A systematic review on the biochemical threshold of mitochondrial genetic variants.

Mitochondrial DNA (mtDNA) variants cause a range of diseases from severe pediatric syndromes to aging-related conditions. The percentage of mtDNA copies carrying a pathogenic variant, variant allele frequency (VAF), must reach a threshold before a biochemical defect occurs, termed the biochemical threshold. Whether the often-cited biochemical threshold of >60% VAF is similar across mtDNA variants and cell types is unclear. In our systematic review, we sought to identify the biochemical threshold of mtDNA variants in relation to VAF by human tissue/cell type. We used controlled vocabulary terms to identify articles measuring oxidative phosphorylation (OXPHOS) complex activities in relation to VAF. We identified 76 eligible publications, describing 69, 12, 16, and 49 cases for complexes I, III, IV, and V, respectively. Few studies evaluated OXPHOS activities in diverse tissue types, likely reflective of clinical access. A number of cases with similar VAFs for the same pathogenic variant had varying degrees of residual activity of the affected complex, alluding to the presence of modifying variants. Tissues and cells with VAFs <60% associated with low complex activities were described, suggesting the possibility of a biochemical threshold of <60%. Using Kendall rank correlation tests, the VAF of the m.8993T > G variant correlated with complex V activity in skeletal muscle (τ = -0.58, P = 0.01, n = 13); however, no correlation was observed in fibroblasts (P = 0.7, n = 9). Our systematic review highlights the need to investigate the biochemical threshold over a wider range of VAFs in disease-relevant cell types to better define the biochemical threshold for specific mtDNA variants.

Importance of survey demographic questions to foster inclusion in medicine and research and reduce health inequities for LGBTQIA2S+ individuals.

A clear, inclusive, and accurate approach to the collection of demographic information in clinical research and medical practice is critical to understanding the healthcare needs of the specific population. Inclusive demography constitutes appropriate and accurate characterization of an individual's sexual orientation and gender identity (SOGI) data. Appropriate demography fosters sense of inclusion and belonging for those belonging to medically marginalized communities such as the lesbian, gay, bisexual, transgender, queer, intersex, asexual, and Indigenous Two-Spirit (LGBTQIA2S+) communities and improves health outcomes. Acquiring inclusive demographics in healthcare research is needed for the following critical reasons. First, LGBTQIA2S+ individuals experience undue psychological harm when their identities are not appropriately captured in survey data, promoting further alienation of the LGBTQIA2S+ community in medicine and research. Second, LGBTQIA2S+ populations are disproportionately burdened by several major cardiovascular and cardiovascular-associated diseases, including hypertension and diabetes. Failure to include these populations, and accurately characterize their participation, in research leads to failure to identify associations between identities and disease, resulting in worse health outcomes. Furthermore, this lack of precision in current data for sex, gender, and sexual orientation may lead to inaccurate data for all populations, not just the LGBTQIA2S+ community. Finally, there are currently major political and social threats and attacks on the LGBTQIA2S+ community and, in particular, on transgender and gender-diverse individuals. Proper medical inclusion and advocacy for the LGBTQIA2S+ community by the medical community may help protect the community from further undue harm through creating sense of belonging and reductions in marginalization-related health inequities.

Hemodynamic Response to Oral Vasodilator Therapy in Systemic Sclerosis-Related Pulmonary Hypertension.

PURPOSE: Although classified as group 1 pulmonary arterial hypertension (PAH), patients with systemic sclerosis-related pulmonary hypertension (SSc-PH) experience poorer clinical response to PAH therapy and increased mortality compared to those with idiopathic PAH. Due to heterogeneity in phenotypes, identifying patients likely to respond to therapy is challenging. The goal of this study was to determine clinical factors associated with hemodynamic response, defined by a > 20% reduction in pulmonary vascular resistance on repeat right heart catheterization. METHODS: We applied a time-to-event model using a retrospective cohort of 39 patients with precapillary SSc-PH, defined by a mean pulmonary artery pressure of ≥ 25 mmHg and pulmonary arterial wedge pressure (PAWP) ≤ 15 mmHg on right heart catheterization. RESULTS: Patients with PAWP ≤ 8 mmHg were nearly fourfold more likely to achieve a hemodynamic response compared to those with PAWP > 8 mmHg (HR 3.88; 95% CI: 1.20, 12.57); each 1 mmHg increase in PAWP was associated with a decreased hazard for hemodynamic response (HR 0.84; 95% CI: 0.70, 1.00). CONCLUSION: In patients with precapillary SSc-PH, PAWP was associated with time to hemodynamic response, suggesting the importance of subclinical cardiac disease in determining hemodynamic response to oral vasodilator therapy.

