The Role of Glutathione in the Management of Cell-Mediated Immune Responses in Individuals with HIV.

Human immunodeficiency virus (HIV) is a major cause of death worldwide. Without appropriate antiretroviral therapy, the infection can develop into acquired immunodeficiency syndrome (AIDS). AIDS leads to the dysregulation of cell-mediated immunity resulting in increased susceptibility to opportunistic infections and excessive amounts of inflammatory cytokines. HIV-positive individuals also demonstrate diminished glutathione (GSH) levels which allows for increased viral replication and increased pro-inflammatory cytokine release, further contributing to the high rates of mortality seen in patients with HIV. Adequate GSH supplementation has reduced inflammation and slowed the decline of CD4+ T cell counts in HIV-positive individuals. We aim to review the current literature regarding the role of GSH in cell-mediated immune responses in individuals with HIV- and AIDS-defining illnesses.

Syntaxin 4 is essential for hearing in human and zebrafish.

Congenital hearing impairment (HI) is a genetically highly heterogeneous disorder in which prompt recognition and intervention are crucial to optimize outcomes. In this study, we used exome sequencing to investigate a large consanguineous Pakistani family with eight affected individuals showing bilateral severe-to-profound HI. This identified a homozygous splice region variant in STX4 (c.232 + 6T>C), which causes exon skipping and a frameshift, that segregated with HI (two-point logarithm of odds (LOD) score = 5.9). STX4, a member of the syntaxin family, is a component of the SNARE machinery involved in several vesicle transport and recycling pathways. In silico analysis showed that murine orthologue Stx4a is highly and widespread expressed in the developing and adult inner ear. Immunofluorescent imaging revealed localization of STX4A in the cell body, cell membrane and stereocilia of inner and outer hair cells. Furthermore, a morpholino-based knockdown of stx4 in zebrafish showed an abnormal startle response, morphological and developmental defects, and a disrupted mechanotransduction function in neuromast hair cells measured via FM1-43 uptake. Our findings indicate that STX4 dysfunction leads to HI in humans and zebrafish and supports the evolutionary conserved role of STX4 in inner ear development and hair cell functioning.

A novel autosomal dominant GREB1L variant associated with non-syndromic hearing impairment in Ghana.

BACKGROUND: Childhood hearing impairment (HI) is genetically heterogeneous with many implicated genes, however, only a few of these genes are reported in African populations. METHODS: This study used exome and Sanger sequencing to resolve the possible genetic cause of non-syndromic HI in a Ghanaian family. RESULTS: We identified a novel variant c.3041G > A: p.(Gly1014Glu) in GREB1L (DFNA80) in the index case. The GREB1L: p.(Gly1014Glu) variant had a CADD score of 26.5 and was absent from human genomic databases such as TopMed and gnomAD. In silico homology protein modeling approaches displayed major structural differences between the wildtype and mutant proteins. Additionally, the variant was predicted to probably affect the secondary protein structure that may impact its function. Publicly available expression data shows a higher expression of Greb1L in the inner ear of mice during development and a reduced expression in adulthood, underscoring its importance in the development of the inner ear structures. CONCLUSION: This report on an African individual supports the association of GREB1L variant with non-syndromic HI and extended the evidence of the implication of GREB1L variants in HI in diverse populations.

Nanoemulsified clove essential oils-based edible coating controls Pseudomonas spp.-causing spoilage of tilapia (Oreochromis niloticus) fillets: Working mechanism and bacteria metabolic responses.

Fish products suffer Pseudomonas-causing spoilage quickly during refrigeration storage, which could be solved by applying edible coating derived from nanoemulsified clove essential oils and fish gelatin (NCEO-FG). This study aimed to evaluate the effects and mechanism of NCEO-FG in preserving tilapia (Oreochromis niloticus) fillets that were inoculated with Pseudomonas spp. (Pseudomonas sp. strain ABa3, P. psychrophila strain ABe3, and P. fragi strain BBa3). NCEO caused remarkable leakage of proteins (198.5-252.8 µg/L) and nucleic acids (0.30-0.34 of OD260). After being incorporated into FG, NCEO-FG effectively delayed the deterioration of tilapia fillets because it significantly reduced the surviving bacteria populations (0.78 - 1.80 log CFU/g reductions) and inhibited the proteolysis and oxidation during cold storage. Further, the metabolic responses of NCEO-FG coated Pseudomonas spp. were revealed using NMR spectroscopy: the reducing levels of metabolites (e.g., pyruvate, amino acids, and betaine) suggested that the NCEO-FG disturbed energy and amino acid metabolisms of bacteria cells. However, the levels of metabolites (e.g., amino acids and osmoprotectants) were upregulated after 3 h and then back to normal concentration after 24 h, which indicated a defense system was built in bacterial cells to tolerate NCEO-FG. In short, this study confirmed that NCEO-FG could control the Pseudomonas-causing spoilage in fish fillets via elucidating the metabolisms.

