Deep sequencing of proteotoxicity modifier genes uncovers a Presenilin-2/beta-amyloid-actin genetic risk module shared among alpha-synucleinopathies.

Whether neurodegenerative diseases linked to misfolding of the same protein share genetic risk drivers or whether different protein-aggregation pathologies in neurodegeneration are mechanistically related remains uncertain. Conventional genetic analyses are underpowered to address these questions. Through careful selection of patients based on protein aggregation phenotype (rather than clinical diagnosis) we can increase statistical power to detect associated variants in a targeted set of genes that modify proteotoxicities. Genetic modifiers of alpha-synuclein (ɑS) and beta-amyloid (Aß) cytotoxicity in yeast are enriched in risk factors for Parkinson's disease (PD) and Alzheimer's disease (AD), respectively. Here, along with known AD/PD risk genes, we deeply sequenced exomes of 430 ɑS/Aß modifier genes in patients across alpha-synucleinopathies (PD, Lewy body dementia and multiple system atrophy). Beyond known PD genes GBA1 and LRRK2, rare variants AD genes (CD33, CR1 and PSEN2) and Aß toxicity modifiers involved in RhoA/actin cytoskeleton regulation (ARGHEF1, ARHGEF28, MICAL3, PASK, PKN2, PSEN2) were shared risk factors across synucleinopathies. Actin pathology occurred in iPSC synucleinopathy models and RhoA downregulation exacerbated ɑS pathology. Even in sporadic PD, the expression of these genes was altered across CNS cell types. Genome-wide CRISPR screens revealed the essentiality of PSEN2 in both human cortical and dopaminergic neurons, and PSEN2 mutation carriers exhibited diffuse brainstem and cortical synucleinopathy independent of AD pathology. PSEN2 contributes to a common-risk signal in PD GWAS and regulates ɑS expression in neurons. Our results identify convergent mechanisms across synucleinopathies, some shared with AD.

Biogenic fabrication of ZnO@EC and MgO@EC using Eucalyptus leaf extract for the removal of hexavalent chromium Cr(VI) ions from water.

Zinc and magnesium oxide nanoparticles were fabricated using green synthesis method for the sequestration of hexavalent chromium Cr(VI) from the aqueous medium. The biogenically prepared ZnO@EC and MgO@EC nanoparticles were successfully loaded on the Eucalyptus. The prepared nanomaterials were characterized using various techniques such as FESEM, TGA, XRD, EDX, FTIR, BET, and elemental mapping. FE-SEM analysis has revealed the surface morphology of ZnO nanoparticles, which were rod-like and spherical in shape, whereas MgO nanoparticles were of irregular shape. Batch mode was selected to remove the hexavalent chromium from aqueous solution using the prepared nanomaterials. The Cr(VI) adsorption was carried out under optimized conditions, viz., pH (3.0), adsorbent dose (0.05 g), contact time (150 min), temperature (25 ± 2 °C), and initial concentration (50 mg/L). The experimental results were compared using the different isotherm models; The observations have indicated that experimental data fit better with Freundlich (R2 = 0.99) and Langmuir (R2 = 0.99) isotherms, respectively. The maximum adsorption capacity of ZnO@EC and MgO@EC for Cr(VI) was found to be 49.3 and 17.4 mg/g, respectively. The regeneration study of the adsorbents was conducted using different desorbing agents viz., ethanol, NaOH, and NaCl. The desorbing agent NaOH performed better and showed removal percentage of 34.24% and 20.18% for ZnO@EC and MgO@EC, respectively, after the three reusability cycles. The kinetics of reaction was assessed using the pseudo-first-order and pseudo-second-order kinetic models. The experimental data of both the nanomaterials ZnO@EC and MgO@EC obeyed pseudo-second-order model with correlation coefficient values 0.999 and 0.983, respectively. The thermodynamic study confirmed that adsorption was feasible, spontaneous, and endothermic. The adsorbents were tested for spiked real water which confirms their applicability and potential in real water systems also. The results indicated fair removal of chromium suggesting applicability of both adsorbents.

Current progress in treatment technologies for plastic waste (bisphenol A) in aquatic environment: Occurrence, toxicity and remediation mechanisms.

Bisphenol-A (BPA) is a type of endocrine disrupting compound (EDC) that is being widely used in the production of polycarbonate and epoxy resins. In the last few years, human exposure to BPA has been extensively high due to the continuous increment in the Annual Growth Rate (AGR) of the BPA global market. The presence and transportation of BPA in the environment could cause serious damage to aquatic life and human health. This paper reviewed the literature on the exposure and toxicity mechanisms of BPA and advanced analytical techniques for the detection of BPA in the environment and human beings. The study indicated that BPA can cause damaging effects on numerous tissues and organs, including the reproductive system, metabolic dysfunction, respiratory system, immune system and central nervous system. On the basis of reported studies on animals, it appears that the exposure of BPA can be carcinogenic and responsible for causing a variety of cancers like ovarian cancer, uterine cancer, prostate cancer, testicular cancer, and liver cancer. This review paper focused mainly on the current progress in BPA removal technologies within last ten years (2012-2022). This paper presents a comprehensive overview of individual removal technologies, including adsorption, photocatalysis/photodegradation, ozonation/advance oxidation, photo-fenton, membranes/nanofilters, and biodegradation, along with removal mechanisms. The extensive literature study shows that each technology has its own removal mechanism and their respective limitations in BPA treatment. In adsorption and membrane separation process, most of BPA has been treated by electrostatic interaction, hydrogen boning and π-π interations mechanism. Whereas in the degradation mechanism, O* and OH* species have played a major role in BPA removal. Some factors could alter the removal potential and efficiency of BPA removal. This review paper will provide a useful guide in providing directions for future investigation to address the problem of BPA-containing wastewater treatment.