A Clinical Decision Tool for Risk Stratifying Patients with Systemic Sclerosis-Related Pulmonary Hypertension.

We devised a scoring system to identify patients with systemic sclerosis (SSc) at risk for pulmonary hypertension (PH) and predict all-cause mortality. Using 7 variables obtained via pulmonary function testing, echocardiography, and computed tomographic chest imaging, we applied the score to a retrospective cohort of 117 patients with SSc. There were 60 (51.3%) who were diagnosed with PH by right heart catheterization. Using a scoring threshold ≥ 0, our decision tool predicted PH with a sensitivity, specificity, and accuracy of 0.87 (95% CI 0.75, 0.94), 0.74 (95% CI 0.60, 0.84), and 0.80 (95% CI 0.72, 0.87), respectively. When adjusted for age at PH diagnosis, sex, and receipt of pulmonary arterial vasodilators, each one-point score increase was associated with an adjusted HR of 1.19 (95% CI 1.05, 1.34) for all-cause mortality. With further validation in external cohorts, our simplified clinical decision tool may better streamline earlier detection of PH in SSc.

Predictors of hematologic response and survival with stem cell transplantation in AL amyloidosis: A 25-year longitudinal study.

High-dose melphalan and stem cell transplantation (HDM/SCT) is an effective treatment for selected patients with AL amyloidosis. We report the long-term outcomes of 648 patients with AL amyloidosis treated with HDM/SCT over 25 years. Hematologic CR was achieved by 39% of patients. The median duration of hematologic CR was 12.3 years, and 45% of patients with a hematologic CR had no evidence of a recurrent plasma cell dyscrasia at 15 years after HDM/SCT. With a median follow-up interval of 8 years, the median event-free survival (EFS) and overall survival (OS) were 3.3 and 7.6 years, respectively. Patients with a hematologic CR had a median OS of 15 years, and 30% of these patients survived >20 years. On multivariable analysis, dFLC >180 mg/L and BM plasma cells >10% were independently associated with shorter EFS, whereas BNP >81 pg/mL, troponin I > 0.1 ng/mL, and serum creatinine >2.0 mg/dL were independently associated with shorter OS. We developed a prognostic score for EFS, which incorporated dFLC >180 mg/L and BMPC% >10% as adverse risk factors. Patients with low-risk (0 factors), intermediate-risk (1 factor), and high-risk (2 factors) disease had median EFS estimates of 5.3, 2.8, and 1.0 years, respectively (p < .001). The 100-day treatment-related mortality rate was 3% in the latest treatment period (2012-2021), and the 25-year risk of t-MDS/AML was 3%. We conclude that HDM/SCT induces durable hematologic responses and prolonged survival with improved safety in selected patients with AL amyloidosis.

Psychoeducation as Precision Health in Military-Related Mild Traumatic Brain Injury.

A significant proportion of Service Members and Veterans (SMVs) experience at least 1 mild traumatic brain injury during military activities (mil-mTBI), which can result in enduring cognitive symptoms. Although multiple cognitive rehabilitation (CR) interventions have been developed for this population, patient psychoeducation focusing on biopsychosocial relationships and health behaviors is often cited as the first line of defense for mil-mTBI sequelae. However, theoretical and conceptual foundations of these psychoeducational techniques are not well articulated. This raises questions about the potency of attempts to boost health literacy in affected SMVs, who represent a highly heterogeneous patient population within a special cultural milieu. To elucidate the significance of this problem and identify opportunities for improvement, we view the psychoeducation of SMVs through the lens of educational principles described in serious mental illness, where "psychoeducation" was first formally defined, as well as contextual and phenomenological aspects of mil-mTBI that may complicate treatment efforts. To advance psychoeducation research and practice in mil-mTBI, we discuss how treatment theory, which seeks to link active treatment ingredients with specific therapeutic targets, and an associated conceptual framework for medical rehabilitation-the Rehabilitation Treatment Specification System-can be leveraged to personalize educational content, integrate it into multicomponent CR interventions, and evaluate its effectiveness.

