The impact of developmental stage, tissue type, and sex on DNA double-strand break repair in Drosophila melanogaster.

Accurate repair of DNA double-strand breaks (DSBs) is essential for the maintenance of genome integrity, as failure to repair DSBs can result in cell death. The cell has evolved two main mechanisms for DSB repair: non-homologous end-joining (NHEJ) and homology-directed repair (HDR), which includes single-strand annealing (SSA) and homologous recombination (HR). While certain factors like age and state of the chromatin are known to influence DSB repair pathway choice, the roles of developmental stage, tissue type, and sex have yet to be elucidated in multicellular organisms. To examine the influence of these factors, DSB repair in various embryonic developmental stages, larva, and adult tissues in Drosophila melanogaster was analyzed through molecular analysis of the DR-white assay using Tracking across Indels by DEcomposition (TIDE). The proportion of HR repair was highest in tissues that maintain the canonical (G1/S/G2/M) cell cycle and suppressed in both terminally differentiated and polyploid tissues. To determine the impact of sex on repair pathway choice, repair in different tissues in both males and females was analyzed. When molecularly examining tissues containing mostly somatic cells, males and females demonstrated similar proportions of HR and NHEJ. However, when DSB repair was analyzed in male and female premeiotic germline cells utilizing phenotypic analysis of the DR-white assay, there was a significant decrease in HR in females compared to males. This study describes the impact of development, tissue-specific cycling profile, and, in some cases, sex on DSB repair outcomes, underscoring the complexity of repair in multicellular organisms.

The Impact of Midodrine on Guideline-Directed Medical Therapy in Patients Admitted With Systolic Heart Failure.

ABSTRACT: Midodrine is occasionally used off-label to treat hypotension associated with advanced heart failure (HF); however, its association with changes in prescription of guideline-directed medical therapy (GDMT) is unknown. We sought to evaluate the effect of midodrine on the GDMT prescription pattern and clinical outcomes of patients with decompensated systolic HF. We retrospectively identified 114 patients admitted to our hospital in 2020 with decompensated systolic HF who were prescribed midodrine on discharge and compared them with 358 patients with decompensated systolic HF who were not prescribed midodrine. At 6 months, the midodrine group had more initiation or up-titration of beta blockers, renin-angiotensin-aldosterone system inhibitors, and sodium-glucose cotransporter-2 inhibitors compared with the nonmidodrine group. Survival at 6 months was similar between the 2 groups, but the midodrine group had more frequent rehospitalization for HF. Our findings suggest that midodrine is associated with improved GDMT in patients with decompensated HF but may be associated with worse prognosis.

A Suggested Model for the Vulnerable Phase of Heart Failure: Assessment of Risk Factors, Multidisciplinary Monitoring, Cardiac Rehabilitation, and Addressing the Social Determinants of Health.

The vulnerable phase (VP) of heart failure (HF) is 30 to 90 days after hospital discharge and is associated with increased rehospitalization and mortality rates. The pathophysiological mechanism that drives the VP is due to the progressive increase in left ventricular filling pressure, which can cause hemodynamic congestion and long-term multiorgan injury. Our team analyzed English-written, peer-reviewed research through PubMed from 2018 to 2022, to gather current information on the VP and generate a multipronged approach toward the assessment and intervention of patients with posthospitalization HF. It is our opinion that a structured approach using remote vital monitoring and risk-stratifying tools will be best to identify patients at risk for decompensatory HF during the VP. Medical management can then be targeted toward these high-risk patients by using an organized multidisciplinary team and a disease management program, which includes remote patient-monitoring systems, addressing social determinants of health, and cardiac rehabilitation, to improve rehospitalization and mortality rates.

A low-cost, portable 32-channel EIT system with four rings based on AFE4300 for body composition analysis.

