postpartum. High program satisfaction was reported at discharge. Conclusion: This study demonstrates the feasibility and acceptability of RPM for perinatal care in a vulnerable population. Positive outcomes were observed, including high patient satisfaction and no maternal or neonatal deaths. Further research should address patient engagement barriers and develop tailored protocols for improved clinical outcomes.

Assessing Telemental Health Uptake and Associated Health Care Resource Implications among Mississippi Medicaid Enrollees with Major Depression.

Objective: Investigate the association between Telemental Health (TMH) uptake and sociodemographic characteristics, and how TMH uptake relates to health care resource utilization and Medicaid expenditures among Mississippi Medicaid enrollees with major depression. Methods: A retrospective cohort study was conducted (2019-2020), comparing those who utilized TMH and those who did not. Results: Among the 21,239 identified enrollees, 806 (3.79%) utilized TMH. The TMH cohort was more likely to be of older age, non-Hispanic White, comprehensive managed care organization enrollees, rural residents, and from areas with a higher area deprivation index, and have higher Charlson comorbidity index scores. The TMH cohort also exhibited higher mental health-related and all-cause outpatient and emergency department utilization, along with higher Medicaid expenditures. Conclusion: As the first study investigating telehealth utilization among Mississippi Medicaid enrollees, this study highlights sociodemographic disparities in telehealth adoption. Addressing barriers hindering telehealth adoption among vulnerable populations and ensuring the availability of quality data are vital for future research.

Reimbursement for HPV Vaccine Cost in the Private Sector: A Comparison Across Specialties.

The human papillomavirus (HPV) vaccine is the most expensive of all routinely recommended pediatric vaccines. Adequate cost reimbursement by 3rd-party payers is a critical enabling factor for clinicians to continue offering vaccines. This study found that net returns from HPV vaccine cost reimbursements are lowest for family physicians ($0.34/dose) and highest for pediatricians ($5.08/dose). Furthermore, a $1 increment in return was associated with an increase in HPV vaccine doses administered (highest for family physicians; 0.08% per dollar). Reimbursement for HPV vaccine costs by private payers is adequate; however, return margins are small for non-pediatric specialties.

Effect of short-course radiotherapy followed by oxaliplatin-based consolidation chemotherapy on organ preservation in locally advanced rectal cancer.

PURPOSE: We analyzed the effectiveness, safety, and mid-term oncological outcomes of short-course radiotherapy (SCRT) and oxaliplatin-based consolidation chemotherapy in patients with locally advanced rectal cancer (LARC). METHODS: We retrospectively evaluated 64 patients with LARC who underwent SCRT and tegafox (tegafur-uracil/leucovorin plus oxaliplatin) or mFOLFOX-6 (5-fluorouracil, leucovorin, and oxaliplatin) consolidation chemotherapy before surgery between January 2015 and December 2020. Tumor response, patient compliance, toxicity, surgical outcomes, overall survival (OS), and disease-free survival (DFS) were analyzed. RESULTS: Sixty-four patients with a mean age of 58.67 years (44 males) were included; 48 (75%) had tumors within 5 cm of the anal verge. Additionally, 93.8% of the patients underwent at least 2 months of chemotherapy, and three required dose reduction. Grade III toxicity occurred in 2 patients, and 10 had a clinical complete response and opted for non-operative management. One patient experienced tumor progression and underwent further treatment without surgery. Among the 53 patients who underwent surgery, 51 (96.2%) had sphincter preservation, 3 had Clavien-Dindo grade III complications, and no mortality occurred. The complete response rate for the entire cohort was 23.4%. Moreover, 47 patients (74.6%) had a neoadjuvant rectal score of < 16 after treatment. After a median follow-up time of 32.01 months, 6 (9.3%) had local recurrence, and 17 (26.6%) had distant metastasis. The 3-year OS, DFS and stoma-free rates were 89.5%, 65.5%, and 78.1% respectively. CONCLUSION: SCRT followed by oxaliplatin-based consolidation chemotherapy is safe and effective for tumor downstaging in LARC, further improving the sphincter preservation rate.

Gemcitabine resistance in non-small cell lung cancer is mediated through activation of the PI3K/AKT/NF-κB pathway and suppression of ERK signaling by reactive oxygen species.