Appropriate triage allows aggressive primary debulking surgery with rates of morbidity and mortality comparable to interval surgery after chemotherapy.

OBJECTIVE: Morbidity and mortality (M/M) after primary debulking surgery (PDS) is often cited as a rationale for neoadjuvant chemotherapy and interval debulking surgery (IDS). We tested if using an evidence-based algorithm to identify patients fit for surgery would reduce M/M after PDS to that seen after IDS. METHODS: We included women who underwent PDS or IDS for advanced epithelial ovarian cancer (EOC) (1/2012-7/2016) guided by the use of a prospective triage algorithm. Outcomes were compared after applying inverse-probability of treatment weighting (IPTW) to adjust for covariate imbalance. RESULTS: Of 334 included patients, 232 (69.5%) underwent PDS and 102 (30.5%) were triaged to IDS. Relative to IDS group, PDS patients were younger (63.9 vs 67.5 years, P=0.01), were less likely to have low albumin (16.8% vs. 32.4%, P<0.001), had longer median operative times (315 vs 263 min, P <0.001), more high complexity surgeries and fewer low complexity surgeries (27.2% vs. 11.8% and 18.5% vs 36.3% respectively, P<0.001). The rates of the following outcomes were comparable for PDS and IDS, respectively: successful cytoreduction (complete, 62.5% vs 66.7%, P=0.47 and optimal, 95.3% vs 98.0%, P=0.36), 30-day grade 3+ complications (IPTW-adjusted 18.3% vs. 12.9%, P=0.22), 90-day mortality (IPTW-adjusted, 2.2% vs. 3.8%, P=0.42), length of hospitalization (P=0.29), and postoperative chemotherapy delivery (P=0.83). 3-year overall survival was higher for PDS group (IPTW-adjusted 64.1% vs. 42.6%, P=0.001). CONCLUSIONS: Use of our validated triage strategy allowed us to offer 70% of women with advanced EOC PDS surgery. Despite more complex surgery, M/M after this approach is low and comparable to IDS, with similar rates of complete resection and superior OS. Use of a validated triage system should be utilized when considering PDS vs neoadjuvant chemotherapy.

Substance and shadow of formamidinium lead triiodide based solar cells.

The current decade has witnessed a surge of progress in the investigation of methyl ammonium lead iodide (MAPbI3) perovskites for solar cell fabrication due to their intriguing electro-optical properties, despite the intrinsic degradation of the material that has restricted its commercialisation. As a promising alternative, solar cells based on its formamidinium analogue, FAPbI3, are currently being actively pursued for having demonstrated a certified efficiency of 24.4%, while the room-temperature conversion to a non-perovskite δ-phase impedes its further commercialisation, and strategies have been adopted to overcome this phase instability. An in-depth and real-time understanding of microstructural relationships with optoelectronic properties and their underlying mechanisms using operando in situ spectroscopic techniques is paramount. Thus, the design and development of a new process, data driven methodology, characterization and evaluation protocols for perovskite absorber layers and the fabricated devices is a judicious research direction. Here, in this perspective, we shed light on the compositional, surface engineering and crystallization kinetics manipulations for FAPbI3, followed by a proposition for unified testing protocols, for scalling of devices from the lab to the market.

Molecular insights of hyaluronic acid-hydroxychloroquine conjugate as a promising drug in targeting SARS-CoV-2 viral proteins.

In-silico anti-viral activity of Hydroxychloroquine (HCQ) and its Hyaluronic Acid-derivative (HA-HCQ) towards different SARS-CoV-2 protein molecular targets were studied. Four different SARS-CoV-2 proteins molecular target i.e., three different main proteases and one helicase were chosen for In-silico anti-viral analysis. The HA-HCQ conjugates exhibited superior binding affinity and interactions with all the screened SAR-CoV-2 molecular target proteins with the exception of a few targets. The study also revealed that the HA-HCQ conjugate has multiple advantages of efficient drug delivery to its CD44 variant isoform receptors of the lower respiratory tract, highest interactive binding affinity with SARS-CoV-2 protein target. Moreover, the HA-HCQ drug conjugate possesses added advantages of good biodegradability, biocompatibility, non-toxicity and non-immunogenicity. The prominent binding ability of HA-HCQ conjugate towards Mpro (PDB ID 5R82) and Helicase (PDB ID 6ZSL) target protein as compared with HCQ alone was proven through MD simulation analysis. In conclusion, our study suggested that further in-vitro and in-vivo examination of HA-HCQ drug conjugate will be useful to establish a promising early stage antiviral drug for the novel treatment of COVID-19.