A proposed low-cost, portable, 32-channel (4 rings of 8-channel) Electrical Impedance Tomography (EIT) system based on the AFE4300 analog front-end for body composition measurement. Each ring allows obtaining the conductivity distribution of 4 cross sections, 4 cm apart; to analyze the behavior of conductivity in a volume. The switching of the 4 rings and the current injection and voltage measurement patterns are done with three Texas Instruments 74HC4067 multiplexers, which are managed by an ESP32 board. The proposed system has an average signal-to-noise ratio of 74.71 dB and a frame rate of 50 fps. The sensitivity tests to impedance and volume changes consisted of introducing 4 tubes of different diameters (2 steel and 2 polyvinyl chloride) into a tank with saline solution; then conductivity distribution images were generated in 4 cross-sections of the tank, using the algorithms Gauss-Newton and Noser. Finally, the global impedance index (GI) is calculated to estimate the volume of each tube inside the tank. The results show that the proposed system is highly sensitive to impedance and volume changes, being a promising system for monitoring tissues, and fluids biological.

Vericiguat: The First Soluble Guanylate Cyclase Stimulator for Reduction of Cardiovascular Death and Heart Failure Hospitalization in Patients With Heart Failure Reduced Ejection Fraction.

Objective: This study aims to review the pharmacology, efficacy, and safety of the soluble guanylate cyclase stimulator, vericiguat, in patients with symptomatic congestive heart failure with ejection fraction less than 45% for the reduction of cardiovascular deaths. Also, to evaluate heart failure-related hospitalization in patients following a hospital discharge secondary to heart failure or those that require outpatient intravenous diuretics. Data source: MEDLINE/Pubmed and National Institutes of Health Clinical Trial Registry were searched between January 1989 to February 2021 using the following terms: vericiguat, soluble guanylate cyclase stimulator, heart failure, (was also known as) BAY 1021189. Study Selection and Data Extraction: The following study designs were included in the analysis: phase I, II, and III clinical trials; systematic reviews; and meta-analyses. Articles were included if they were published in English and evaluated vericiguat pharmacology, pharmacokinetics, efficacy, and safety. Data Synthesis: The Food and Drug Administration approved vericiguat for the reduction of cardiovascular death and hospitalization after having a related hospitalization or the need for outpatient intravenous diuretics, in those with symptomatic chronic heart failure and ejection fraction less than 45%. In the VICTORIA trial, vericiguat demonstrated a 10% reduction in risk of death from cardiovascular causes or first hospitalization for heart failure compared with placebo. Vericiguat was well tolerated overall with hypotension, syncope, and anemia noted as the most common side effects, similar to the other agent in its class. Conclusion: Vericiguat may be appropriate as add-on therapy for patients already on guideline-directed medical therapy with recent decompensated HFrEF to reduce hospitalization.

Referral for Cardiac Amyloidosis in Patients Who Underwent Transcatheter Aortic Valve Replacement: Results of the Quality Outcome Project.

Background Transthyretin cardiac amyloidosis (ATTR) is an important comorbidity present in severe aortic stenosis (AS). The purpose of this study was to raise awareness of ATTR in patients who underwent transcatheter aortic valve replacement (TAVR) for severe AS among healthcare providers and patients. Methodology We reviewed 197 consecutive TAVR cases performed from 2019 to 2020. Adapting predefined high-risk features for ATTR based on prior literature, we contacted the patients to discuss our clinical suspicion of ATTR and offered a referral to a cardiac amyloid specialist. Results We identified 125 (69.4%) patients who had high-risk features of ATTR. Of the 105 patients contacted, 44 patients agreed to referral, 46 patients were not able to be contacted after several attempts, and 15 patients declined referral. Of the 44 patients who agreed to the referral, 20 patients completed the evaluation for cardiac amyloidosis, all of whom were negative for transthyretin and light-chain cardiac amyloidosis. Conclusions Our attempt to detect ATTR in prior TAVR patients was unsuccessful two to three years post-TAVR. We believe that early detection of cardiac amyloidosis close to the timing of TAVR is important and the most effective means.

Complications of standard versus long cephalomedullary nails in the treatment of unstable extracapsular proximal femoral fractures: A randomized controlled trial.