Risk Factors of Mortality in Patients Hospitalized With Chronic Duodenal Ulcers.

BACKGROUND: We aimed to identify risk factors of mortality in patients hospitalized with duodenal ulcers (DUs). METHODS: A National Inpatient Sample-based retrospective cohort study from 2005 to 2014 was conducted on patients undergoing emergency admission for chronic DUs. Demographics, clinical data, and outcomes were collected. Multivariable logistic regression model was applied to find the risk factors of mortality. RESULTS: 70 641 patients were included in this study, of which 30 525 (43%) were non-elderly (< 65 years) and 40 116 (57%) were elderly (65+ years) patients. 72% of non-elderly and 57% of elderly patients were males. Mortality rate of men vs women was similar in non-elderly group (1.9% vs 2%, respectively), whereas it significantly differed in elderly patients (4.5% vs 5.3%, respectively, P<.0001). Time to operation was 1.15 (1.83) days in survived vs 1.55 (3.86) days in deceased non-elderly patients (P < .001). Time to operation was .85 (1.73) days in survived vs 1.79 (7.28) days in deceased elderly patients (P < .001). In patients with operation, age, delayed operation, frailty, and presence of perforation were the main risk factors of mortality in both elderly and non-elderly patients. Invasive diagnostic procedure was shown as a protective factor in elderly patients. In the final model for patients with no operation, age, hospital length of stay, and frailty were the main risk factors of mortality in both elderly and non-elderly patients. Invasive diagnostic procedure was revealed as a protective factor in all patients as well. CONCLUSION: Early operation in patients with DU requiring surgical intervention is essential to improve the outcomes.

Predictors for development of critical illness amongst older adults with COVID-19: Beyond age to age-associated factors.

INTRODUCTION: Older adults with COVID-19 have disproportionately higher rates of severe disease and mortality. It is unclear whether this is attributable to age or attendant age-associated risk factors. This retrospective cohort study aims to characterize hospitalized older adults and examine if comorbidities, frailty and acuity of clinical presentation exert an age-independent effect on COVID-19 severity. METHODS: We studied 275 patients admitted to the National Centre of Infectious Disease, Singapore. We measured: 1)Charlson Comorbidity Index(CCI) as burden of comorbidities; 2)Clinical Frailty Scale(CFS) and Frailty Index(FI); and 3)initial acuity. We studied characteristics and outcomes of critical illness, stratified by age groups (50-59,60-69 and ≥70). We conducted hierarchical logistic regression in primary model(N = 262, excluding direct admissions to intensive care unit) and sensitivity analysis(N = 275): age and gender in base model, entering CCI, frailty (CFS or FI) and initial acuity sequentially. RESULTS: The ≥70 age group had highest CCI(p<.001), FI(p<.001) and CFS(p<.001), and prevalence of geriatric syndromes (polypharmacy,53.5%; urinary symptoms,37.5%; chronic pain,23.3% and malnutrition,23.3%). Thirty-two (11.6%) developed critical illness. In the primary regression model, age was not predictive for critical illness when a frailty predictor was added. Significant predictors in the final model (AUC 0.809) included male gender (p=.012), CFS (p=.038), and high initial acuity (p=.021) but not CCI or FI. In sensitivity analysis, FI (p=.028) but not CFS was significant. CONCLUSIONS: In hospitalized older adults with COVID-19, geriatric syndromes are not uncommon. Acuity of clinical presentation and frailty are important age-independent predictors of disease severity. CFS and FI provide complimentary information in predicting interval disease progression and rapid disease progression respectively.

Alternative Access Transcatheter Aortic Valve Replacement in Nonagenarians versus Younger Patients.