Lung cancer is one of the most common cancers in the world. Chemotherapy is a standard clinical treatment. However, tumor cells often develop multidrug resistance after chemotherapy, an inevitable bottleneck in cancer treatment. Therefore, this study used gemcitabine-resistant (GEM-R) CL1-0 lung cancer cells. First, we used flow cytometry and western blot analysis to examine differences in performance between resistant and parental cells. The results showed that compared with parental cells, GEM-R CL1-0 cells significantly enhanced the activation of the AKT pathway, which promoted survival and growth, and decreased the activation of the reactive oxygen species-extracellular signal-regulated kinase (ROS)-ERK pathway. Next, the AKT and ERK pathways' role in tumor growth was further explored in vivo using a xenograft model. The results showed that enhancing AKT and inhibiting ERK activation reduced GEM-induced inhibition of tumor growth. Finally, combining the above results, we found that GEM-R CL1-0 cells showed reduced sensitivity to GEM by activating the phosphatidylinositol 3-kinase/AKT/NF-kB pathway and inhibiting the ROS-ERK pathway leading to resistance against GEM. Therefore, the AKT and ERK pathways are potential targets for improving the sensitivity of cancer cells to anticancer drugs.

Longitudinal care continuity and avoidable hospitalization: the application of claims-based measures.

BACKGROUND: Longitudinal continuity between a patient and his/her primary care physician is an important aspect in measuring continuity of care (COC). The majority of previous studies employed questionnaire surveys to patients to measure the continual relationship between patients and their physicians. This study aimed to construct a provider duration continuity index (PDCI) by using longitudinal claims data and to examine its agreement with commonly used COC measures. Then, this study investigated the effects of the various types of COC measure on the likelihood of avoidable hospitalization while considering the level of comorbidity. METHODS: This study constructed a 4-year panel (from 2014 to 2017) of the nationwide health insurance claims data in Taiwan. In total, 328,044 randomly selected patients with 3 or more physician visits per year were analyzed. Two PDCIs were constructed to measure the duration of interaction between a patient and his/her physicians over time. The agreement between the PDCIs and three commonly used COC indicators, the Usual Provider of Care index, the Continuity of Care Index, and the Sequential Continuity Index, were examined. Generalized estimating equations were conducted to examine the association between COC and avoidable hospitalization by the level of comorbidity. RESULTS: The results showed that the correlations among the three commonly used COC indicators were high (γ = 0.787 ~ 0.958) and the correlation between the two longitudinal continuity measures was moderate (γ = 0.577 ~ 0.579), but the correlations between the commonly used COC indicators and the two PDCIs were low (γ = 0.001 ~ 0.257). All COC measures, both the PDCIs and the three commonly used COC indicators, showed independent protective effects on the likelihood of avoidable hospitalization in three comorbidity groups. CONCLUSION: The duration of interaction between patients and physicians is an independent domain in measuring COC and has a significant effect on health care outcomes.

Fisetin attenuates doxorubicin-induced cardiotoxicity by inhibiting the insulin-like growth factor II receptor apoptotic pathway through estrogen receptor-α/-ß activation.

Doxorubicin (DOX), an effective chemotherapeutic drug, has been used to treat various cancers; however, its cardiotoxic side effects restrict its therapeutic efficacy. Fisetin, a flavonoid phytoestrogen derived from a range of fruits and vegetables, has been reported to exert cardioprotective effects against DOX-induced cardiotoxicity; however, the underlying mechanisms remain unclear. This study investigated fisetin's cardioprotective role and mechanism against DOX-induced cardiotoxicity in H9c2 cardiomyoblasts and ovariectomized (OVX) rat models. MTT assay revealed that fisetin treatment noticeably rescued DOX-induced cell death in a dose-dependent manner. Moreover, western blotting and TUNEL-DAPI staining showed that fisetin significantly attenuated DOX-induced cardiotoxicity in vitro and in vivo by inhibiting the insulin-like growth factor II receptor (IGF-IIR) apoptotic pathway through estrogen receptor (ER)-α/-ß activation. The echocardiography, biochemical assay, and H&E staining results demonstrated that fisetin reduced DOX-induced cardiotoxicity by alleviating cardiac dysfunction, myocardial injury, oxidative stress, and histopathological damage. These findings imply that fisetin has a significant therapeutic potential against DOX-induced cardiotoxicity.