AIMS: To compare in a prospective randomized trial the mechanical complications in patients with unstable extracapsular proximal femur fractures without subtrochanteric extension (AO/OTA 31-A2 and 31-A3) METHODS: We prospectively studied 182 patients with unstable extracapsular proximal femur fractures without fractures lines extending more than 3 cm below the lesser trochanter, randomized to receive either a 'standard' (240 mm) nail or a long nail and followed them up for 1 year. RESULTS: We found no difference in the incidence of mechanical or general complications between the two groups, no cut-outs, no fractures of the tip the implant, 1 cut-through and 2 malrotations in the LN group, 2 non-unions that were reoperated, one on each group. The commonest complication was blade lateral migration, 13 (14%) patients in SN and 6 (9%) in the LN. The operating time was shorter in the SN group 51 minutes compared to 67 minutes in the LN group (p=0.000075). The mortality at 1,3 and 12 months in the SN group was of 2%, 6%, 12% while in the LN group was 12%, 18% and 22%. These differences where significative at 1 (p=0.007) and 3 months (p=0.013), but not at 12 months (p=0.075). CONCLUSIONS: We recommend the use of standard nails (240 mm) for this group of fractures, since it does not produce more mechanical complications, and it is faster, cheaper and easier to interlock distally.

Correction: Referral for Cardiac Amyloidosis in Patients Who Underwent Transcatheter Aortic Valve Replacement: Results of the Quality Outcome Project.

[This corrects the article DOI: 10.7759/cureus.45024.].

No impact of combining multi-ingredient supplementation with exercise on body composition and physical performance, in healthy middle-aged and older adults: A systematic review and meta-analysis.

BACKGROUND: Protein-based multi-ingredient (MTN) supplements have been suggested as a safe and effective way of enhancing exercise outcomes. However, their effectiveness remains controversial when compared to isocaloric and single-nutrient supplements. This review aims to systematically summarise the current knowledge of multi-ingredient supplementation to optimise body composition and physical performance in middle-aged and older adults. MATERIAL AND METHODS: A systematic review with meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The search of the literature was conducted using PubMed, EBSCOhost, Google Scholar, Web of Science, and SPORTDiscus from June to October 2021. Every publication identified from the outset to October 2021 was considered. The main inclusion criteria comprised randomized controlled trial (RCT) studies conducted in adults (≥45 years old), following resistance- or endurance-based training programmes for a period of 6 weeks or longer, combined with MTN supplementation and a calorie equivalent comparator (COMP) supplement (e.g., carbohydrates). Continuous data on body composition [fat-free mass (FFM) or lean body mass], strength, and functional capacity as markers of physical performance were pooled using a random-effects model. RESULTS: Initially, 3329 publications were identified. Data from nine RCTs were ultimately included, involving 476 participants. The overall quality of the included studies was high, demonstrating a low risk of bias. Compared to COMP, no significant further benefits of ingesting MTN were identified for FFM (kg) (g = 0.044, 95 % CI -0.14 to 0.22), upper-body strength (kg) (g = 0.046, 95 % CI -0.24 to 0.33), lower-body strength, leg press exercise (kg) (g = 0.025, 95 % CI -0.26 to 0.31), leg extension exercise (kg) (g = 0.106, 95 % CI -0.15 to 0.36) and functional capacity (time in seconds) (g = 0.079, 95 % CI -0.12 to 0.27). CONCLUSIONS: No additional benefits of ingesting MTN vs. COMP to maximise exercise-induced outcomes on body composition and physical performance in healthy physically active middle-aged and older adults have been identified.

Premature Bioprosthetic Mitral Valve Dysfunction Due to Flail Leaflet Treated With Transcatheter Mitral Valve Replacement; a Case Report.

Early bioprosthetic mitral valve failure is uncommon, but cases can present with symptomatic heart failure and require careful attention and evaluation. Transcatheter valve replacement is a minimally invasive treatment for mitral valve dysfunction that can have a considerable impact, particularly for those who are at high surgical risk or have a history of bioprosthetic valve failure. We present a rare case of significant mitral regurgitation due to the unexpected premature failure of a bioprosthetic valve that was implanted three years prior. This patient was treated with transcatheter mitral valve replacement with the implantation of an Edwards SAPIEN Ultra (Edwards Lifesciences) valve.

Heart failure ejection fraction class conversions: impact of biomarkers, co-morbidities, and pharmacotherapy.