BACKGROUND: Numerous studies have documented the safety of alternatives access (AA) transcatheter aortic valve replacement (TAVR) for patients who are not candidates for transfemoral or surgical approach. There is a scarcity of studies relating use of AA TAVR in nonagenarian patients, a high-risk, frail group. Our study sought to investigate the clinical outcomes of nonagenarians who underwent AA TAVR for aortic stenosis, with comparison of nonagenarians age ≥90 years with patients age <90 years. METHODS: A cohort study of 171 consecutive patients undergoing AA TAVR (transapical [TA, n = 101, 59%], transaxillary [TAX, n = 56, 33%], transaortic [TAO, n = 11, 6%], and transcarotid [TC, n = 3, 2%]) from 2012 to 2019 was analyzed. Baseline, operative, and postoperative characteristics, as well as actuarial survival outcomes, were compared. RESULTS: AA TAVR patients had decreased aortic valve gradients with no difference detected in nonagenarians and younger patients. Operative mortality was 8% (n = 14; nine TA, three TAO, and two TAX). Compared to younger patients, significantly more nonagenarians were recorded to have new onset atrial fibrillation (7 vs. 5%, p < 0.01*). No significant difference in mortality or postoperative complications, such as stroke, pacemaker requirements, was detected. Actuarial survival at 1 and 5 years was 86 versus 87% (nonagenarians vs younger patients) and 36 versus 22%, respectively, with log-rank = 0.97. CONCLUSION: AA TAVR in nonagenarian patients who are not candidates for transfemoral approach can be efficaciously performed with comparable clinical outcomes to younger patients, age <90 years. Furthermore, some access sites should be avoided when possible; notably TA was associated with increased mortality, stroke, and new onset atrial fibrillation.

Head injury and neuropsychiatric sequelae in asylum seekers.

OBJECTIVE: Asylum seekers experience a high burden of physical and psychological trauma, yet there is a scarcity of literature regarding the epidemiology and sequelae of head injury (HI) in asylum seekers. We examined HI prevalence and association with neuropsychiatric comorbidities in asylum seekers. METHODS: A retrospective cross-sectional study was performed through review of 139 medical affidavits from an affidavit database. Affidavits written from 2010 to 2018 were included. Demographic and case-related data were collected and classified based on the presence of HI. For neuropsychiatric sequelae, the primary study outcome was headache and the secondary outcomes were depression, posttraumatic stress disorder, and anxiety. Multivariable logistic regression was performed to examine the association between HI and neuropsychiatric sequelae, adjusted for demographic and clinical characteristics. RESULTS: A total of 139 medical affidavits of asylum seekers were included. The mean age was 27.4 ± 12.1 years, 56.8% were female, and 38.8% were <19 years. Almost half (42.5%) explicitly self-reported history of HI. Compared to clients who did not report HI, clients with HI were older and more likely to report a history of headache, physical abuse, physical trauma, concussion, and loss of consciousness. After adjustment for demographic and clinical characteristics, clients with HI had greater odds for neuropsychological sequelae such as headache (odds ratio [OR] 4.2, 95% confidence interval [CI] 2.0-8.7) and depression (OR 2.5, 95% CI 1.1-5.7). CONCLUSIONS: We observed a high prevalence of HI in asylum seekers. Comprehensive screening for HI and neuropsychiatric comorbidities is encouraged when evaluating asylum seekers.

Human rights-based approach to global surgery: A scoping review.

BACKGROUND: Health is a basic human right, yet surgery remains a neglected stepchild of global health. Worldwide, five billion people lack access to safe, timely, and affordable surgical and anesthesia care when needed. This disparity results in over 18 million preventable deaths each year and is responsible for one-third of the global burden of disease. Here, we evaluate the role of surgical care in protecting human rights and attempt to make a human rights argument for universal access to safe surgical care. MATERIAL AND METHODS: A scoping review was done using the PubMed/MEDLINE, Embase, and Scopus databases to identify articles evaluating human rights and disparities in accessing surgical care globally. A conceptual framework is proposed to implement global surgical interventions with a human rights-based approach. RESULTS: Disparities in accessing surgical care remain prevalent around the world, including but not limited to gender inequality, socioeconomic differentiation, sexual stigmatization, racial and religious disparities, and cultural beliefs. Lack of access to surgery impedes lives in full health and economic prosperity, and thus violates human rights. Our normative framework proposes human rights principles to make surgical policy interventions more inclusive and effective. CONCLUSION: Acknowledging human rights in the provision of surgical care around the world is critical to attain and sustain the Sustainable Development Goals and universal health coverage. National Surgical, Obstetric, and Anesthesia Planning and wider health systems strengthening require the integration of human rights principles in developing and implementing policy interventions to ensure equal and universal access to comprehensive health care services.

Diffuse large B-cell and follicular lymphoma presenting as a slowly growing compressive goiter: A case report and literature review.