Stabilization of Cardiac Function With Diflunisal in Transthyretin (ATTR) Cardiac Amyloidosis.

BACKGROUND: Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is an underappreciated cause of heart failure that results from misfolded TTR (prealbumin) protein. Diflunisal is an approved non-steroidal anti-inflammatory drug that stabilizes TTR, with limited data available regarding effects on cardiac structure and function. METHODS AND RESULTS: ATTR-CM patients (n=81, 41% treated with 250 mg twice-daily diflunisal by clinical practice) were retrospectively identified with baseline and follow-up (median interval 1 year) serum biomarker and echocardiographic data compared, including global longitudinal strain (GLS). Chi-squared and Wilcoxon tests assessed differences between subjects, divided by treatment group, and univariable and multivariable linear regression was performed. At baseline, patients treated with diflunisal were younger (68 vs 77 years, P = .0001), with lower B-type natriuretic peptide (BNP; 249 vs 545 pg/mL, P = .009) and serum creatinine (1.1 vs 1.2 mg/dL, P = .04), but similar TTR concentration (P = .31), cardiac troponin I (P = .06), and GLS (P = .67). At follow-up, diflunisal untreated versus treated patients showed differences in TTR concentration (19 vs 33 mg/dL, P = .01) and favorable differences in left atrial volume index (+4.6 vs -1.4 mL/m2, P = .002) and cardiac troponin I (+0.03 vs -0.01 ng/mL, P = .01) for the entire cohort. Among the subset with wild-type ATTR (n=53), diflunisal treatment was associated with differences in GLS (+1.2% untreated vs +0.1% treated, P = .03). Changes in wall thickness (P = .2), left ventricular ejection fraction (P = .71), and BNP (P = .42) were similar between groups. CONCLUSIONS: In ATTR-CM, diflunisal treatment resulted in measurable differences in some parameters of cardiac structure and function after only 1 year of administration. Further longer-term analysis is warranted.

Histone H2A.Z subunit exchange controls consolidation of recent and remote memory.

Memory formation is a multi-stage process that initially requires cellular consolidation in the hippocampus, after which memories are downloaded to the cortex for maintenance, in a process termed systems consolidation. Epigenetic mechanisms regulate both types of consolidation, but histone variant exchange, in which canonical histones are replaced with their variant counterparts, is an entire branch of epigenetics that has received limited attention in the brain and has never, to our knowledge, been studied in relation to cognitive function. Here we show that histone H2A.Z, a variant of histone H2A, is actively exchanged in response to fear conditioning in the hippocampus and the cortex, where it mediates gene expression and restrains the formation of recent and remote memory. Our data provide evidence for H2A.Z involvement in cognitive function and specifically implicate H2A.Z as a negative regulator of hippocampal consolidation and systems consolidation, probably through downstream effects on gene expression. Moreover, alterations in H2A.Z binding at later stages of systems consolidation suggest that this histone has the capacity to mediate stable molecular modifications required for memory retention. Overall, our data introduce histone variant exchange as a novel mechanism contributing to the molecular basis of cognitive function and implicate H2A.Z as a potential therapeutic target for memory disorders.

Psychological predictors of functional outcomes in service members with traumatic brain injury.