AIMS: Temporal conversions among ejection fraction (EF) classes can occur across the heart failure (HF) spectrum reflecting amended structural and functional outcomes unaccounted for by current taxonomy. This retrospective study aims to investigate the differences in serum laboratory values, guideline-directed medical therapy (GDMT), and co-morbidity burden across EF conversion groups. METHODS AND RESULTS: Heart failure patients at least 18-year-old who obtained at least two echocardiograms between January 2018 and January 2020 were identified using ICD-10 codes. Analysis of variance, chi-square tests, and analysis of means for proportions were used as appropriate to identify associations with class conversion groups. A total of 874 patients who underwent 1748 echocardiograms on unique visits were categorized according to initial EF as HF with preserved EF (HFpEF) (n = 531, 61%), HF with mildly reduced or midrange EF (HFmrEF) (n = 132, 15%), or HF with reduced EF (HFrEF) (n = 211, 24%). In accordance with follow-up EF, class conversions were categorized into HF with improved EF (HFiEF) (n = 143, 16%), HF with worsened EF (HFwEF) (n = 171, 20%), or HF with stable EF (HFsEF) (n = 560, 64%). The average age was 75 ± 13 years old; 54% were male, 85% were Caucasian, 11% were African American, and 4% other. The mean time between EF assessments was 208.6 ± 170.2 days. Serum sodium levels were greater in HFwEF (139 ± 3 mmol/L) when compared with HFsEF (138 ± 4 mmol/L) (P = 0.05). Pro-BNP levels were higher in HFiEF (12 150 ± 19 554 pg/mL) versus HFsEF (6671 ± 10 525 pg/mL) (P = 0.007). Angiotensin receptor-neprilysin inhibitors (ARNI) were more frequently ordered on index visit in HFiEF (P = 0.03), but no other significant differences in GDMT were identified. Despite similar Elixhauser Co-morbidity Measure (ECM) scores, ECM categorical analysis revealed that HFwEF was more likely to have an established diagnosis of depression (P = 0.03) and a spectrum of psychiatric illnesses (P = 0.03) on preliminary visit. HFsEF was less likely to have an established diagnosis of blood loss anaemia (P = 0.04). Metastatic cancer was more likely to have been diagnosed in HFiEF and less likely in HFsEF (P = 0.002). CONCLUSIONS: Despite similar ECM scores, EF class conversion groups demonstrated salient differences in average serum sodium and pro-BNP levels. Inpatient ARNI orders, psychiatric, hematologic, and oncologic co-morbidity patterns were also significantly different. Findings demonstrate blood-based biomarker patterns and targetable co-morbid conditions which may play a role in future EF class conversion. Dedicated studies evaluating measurements related to GDMT dose-titration, quality of life, and functionality are the next steps in this field of HF.

Risk Factors of DAIR Failure and Validation of the KLIC Score: A Multicenter Study of Four Hundred Fifty-Five Patients.

Background: Debridement, antibiotic agents, and implant retention (DAIR) is a currently accepted approach for the treatment of early prosthetic joint infections (PJI). The success of a DAIR procedure has shown variable results throughout the published literature. Scoring systems such as the Kidney, Liver, Index surgery, Cemented prosthesis, and C-reactive protein value (KLIC) score for the selection of patients that are likely to benefit from DAIR have proved to be helpful in decision making. Our study aims to further validate the KLIC score using a large external multicentric cohort and to evaluate other risk factors for failure. Patients and Methods: A retrospective analysis of patients with an early acute PJI who were treated with DAIR and recorded in a database of eight Spanish university hospitals was performed. According to pre-operative variables of the KLIC study, patients were categorized into five groups: group A, ≤2 points; group B, 2.5-3.5 points; group C, 4-5 points; group D, 5.5-6.5 points; and group E, ≥7 points. Failure rates were compared between groups at 60 days and after 60 days of DAIR. Further variables for risk of failure were also analyzed. Results: A total of 455 patients with early acute PJI were included in the analyses. At 60 days, patients presenting with pre-operative elevated C-reactive protein serum levels, Staphylococcus aureus, and polymicrobial infections were associated with failure. Failure rates recorded were 12% for group A (n = 210), 18% for group B (n = 83), 26% for group C (n = 89), 24% for group D (n = 66), and 0% for group E (n = 7). Univariable analysis between consecutive groups of the KLIC score showed no differences for failure before 60 days of the DAIR procedure. Scheduled surgery and having the procedure performed by a specialized unit were also identified as important factors for DAIR success. Conclusions: Our results suggest the KLIC score was not useful for predicting failure in our cohort. Furthermore, our results indicate a specialized unit should conduct DAIR procedures.