Healthcare Provider Perspectives Regarding Use of Medical Interpreters During End-of-Life Conversations With Limited English Proficient Patients.

BACKGROUND: Healthcare providers increasingly care for patients with Limited English Proficiency (LEP). There is limited research evaluating healthcare provider utilization practices, attitudes, perceived benefits and barriers regarding the use of medical interpreters in end of life (EOL) and goals of care (GOC) conversations. OBJECTIVES: To elicit healthcare providers' opinions of the role, factors that impact decisions to use medical interpreters and perceived utility of using medical interpreters when conducting EOL and GOC conversations with LEP patients and their families. DESIGN: Cross-sectional survey of internal medicine trainees and attending physicians from a U.S. medical center. RESULTS: A total of 117 surveys were collected with a response rate of 51%. In-person medical interpreters received higher ratings with regard to their helpfulness compared to telephone medical interpreters during EOL and GOC conversations. Being an attending physician and having received training in the use of a medical interpreter predicted higher composite scores reflecting greater awareness of the roles of medical interpreters and endorsement of best communication practices. In-person interpreters were viewed by a subset of participants as "standard of care" during EOL and GOC conversations. CONCLUSION: Having more years in practice and receiving training in the use of medical interpreters correlated with more favorable attitudes toward the role of medical interpreters and positive communication practices. Incorporating early training in the use of medical interpreters could help enhance communication practices and outcomes during EOL and GOC conversations with LEP patients.

Sustainable treatment and nutrient recovery from leafy waste through vermicomposting.

The present investigation was carried out to evaluate the vermicomposting potential of two cruciferous vegetables' residual biomasses under laboratory conditions. Cabbage and cauliflower residual biomasses were spiked with 60% cow dung and vermicomposted for 90 days. The results showed a decrease in pH (5.3-9.8%), Total Organic Carbon (36.7-42.8%); increase in Electrical Conductivity (33-99.4%) and ash content (144.7-187.8%) after vermicomposting. Significant reduction in C:N ratio (49.5-76.4%) and C:P ratio (62.8-66.04%), increase in Total Kjeldahl Nitrogen (49.3-85.3%), Total Available Phosphorus (68.2-98.1%), Total Potassium (91.8-120.3%) were observed. FT-IR spectra of the vermicomposts had lesser band heights and peak intensities than raw materials. This evidenced decomposition of organic compounds and vermicompost stability. Germination Index values was calculated to determine the phytotoxicity level. Earthworms' growth and prolificacy was evaluated in terms of biomass gain, cocoons production and worm growth rate. Finally, it was inferred that cruciferous vegetables' biomass can be used for vermicomposting. The cauliflower residual biomass has shown better decomposition efficiency than cabbage residual biomass.

Management of banana crop waste biomass using vermicomposting technology.

This study reports the vermicomposting of banana crop waste biomass by Eisenia fetida. Cow dung has been used as bulking agent in this study. The experiment was conducted in six vermireactors containing different ratios of banana leaf waste biomass (BL) and cow dung (CD) for 105 days. Earthworm activity significantly reduced pH, TOC, C:N and C:P ratio of the wastes. Whereas macronutrients and micronutrients content increased after vermicomposting. TOC content of wastes reduced by 40-64% and C:N ratio of the vermicomposts was in the range of 8.9-24.3. The benefit ratio for heavy metals (Cu, Fe, Zn, Cd, Pb, Mn and Cr) was in the range of 0.23-3.44. The results indicated that the growth and fecundity of the earthworms was best in the vermireactors having 20-40% BL. Finally, it was concluded that vermicomposting can be included in the overall scheme of banana crop waste management.

An EBV+ lymphoepithelioma-like cholangiocarcinoma in a young woman with chronic hepatitis B.

Epstein-Barr virus (EBV) is implicated in the tumorigenesis of a variety of malignancies, including Burkitt's lymphoma, Hodgkin's disease and nasopharyngeal carcinoma (NPC). EBV+ lymphoepithelioma-like cholangiocarcinoma (LELCC) is a rare type of intrahepatic cholangiocarcinoma with a distinct pathology and poorly understood treatment options. Morphologically, this neoplasm resembles undifferentiated NPC, a commonly EBV+ tumour with a prominent lymphoid infiltrate. Almost all of the current literature regarding LELCC describes early stage tumours that are treated surgically and achieve good outcomes. In contrast, this report documents a late stage LELCC treated unsuccessfully with systemic chemotherapy.