INTRODUCTION: Neck ultrasonography with fine-needle aspiration cytology (FNAC) is the diagnostic modality of choice for clinicians who routinely work up a thyroid mass. Distinguishing chronic lymphocytic infiltration from a lymphoproliferative process with FNAC in patients with Hashimoto's thyroiditis presenting with a goiter can be particularly challenging. CASE DESCRIPTION: A 58 y.o. female with a history of a goiter showing interval growth and compressive symptoms over 18 months, was treated with a thyroid lobectomy. Surgical pathology demonstrated a thyroid lymphoma (TL) with mixed follicular and diffuse large B cell (DLBCL) components, not initially diagnosed by FNAC. Staging workup showed the involvement of chest lymph nodes only, consistent with Stage IIE disease. She was treated with combination chemotherapy and immunotherapy, followed by involved-field radiotherapy. DISCUSSION: TL often arises in a background of chronic lymphocytic thyroiditis which can make its histological diagnosis a challenge. The disease is heterogeneous in histological subtype and progression. CONCLUSION: While TL usually presents as a rapidly growing neck mass, indolent types can present as a slow growing mass with subsequent transformation. Patients may benefit from avoiding unnecessary diagnostic steps, including surgery, and potential delays in treatment by performing a core needle biopsy when a lymphoproliferative process cannot be excluded if FNAC was initially performed.

Warm Blood Cardioplegia for Myocardial Protection: Concepts and Controversies.

Warm blood cardioplegia has been an established cardioplegic method since the 1990s, yet it remains controversial in regard to myocardial protection. This review will describe the physiologic and technical concepts behind warm blood cardioplegia, as well as outline the current basic and clinical research that evaluates its usefulness. Controversies regarding this technique will also be reviewed. A long history of experimental data indicates that warm blood cardioplegia is safe and effective and thus suitable myocardial protection during cardiopulmonary bypass surgeries.

Rapid broadband discrete nanomechanical mapping of soft samples on atomic force microscope.

In this paper, an approach to achieve rapid broadband discrete nanomechanical mapping of soft samples using an atomic force microscope is developed. Nanomechanical mapping (NM) is needed to investigate, for example, dynamic evolution of the nanomechanical distribution of the sample-provided that the mapping is fast enough. The throughput of conventional NM methods, however, is inherently limited by the continuous scanning involved where the probe visits each sampling location continuously. Thus, we propose to significantly reduce the number of measurements through discrete mapping where only discrete sampling locations of interests are visited and measured. An online-searching learning-based technique is utilized to achieve rapid probe engagement and withdrawal with the interaction force minimized at each sampling location. Then, a control-based nanoindentation measurement technique is used to quickly acquire the nanomechanical property at each location, over frequencies that can be chosen arbitrarily in a broad range. Finally, a decomposition-based learning approach is explored to achieve rapid probe transitions between the sampling locations. The proposed technique is demonstrated through experiments using a Polydimethylsiloxane (PDMS) sample and a PDMS-epoxy sample as examples.

Geospatial Analysis of Trauma Burden and Surgical Care Capacity in Teso Sub-region of Eastern Uganda.

INTRODUCTION: Over 90% of injury-related deaths occur in low- and middle-income countries. Relating spatial distribution of injury burden and trauma care capacity is crucial for effective resource allocation. Our study assesses trauma burden and emergency and essential surgical care (EESC) quality in Teso Sub-region Eastern Uganda through a spatial analysis of trauma burden in relation to surgical capacity at the district level. METHODS: In this study, we surveyed trauma patients presenting at Soroti Regional Referral Hospital (SRRH) and assessed EESC capacity of district hospitals. We used geospatial techniques to relate trauma burden and capacity and characterized delay using the three-delay framework. RESULTS: We surveyed 131 trauma patients presenting to SRRH for trauma-related injuries from June 1 to July 15, 2017. Almost all trauma incidents (n = 129, 98.4%) occurred within a 2-h ideal drive time to SRRH. From time of injury to receiving care, median time totaled to approximately 9.25 h. District hospital exhibited decreased EESC capacity (personnel, infrastructure, procedures, equipment, and supplies (PIPES) score range 2.2-5.5, mean 4.2) compared to SRRH (PIPES score 8.1). CONCLUSION: Trauma patients face delays in each step of the care-seeking process from deciding to seek care, arriving at care site, and receiving treatment. Synergistic effects of a poor prehospital care, EESC deficiencies on district and regional levels, cost of seeking care contribute to delays that likely result in increased morbidity and mortality. Improved resource allocation, training at the district level, and strengthening system-level organization of emergency medical services could avert preventable death and disability.

Premature ventricular contractions activate vagal afferents and alter autonomic tone: implications for premature ventricular contraction-induced cardiomyopathy.