Cardiac Transthyretin Amyloidosis: Hidden in Plain Sight.

Amyloidosis is an underappreciated medical condition with symptoms camouflaging as common medical comorbidities leading to its underdiagnosis due to its systemic involvement. Despite common misconceptions, amyloidosis and its systemic comorbidities are more prevalent and treatable than previously acknowledged by the medical community. There are two major forms of amyloidosis: amyloid light-chain and transthyretin amyloidosis. Each of these have a distinct pathophysiology, diagnostic work-up, treatment, and prognosis. The patient described in this study was diagnosed with transthyretin cardiac amyloidosis months after presenting with heart failure of unknown etiology. Usually, clinicians presume that heart failure results from common comorbidities such as hypertension, diabetes, and hyperlipidemia. Here, the correct etiology was transthyretin cardiac amyloidosis. The patient had five admissions for heart failure symptoms prior to a physician identifying the etiology as cardiac transthyretin amyloidosis. After initiating the transthyretin stabilizer tafamidis, the patient did not experience another heart failure exacerbation. This vignette provides an example of the clinical presentation, diagnostic work-up, and treatment of a patient with cardiac transthyretin amyloidosis. The review of the literature focuses on the epidemiology, and clinical symptoms that should prompt an evaluation for cardiac amyloidosis as well as the diagnostic and therapeutic options are available. Transthyretin cardiac amyloidosis is a rare and underdiagnosed disease, while heart failure is a highly prevalent condition. This clinical vignette seeks to provide education and awareness to an overlooked medical disorder.

The Role of Drosophila CtIP in Homology-Directed Repair of DNA Double-Strand Breaks.

DNA double-strand breaks (DSBs) are a particularly genotoxic type of DNA damage that can result in chromosomal aberrations. Thus, proper repair of DSBs is essential to maintaining genome integrity. DSBs can be repaired by non-homologous end joining (NHEJ), where ends are processed before joining through ligation. Alternatively, DSBs can be repaired through homology-directed repair, either by homologous recombination (HR) or single-strand annealing (SSA). Both types of homology-directed repair are initiated by DNA end resection. In cultured human cells, the protein CtIP has been shown to play a role in DNA end resection through its interactions with CDK, BRCA1, DNA2, and the MRN complex. To elucidate the role of CtIP in a multicellular context, CRISPR/Cas9 genome editing was used to create a DmCtIPΔ allele in Drosophila melanogaster. Using the DSB repair reporter assay direct repeat of white (DR-white), a two-fold decrease in HR in DmCtIPΔ/Δ mutants was observed when compared to heterozygous controls. However, analysis of HR gene conversion tracts (GCTs) suggests DmCtIP plays a minimal role in determining GCT length. To assess the function of DmCtIP on both short (~550 bp) and long (~3.6 kb) end resection, modified homology-directed SSA repair assays were implemented, resulting in a two-fold decrease in SSA repair in both short and extensive end resection requirements in the DmCtIPΔ/Δ mutants compared to heterozygote controls. Through these analyses, we affirmed the importance of end resection on DSB repair pathway choice in multicellular systems, described the function of DmCtIP in short and extensive DNA end resection, and determined the impact of end resection on GCT length during HR.

A Case of Infiltrative Cardiomyopathy Secondary to Primary Hyperoxaluria Type 2 - Utilization of Multimodality Imaging.

Primary hyperoxaluria is a rare genetic disorder characterized by oxalate crystal deposition, including in the heart. Hyperoxaluria-associated cardiomyopathy manifests as restrictive infiltrative cardiomyopathy. We present a case of a 52-year-old male with a past medical history of type 2 primary hyperoxaluria, end-stage renal disease on hemodialysis, paroxysmal atrial fibrillation, and hypertension, who presented with dyspnea and lethargy. Transthoracic echocardiogram showed cardiomyopathy with ejection fraction (EF) of 35-40% with severe hypokinesis of apical myocardium. Endomyocardial biopsy revealed interstitial fibrosis and crystal deposition consistent with oxalate. Cardiac MRI showed late gadolinium enhancement with subendocardial, nearly transmural fibrosis of lateral wall along with mid myocardial involvement of anterior and septal wall. To the best of our knowledge, this is the first case of type 2 primary hyperoxaluria-associated cardiomyopathy utilizing transthoracic echo, endomyocardial biopsy, and cardiac MRI.