PRIMARY OBJECTIVE: Research is increasingly demonstrating the significant impact that non-medical factors can have on outcomes of service members (SMs) with mild traumatic brain injury (mTBI). Thus, the current study examined which demographic, TBI-related factors, and psychological variables are most predictive of functional outcomes. RESEARCH DESIGN: Retrospective database analysis from medical chart review. METHODS AND PROCEDURES: One hundred forty-one patients who received rehabilitation services at an outpatient TBI military treatment facility between 2013 and 2018. Data collected included demographic variables, time since injury, neuropsychological measures, psychological diagnoses, Personality Assessment Inventory (PAI) scores, and Walter Reed Functional Impairment Scale (FIS). Hierarchical linear regression models were used to predict functional outcomes (measured by FIS total, work, social functioning scales). MAIN OUTCOMES AND RESULTS: Results indicated that comorbid PTSD diagnosis and PAI Negative Impression Management (NIM) score were predictive of total functional, work, and social outcomes, over and above demographic and TBI-related factors. CONCLUSIONS: Current findings confirmed the importance of evaluating and treating psychological factors, as well as exploring one's responding style (NIM), when managing chronic mTBI in SMs. Given ongoing findings of psychological underpinnings to mTBI outcome, there is further need to focus on early interventions to optimize psychological and functional outcomes for SMs.

Using an evidence-based triage algorithm to reduce 90-day mortality after primary debulking surgery for advanced epithelial ovarian cancer.

OBJECTIVE: To evaluate the impact of an evidence-based triage algorithm to decide between primary debulking surgery (PDS) and neoadjuvant chemotherapy followed by interval debulking surgery (NACT/IDS) for advanced epithelial ovarian cancer (EOC). METHODS: Surgical morbidity and mortality (M/M) after PDS for stage IIIC-IV EOC at Mayo Clinic after implementation of the triage algorithm (contemporary cohort, 2012-July 2016) were compared to that of a historic PDS cohort (2003-2011). RESULTS: Mean age of the 232 women who met inclusion criteria in the contemporary cohort was 63.9 years. We observed a 71% decrease in 90-day mortality from 8.9% to 2.6% (P = 0.002) between the contemporary and historic cohorts. Accordion grade 3+ postoperative complications within 30 days after surgery decreased from 22.3% to 18.3% (P = 0.19). Among those with a grade 3+ complication, 90-day mortality rates decreased from 28.3% in the historic cohort to 2.4% in the contemporary cohort (P < 0.001) suggesting patients were better able to tolerate complex surgery. When compared to the historic PDS cohort, oncologic outcomes were also improved in the contemporary PDS cohort. Complete as well as optimal (residual disease ≤1 cm) cytoreduction rates increased (45.5% vs. 62.5% and 84.5% vs. 95.3%, respectively, P < 0.001), and the proportion of women starting chemotherapy within 42 days of surgery increased (57.4% vs. 69.8%, P = 0.001). Three-year overall survival was 53% in the historic cohort and 66% in the contemporary cohort (P < 0.001). CONCLUSIONS: Use of the Mayo triage algorithm for EOC was associated with reduced 90-day mortality after PDS and improved oncologic outcomes. Surgical risk assessment is a critical aspect of treatment planning in the primary management of EOC and should be incorporated into practice.

Impact of Genetic Testing in Transthyretin (ATTR) Cardiac Amyloidosis.

PURPOSE OF REVIEW: The review's main focus centers on the genetics of hereditary cardiac amyloidosis, highlighting the opportunities and challenges posed by the widespread availability of genetic screening and diagnostic cardiac imaging. RECENT FINDINGS: Advancements in cardiac imaging, heightened awareness of the ATTR amyloidosis diagnosis, and greater access to genetic testing have all led to an increased appreciation of the prevalence of ATTR cardiac amyloidosis. Elucidation of the TTR molecular structure and effect of mutations on TTR function have allowed for novel TTR therapy development leading to clinical implementation of transthyretin stabilizers and transthyretin gene silencers. The transthyretin amyloidoses are a diverse group of protein misfolding disorders with cardiac and peripheral/autonomic nervous system manifestations due to protein deposition. Genetic screening allows for the early identification of asymptomatic TTR mutation carriers. With the advent of TTR-specific therapeutics, clinical guidance is necessary for the management of individuals with mutations in the TTR gene without evidence of disease.

First spot urine sodium after initial diuretic identifies patients at high risk for adverse outcome after heart failure hospitalization.