Ohwia caudata aqueous extract attenuates doxorubicin-induced mitochondrial dysfunction in Wharton's jelly-derived mesenchymal stem cells.

Mitochondrial dysfunction has been linked to many diseases, including organ degeneration and cancer. Wharton's jelly-derived mesenchymal stem cells provide a valuable source for stem cell-based therapy and represent an emerging therapeutic approach for tissue regeneration. This study focused on screening the senomorphic properties of Ohwia caudata aqueous extract as an emerging strategy for preventing or treating mitochondrial dysfunction in stem cells. Wharton's jelly-derived mesenchymal stem cells were incubated with 0.1 µM doxorubicin, for 24 h to induce mitochondrial dysfunction. Next, the cells were treated with a series concentration of Ohwia caudata aqueous extract (25, 50, 100, and 200 µg/mL) for another 24 h. In addition, an untreated control group and a doxorubicin-induced mitochondrial dysfunction positive control group were maintained under the same conditions. Our data showed that Ohwia caudata aqueous extract markedly suppressed doxorubicin-induced mitochondrial dysfunction by increasing Tid1 and Tom20 expression, decreased reactive oxygen species production, and maintained mitochondrial membrane potential to promote mitochondrial stability. Ohwia caudata aqueous extract retained the stemness of Wharton's jelly-derived mesenchymal stem cells and reduced the apoptotic rate. These results indicate that Ohwia caudata aqueous extract protects Wharton's jelly-derived mesenchymal stem cells against doxorubicin-induced mitochondrial dysfunction and can potentially prevent mitochondrial dysfunction in other cells. This study provides new directions for the medical application of Ohwia caudata.

Phosphorylation of Bcl-2 by JNK confers gemcitabine resistance in lung cancer cells by reducing autophagy-mediated cell death.

The most common cancer-related death in the world is non-small cell lung cancer (NSCLC). Gemcitabine (GEM) is a common and effective first-line chemotherapeutic drug for the treatment of NSCLC. However, the long-term use of chemotherapeutic drugs in patients usually induces cancer cell drug resistance, leading to poor survival, and prognosis. In this study, to observe and explore the key targets and potential mechanisms of NSCLC resistance to GEM, we first cultured lung cancer CL1-0 cells in a GEM-containing medium to induce CL1-0 cells to develop GEM resistance. Next, we compared protein expression between the parental and GEM-R CL1-0 cell groups. We observed significantly lower expression of autophagy-related proteins in GEM-R CL1-0 cells than in parental CL1-0 cells, indicating that autophagy is associated with GEM resistance in CL1-0 cells. Furthermore, a series of autophagy experiments revealed that GEM-R CL1-0 cells had significantly reduced GEM-induced c-Jun N-terminal kinase phosphorylation, which further affected the phosphorylation of Bcl-2, thereby reducing the dissociation of Bcl-2 and Beclin-1 and ultimately reducing the generation of GEM-induced autophagy-dependent cell death. Our findings suggest that altering the expression of autophagy is a promising therapeutic option for drug-resistant lung cancer.

Systematic review: Effect of mobile applications on college students with depressive symptoms.

AIM: To evaluate the effects of mobile applications (apps) on college students with depressive symptoms. DESIGN: Depression among college students is a school health issue, although little is known regarding effective app-based interventions for managing depressive symptoms. This review follows the concept of (1) theoretical guidance framework on app design, (2) app-based intervention study design and (3) effect of app-based interventions. DATA SOURCES: Cochrane Library, CINAHL Plus with Full Text and PubMed were searched in October 2022. METHODS: English-language reports of app-based interventions for college students with depressive symptoms. Quality appraisal and data extraction of selected articles was conducted by two independent reviewers using the mixed methods appraisal tool. Data synthesis using core outcome and findings of intervention. RESULTS: Five studies have shown that depressive symptoms significantly decreased after app use, specifically indicating the effects that occur in 4 weeks. Although four studies have applied the theoretical framework to the app design, the findings showed the low implementation of the intervention activities as originally designed and at the specified dosage and difficulty in understanding the processes through which the intervention resolves the depressive symptoms. CONCLUSION: App-based intervention can decrease depressive symptoms; furthermore, 4 weeks was the time point at which the changes were expected to occur. However, the theory-based app design for the depression population was rarely related, and studies clearly explaining the intervention measures, intervention dosage and duration required to achieve effectiveness are needed. IMPACT: This study provides the synthesis of evidence-based app interventions to manage depressive symptoms to zoom in on different views and we suggest using the applications for at least 4 weeks before changes are expected to occur. PATIENT OR PUBLIC CONTRIBUTION: No patient or public involvement in this study.