Effects of Multi-Ingredient Preworkout Supplementation across a Five-Day Resistance and Endurance Training Microcycle in Middle-Aged Adults.

Preworkout multi-ingredient admixtures are used to maximise exercise performance. The present double-blind, cross-over study compared the acute effects of ingesting a preworkout multi-ingredient (PREW) admixture vs. carbohydrate (CHO) over a week (microcycle) comprising three resistance training (RT) workouts alternated with two 30-min low-intensity endurance sessions (END) on RT volume (kg lifted) and END substrate oxidation. Additionally, postworkout decreases of muscle function and subjective responses were analysed. Following a baseline assessment, fourteen recreationally trained, middle-aged adults (seven females, 48.8 ± 4.7 years old) completed two identical microcycles separated by a two-week washout period while receiving either PREW or CHO (15 min prior to workout). The RT volume, per session (SVOL) and for the entire week (WVOL), was calculated. Fatty acid oxidation (FAO) during 30-min cycling corresponding to their individually determined maximal fat oxidation was measured using expired gasses and indirect calorimetry. Assessments of performance and tensiomyography were conducted within 20 min after each RT. Higher (p = 0.001) SVOL and WVOL along with a larger proportion of FAO (p = 0.05) during the second END workout were determined under the PREW treatment. No other statistically significant differences were observed between conditions. Compared to CHO, a preworkout multi-ingredient appears to increase resistance volume and favour fat oxidation during low-intensity endurance exercises.

Chromosome Preference During Homologous Recombination Repair of DNA Double-Strand Breaks in Drosophila melanogaster.

DNA double-strand breaks (DSBs) are especially toxic DNA lesions that, if left unrepaired, can lead to wide-ranging genomic instability. Of the pathways available to repair DSBs, the most accurate is homologous recombination (HR), where a homologous sequence is used as a donor template to restore genetic information at the break site. While much of the biochemical aspects of HR repair have been characterized, how the repair machinery locates and discriminates between potential homologous donor templates throughout the genome remains elusive. We use Drosophila melanogaster to investigate whether there is a preference between intrachromosomal and interhomolog donor sequences in mitotically dividing cells. Our results demonstrate that, although interhomolog HR is possible and frequent if another donor template is not available, intrachromosomal donor templates are highly preferred. This is true even if the interhomolog donor template is less diverged than the intrachromosomal donor template. Thus, despite the stringent requirements for homology, the chromosomal location of the donor template plays a more significant role in donor template choice.

Complexin has opposite effects on two modes of synaptic vesicle fusion.

BACKGROUND: Synaptic transmission can occur in a binary or graded fashion, depending on whether transmitter release is triggered by action potentials or by gradual changes in membrane potential. Molecular differences of these two types of fusion events and their differential regulation in a physiological context have yet to be addressed. Complexin is a conserved SNARE-binding protein that has been proposed to regulate both spontaneous and stimulus-evoked synaptic vesicle (SV) fusion. RESULTS: Here we examine complexin function at a graded synapse in C. elegans. Null complexin (cpx-1) mutants are viable, although nervous system function is significantly impaired. Loss of CPX-1 results in a 3-fold increase in the rate of tonic synaptic transmission at the neuromuscular junction, whereas stimulus-evoked SV fusion is decreased 10-fold. A truncated CPX-1 missing its C-terminal domain can rescue stimulus-evoked synaptic vesicle exocytosis but fails to suppress tonic activity, demonstrating that these two modes of exocytosis can be distinguished at the molecular level. A CPX-1 variant with impaired SNARE binding also rescues evoked, but not tonic, neurotransmitter release. Finally, tonic, but not evoked, release can be rescued in a syntaxin point mutant by removing CPX-1. Rescue of either form of exocytosis partially restores locomotory behavior, indicating that both types of synaptic transmission are relevant. CONCLUSION: These observations suggest a dual role for CPX-1: suppressing SV exocytosis, driven by low levels of endogenous neural activity, while promoting synchronous fusion of SVs driven by a depolarizing stimulus. Thus, patterns of synaptic activity regulate complexin's inhibitory and permissive roles at a graded synapse.