Mechanisms behind development of premature ventricular contraction (PVC)-induced cardiomyopathy remain unclear. PVCs may adversely modulate the autonomic nervous system to promote development of heart failure. Afferent neurons in the inferior vagal (nodose) ganglia transduce cardiac activity and modulate parasympathetic output. Effects of PVCs on cardiac parasympathetic efferent and vagal afferent neurotransmission are unknown. The purpose of this study was to evaluate effects of PVCs on vagal afferent neurotransmission and compare these effects with a known powerful autonomic modulator, myocardial ischemia. In 16 pigs, effects of variably coupled PVCs on heart rate variability (HRV) and vagal afferent neurotransmission were evaluated. Direct nodose neuronal recordings were obtained in vivo, and cardiac-related afferent neurons were identified based on their response to cardiovascular interventions, including ventricular chemical and mechanical stimuli, left anterior descending (LAD) coronary artery occlusion, and variably coupled PVCs. On HRV analysis before versus after PVCs, parasympathetic tone decreased (normalized high frequency: 83.6 ± 2.8 to 72.5 ± 5.3; P < 0.05). PVCs had a powerful impact on activity of cardiac-related afferent neurons, altering activity of 51% of neurons versus 31% for LAD occlusion (P < 0.05 vs. LAD occlusion and all other cardiac interventions). Both chemosensitive and mechanosensitive neurons were activated by PVCs, and their activity remained elevated even after cessation of PVCs. Cardiac afferent neural responses to PVCs were greater than any other intervention, including ischemia of similar duration. These data suggest that even brief periods of PVCs powerfully modulate vagal afferent neurotransmission, reflexly decreasing parasympathetic efferent tone.NEW & NOTEWORTHY Premature ventricular contractions (PVCs) are common in many patients and, at an increased burden, are known to cause heart failure. This study determined that PVCs powerfully modulate cardiac vagal afferent neurotransmission (exerting even greater effects than ventricular ischemia) and reduce parasympathetic efferent outflow to the heart. PVCs activated both mechano- and chemosensory neurons in the nodose ganglia. These peripheral neurons demonstrated adaptation in response to PVCs. This study provides additional data on the potential role of the autonomic nervous system in PVC-induced cardiomyopathy.

Alternative Access Versus Transfemoral Transcatheter Aortic Valve Replacement in Nonagenarians.

OBJECTIVES: Previous studies suggest that alternative access (AA) such as transapical (TA) approach to transcatheter aortic valve replacement (TAVR) is inferior to transfemoral (TF) approach. However, there is a paucity of data characterizing these outcomes, and studies often do not consider transaortic (TAO) and transaxillary (TAX) TAVR approaches. Therefore, the purpose of this study was to compare the outcomes of nonagenarians undergoing AA-TAVR compared to TF-TAVR. METHODS: A concurrent cohort study of 148 consecutive nonagenarian patients (≥90 years old) undergoing TAVR from April 2012 to July 2017 was carried out. We stratified the patient cohort into two groups based on access approach: TF-TAVR (n = 112); and AA-TAVR (n = 36), which included TA (n = 24), TAX (n = 8), and TAO (n = 4) approaches. Preoperative, operative, and postoperative outcomes and 5-year actuarial survival rates were analyzed. RESULTS: Compared to TF-TAVR, patients undergoing AA-TAVR were more likely to require blood transfusions (28% vs 69%; P<.001) and readmission (16% vs 58%; P<.001). AA-TAVR also resulted in significantly higher rates of postoperative complications, such as stroke (1% vs 8%; P=.02) and atrial fibrillation (19% vs 36%; P=.03). There was no significant difference in aortic valve gradients (P>.05), operative mortality rate (6% vs 8%; P=.66), or actuarial 5-year survival rate (68% vs 44%, log-rank P=.10). CONCLUSION: There is a higher risk of adverse events following AA-TAVR compared with TF-TAVR. Therefore, TF-TAVR is recommended when feasible, with AA approach as a viable back-up option in nonagenarians.

Recent Advances in Understanding the Pathogenesis of Cardiovascular Diseases and Development of Treatment Modalities.

Cardiovascular Diseases (CVDs) are a leading cause of morbidity and mortality worldwide. The underlying pathology for cardiovascular disease is largely atherosclerotic in nature and the steps include fatty streak formation, plaque progression and plaque rupture. While there is optimal drug therapy available for patients with CVD, there are also underlying drug delivery obstacles that must be addressed. Challenges in drug delivery warrant further studies for the development of novel and more efficacious medical therapies. An extensive understanding of the molecular mechanisms of disease in combination with current challenges in drug delivery serves as a platform for the development of novel drug therapeutic targets for CVD. The objective of this article is to review the pathogenesis of atherosclerosis, first-line medical treatment for CVD, and key obstacles in an efficient drug delivery.