Safety and antibody response of recipients who unexpectedly received undiluted prime dose of BNT162b2 COVID-19 vaccine in Taiwan.

We reported 25 recipients (14 females and 11 males) aged from 18 to 65 years who unexpectedly received a primary dose of undiluted BNT162b2 vaccine (180 µg). The most common adverse reactions included injection site pain (n = 22), followed by fever (9), fatigue (8), chest tightness (6), and dizziness (6). The most common laboratory abnormalities were anemia (n = 4) and elevated liver transaminase level (4), followed by abnormal leukocyte counts (3) and elevated D-dimer level (3). The adverse reactions and laboratory abnormalities of these recipients were mild and spontaneously recovered within a few weeks. Significant elevations of anti-SARS-CoV-2 spike IgG titers after a booster dose of the BNT162b2 were found. Similar to reports of BNT162b2 clinical trials, the adverse reactions and laboratory abnormalities of these recipients were mild, and they spontaneously recovered within a few weeks. These results provide clinical and immunological effects of undiluted BNT162b2 vaccine inoculation.

Machine Learning-Based Human Posture Identification from Point Cloud Data Acquisitioned by FMCW Millimetre-Wave Radar.

Human posture recognition technology is widely used in the fields of healthcare, human-computer interaction, and sports. The use of a Frequency-Modulated Continuous Wave (FMCW) millimetre-wave (MMW) radar sensor in measuring human posture characteristics data is of great significance because of its robust and strong recognition capabilities. This paper demonstrates how human posture characteristics data are measured, classified, and identified using FMCW techniques. First of all, the characteristics data of human posture is measured with the MMW radar sensors. Secondly, the point cloud data for human posture is generated, considering both the dynamic and static features of the reflected signal from the human body, which not only greatly reduces the environmental noise but also strengthens the reflection of the detected target. Lastly, six different machine learning models are applied for posture classification based on the generated point cloud data. To comparatively evaluate the proper model for point cloud data classification procedure-in addition to using the traditional index-the Kappa index was introduced to eliminate the effect due to the uncontrollable imbalance of the sampling data. These results support our conclusion that among the six machine learning algorithms implemented in this paper, the multi-layer perceptron (MLP) method is regarded as the most promising classifier.

The usability of an AAC pain description system for patients with acquired expressive communication disorders.

Augmentative and alternative communication (AAC) has been used by patients with acquired expressive communication disorders as an alternative to natural speech. The use of symbols to express pain, which is intangible, is challenging because designing a series of comprehensible symbols to represent personal experiences such as pain is not straightforward. This study describes (a) the development of symbols to express pain that were derived from Chinese pain-related similes and metaphors for an AAC mobile application developed specifically for this study known as PainDiary and (b) an assessment of the appropriateness of the app compared to conventional methods of collecting pain information. The symbols depicted headache pain and discomfort, which is prevalent among neurosurgical patients. The participants were 31 patients diagnosed with acquired expressive communication disorders who were receiving treatment in a neurosurgery general ward of Chang Gung Memorial Hospital in Taiwan and 14 nurses who worked on the ward. Pain information was collected by nurses using conventional methods and the PainDiary app. Assessment data, including the accuracy and efficiency of and user satisfaction with PainDiary, are compared. The results show that use of the app was effective in reporting pain and that patients required less time to report a pain event. The results further indicate that the PainDiary app was better received by younger individuals than by their older counterparts.

Risk of NSAID-associated anastomosis leakage after colorectal surgery: a large-scale retrospective study using propensity score matching.