BACKGROUND: Relief of congestion is the primary goal of initial therapy for acute decompensated heart failure (ADHF). Early measurement of urine sodium concentration (UNa) may be useful to identify patients with diminished response to diuretics. The aim of this study was to determine if the first spot UNa after diuretic initiation could select patients likely to require more intensive therapy during hospitalization. METHODS: At the time of admission, 103 patients with ADHF were identified prospectively, and UNa was measured after the first dose of intravenous diuretic. Clinical outcomes were compared for patients with UNa >60 mmol/L and UNa of ≤60 mmol/L, with the primary outcome of a composite of death at 90 days, mechanical circulatory support during admission, and requirement of inotropic support at discharge. RESULTS: Patients with UNa ≤60 had lower admission blood pressure, had less chronic neurohormonal antagonist prior to admission, and were more than twice as likely to experience the primary end point (hazard ratio 2.40, 95% CI 1.02-5.66, P = .045), which was marginally significant after adjusting for renal function and baseline home loop diuretic. Worsening renal function was significantly more common in patients with UNa <60 (23.6% vs 6.5%, P = .05). Although the initial assessment of congestion was similar at admission, patients with low early UNa had a longer length of stay (11 vs 6 days, P < .006) than patients with UNa >60. CONCLUSIONS: Assessment of spot UNa after initial intravenous loop diuretic administration may facilitate identification and triage of a population of HF patients at increased risk for adverse events and prolonged hospitalization.

Hypertrophic Cardiomyopathy in Children, Adolescents, and Young Adults Associated With Low Cardiovascular Mortality With Contemporary Management Strategies.

BACKGROUND: Youthful age has been considered the time of greatest risk for patients with hypertrophic cardiomyopathy (HCM), largely because of the possibility of sudden death. The last 2 decades have witnessed more reliable identification of at-risk patients and utilization of implantable cardioverter-defibrillators for prevention of sudden death, and other contemporary treatment options. Whether such management advances have significantly altered the considerable mortality rate for young HCM patients remains unresolved. METHODS AND RESULTS: We studied long-term outcome in 474 consecutive HCM patients between 7 and 29 years of age presenting at 2 referral institutions. Over 7.1±5.1 years of follow-up (6.0 [3.0, 10.0]), 452 patients (95%) survived, with 95% experiencing no or mild symptoms. HCM-related death occurred in 18 patients (3%; 0.54%/y): arrhythmic sudden death (n=12), progressive heart failure and heart transplant complications (n=5), or postoperatively (n=1). In contrast, aborted life-threatening events occurred in 63 other high-risk patients (13%) with implantable cardioverter-defibrillator interventions for ventricular tachyarrhythmias (n=31), resuscitated out-of-hospital cardiac arrest (n=20), or heart transplant for advanced heart failure (n=12), 1.8%/y, 3-fold higher than HCM mortality. Five- and 10-year survival (considering only HCM deaths) was high (97% and 94%, respectively), virtually identical to that reported in middle-aged adult HCM patients (98% and 94%, P=0.23). CONCLUSIONS: In a large hospital-based cohort of young HCM patients, representing an age group considered at greatest risk, low mortality rates can be achieved with the application of contemporary cardiovascular treatment strategies, largely because of reliable identification of high-risk patients who benefited from implantable cardioverter-defibrillators for sudden death prevention, thereby creating the opportunity for extended longevity and good quality of life.

Dissipation kinetics of beta-cyfluthrin and imidacloprid in tea and their transfer from processed tea to infusion.

Dissipation kinetics of mixed formulation consisting beta-cyfluthrin and imidacloprid in tea crop under an open field ecosystem was investigated. The mixed formulation was applied on tea plant at recommended (27 + 63) and double the recommended (54 + 126g a.i./ha) dose and residues were determined using gas chromatography-electron capture detector and high performance liquid chromatography-photodiode array detector for beta-cyfluthrin and imidacloprid, respectively. The limit of quantification of analytical method was 0.05µg/g and the average recoveries were ranged from 88.36% to 103.49% with relative standard deviations of less than 6% at three spiked levels. The experimental results showed that in the green tea leaves imidacloprid dissipated faster than beta-cyfluthrin with the half-life ranging between 1.20-1.39 and 2.89-3.15days, respectively. The beta-cyfluthrin residues present in the processed tea not transferred into the tea infusion during the infusion process and imidacloprid transferred in the range 43.12-49.7%. On the basis of the transfer of residues from processed tea to infusion, a waiting period of 17 days for tea plucking after pesticide application at recommended dose may be suggested.