PURPOSE: NSAIDs are commonly used as opioid-sparing analgesics in colorectal surgery. Many efforts are made to elucidate the risk of NSAID-associated anastomotic leakage after colorectal surgery. However, these results still remain controversial. In this study, we applied large-scale retrospective analysis using propensity score matching to fully clarify the association between risk of anastomotic leakage and use of NSAID after colorectal surgery. METHODS: All colorectal cancer patients receiving operation during February 2008 to August 2018 in our multi-institution medical organization research database were enrolled. It is worthy to mention that only patients requiring re-operation within 21 days after colorectal surgery due to anastomotic leakage were counted as anastomosis leakage. Furthermore, a propensity score TriMatch analysis was performed to prevent from interference of confounding factors. RESULTS: A total of 10,584 patients were included in this study and divided into three groups, no NSAIDs group, non-selective NSAIDs group, and selective COX-2 inhibitors group, respectively. Before tri-matching analysis, significant differences in anastomotic leakage rate were observed. After propensity score matching analysis, the ratio of anastomotic leakage requiring re-operation occurred in 2.0%, 3.6%, and 2.0% in no NSAIDs, non-selective NSAIDs, and selective COX-2 inhibitors group, respectively. No significant difference was observed in these three groups. CONCLUSION: These results suggest that NSAIDs are not associated with incidence of anastomosis leakage following colorectal surgery. To our knowledge, it is the first study demonstrating that NSAIDs is not associated with incidence of anastomosis leakage following colorectal surgery using propensity score matching at a larger-scale retrospective study.

Low-dose rapamycin prevents Ang-II-induced toxicity in Leydig cells and testicular dysfunction in hypertensive SHR model.

Hypertension is a common chronic cardiovascular disease reported among both men and women. Hypertension in males affects the testis and reproduction function; however, the pathogenesis is poorly understood. Rapamycin has been reported to have a variety of beneficial pharmacological effects; however, high-doses rapamycin does have side effects such as immunosuppression. The present study investigates whether low-dose rapamycin can reduce the damage caused by hypertension to the testis of spontaneously hypertensive rats (SHRs) and further examines molecular mechanism of low-dose rapamycin in preventing testicular toxicity induced by angiotensin II (Ang II). Low rapamycin dose restores the testicle size, histological alterations, 3ß-hydroxysteroid dehydrogenase (3ß-HSD) expression, and prevents apoptosis in SHR rats. Ang II downregulates angiotensin-converting enzyme-2 (ACE2) expression through AT1R, p-ERK, and MAS receptor in LC-540 Leydig cells in a dose-dependent manner. Low doses of rapamycin effectively upregulate steroidogenic enzymes, steroidogenic acute regulatory protein and 3ß-HSD expression in Leydig cells. Rapamycin upregulates ACE2 expression through p-PKAc and p-PI3k in Ang II-treated cells. Further, rapamycin curbs mitochondrial superoxide generation and depleted mitochondrial membrane potential induced by Ang II through activation of Nrf2-mediated Gpx4 and superoxide dismutase 2 expression. Our results revealed the involvement of ACE2, AT1R, AT2R, PKAc, and oxidative stress in Ang-II-induced testicular toxicity, suggesting low-dose rapamycin could be a potential therapeutic candidate to attenuate testicular toxicity.

Trajectories of social support are associated with health outcomes and depressive symptoms among older Taiwanese adults with diabetes following hip-fracture surgery.

OBJECTIVE: This study examined trajectories of social support and their relationships with health outcomes over 2 years post hip-fracture surgery for older adults with diabetes mellitus (DM). METHODS: This was a secondary analysis of data derived from a clinical trial, which included 158 hip fractured older adults with DM who had completed the Medical Outcomes Study Social Support Survey at 1-, 12-, 18-, and 24-months following hospital discharge. Health outcomes for self-care, physical and nutritional status, mental health, and depression were assessed at 3-month intervals up to 24-months after hospital discharge. Trajectories of social support were derived with latent class analysis while hierarchical linear models were employed to assess the associations of social-support trajectory with health outcomes. RESULTS: Four social-support trajectories were derived for persons with DM following hip-fracture surgery: poor and declining (n = 18, 11.4%), moderate and stable (n = 29, 18.4%), high but declining (n = 34, 21.5%), and high and stable (n = 77, 48.7%). Relative to those in the poor and declining group, participants in the high and stable trajectory group performed better in Activities of Daily Living and quadriceps muscle power, had better mental Health-Related Quality of Life and nutritional status, and had fewer depressive symptoms. These differences persisted over the 2 years following hospital discharge. CONCLUSIONS: These results suggest social support for persons with DM should be continually assessed following hip-fracture surgery.