Impact of gaps in care for malnourished patients on length of stay and hospital readmission.

BACKGROUND: Few published articles have focused on identifying the gaps in care that follow a malnutrition diagnosis and their effects on length of stay (LOS) and 90-day readmission. We hypothesized that length of stay and readmission were associated with these gaps in care. METHODS: Two registered dietitians retrospectively reviewed charts of 229 adult malnourished patients admitted to a medicine unit to determine their system level gap in care: communication, test delay, or discharge planning. In this secondary analysis, both readmission and length of stay were regressed on each gap in care. RESULTS: Any system level gap was associated with a greater length of stay (ß: 1.48, 95% CI: 1.15-1.91) and specifically the gap related to procedure/testing (ß: 2.01, 95% CI: 1.62-2.47) resulted in a two-fold increase in length of stay. There was no association between 90-day readmission and any of the gaps in care. CONCLUSIONS: There was a strong association between those who had any gap in their care and increased length of stay. Mitigating gaps in care may decrease length of stay and, in turn, result in less risk of infection and could potentially lead to reduced healthcare costs.

Evaluating Gaps in Care of Malnourished Patients on General Medicine Floors in an Acute Care Setting.

BACKGROUND: As described in detail in the literature, patients identified with malnutrition are at increased risk for poor clinical outcomes. Despite this knowledge, malnourished patients do not always receive optimal nutrition management while admitted into a hospital because of what we describe as gaps in care throughout their admission. We hypothesized that the 3 main gaps in care were poor dietitian-doctor communication, excessive time spent nil per os (NPO) for procedures and testing, and/or inaccurate or incomplete dietary discharge instructions. The objectives of this study were to determine and to characterize gaps in nutrition care after a malnutrition diagnosis. METHODS: This retrospective study involved postdischarge chart reviews of malnourished adult medicine patients admitted to an acute care facility from September 1, 2014, to November 30, 2014 (n = 242). RESULTS: Of the malnourished patients, 76% had at least 1 gap in care. The most prevalent gap (68%) involved discharge diet instructions, most often because of the omission of the dietitian recommendation for oral supplementation. Thirty-five percent of malnourished patients had a gap in care because of procedures or testing extending the period held NPO, and 13% had a gap in care because of poor communication, thus delaying orders and/or interventions. CONCLUSIONS: This is the first study to evaluate gaps in care of patients diagnosed with malnutrition. Identification of these gaps allows us the opportunity to develop strategies for this vulnerable population to improve areas such as discharge documentation and time spent NPO to provide the best and safest nutrition care.

Impact of Hospitalist-Led Interdisciplinary Antimicrobial Stewardship Interventions at an Academic Medical Center.

BACKGROUND: Approximately 20%-50% of antimicrobial use in hospitals is inappropriate. Limited data exist on the effect of frontline provider engagement on antimicrobial stewardship outcomes. METHODS: A three-arm pre-post quality improvement study was conducted on three adult internal medicine teaching services at an urban academic hospital. Data from September through December 2016 were compared to historic data from corresponding months in 2015. Intervention arms were (1) Educational bundle (Ed-only); (2) Educational bundle plus antimicrobial stewardship rounds twice weekly with an infectious disease-trained clinical pharmacist (Ed+IDPharmDx2); and (3) Educational bundle plus internal medicine-trained clinical pharmacist embedded into daily attending rounds (Ed+IMPharmDx5). RESULTS: Total antibiotic use decreased by 16.8% (p < 0.001), 6.8% (p = 0.08), and 33.0% (p < 0.001) on Ed-only, Ed+IDPharmDx2, and Ed+IMPharmDx5 teams, respectively. Broad-spectrum antibiotic use decreased by 26.2% (p < 0.001), 7.8% (p = 0.09), and 32.4% (p < 0.001) on the Ed-only, Ed+IDPharmDx2, and Ed+IMPharmDx5 teams, respectively. Duration of inpatient antibiotic therapy decreased from 4 to 3 days on the Ed+IMPharmDx5 team (p = 0.01). Length of stay for patients who received any antibiotic decreased from 9 to 7 days on the Ed-only team (p < 0.001) and from 9 to 6 days on the Ed+IMPharmDx5 team (p < 0.001). There was no significant change in 30-day readmission to the same facility, transfer to ICU, or in-hospital mortality for any team. CONCLUSION: Multidisciplinary, frontline provider-driven approaches to antimicrobial stewardship may contribute to reduced antibiotic use and length of hospital stay.

Breaking the mold: A case of pulmonary mucormycosis treated with isavuconazole.

Pulmonary mucormycosis is a rare opportunistic invasive fungal infection that disproportionately affects immunocompromised hosts and carries high morbidity and mortality. It is traditionally treated with combined pharmacologic and surgical modalities. Here we present a case of pulmonary mucormycosis in a patient whose disease burden precluded surgical management, and in whom acute kidney injury necessitated therapy with an alternative to the recommended pharmacologic antifungal therapy.

New uses of old technology: Can nurse-pagers improve communication between resident-physicians and nurses.

BACKGROUND: Alphanumeric paging is underutilized, despite being the standard mode of communication between physicians and nurses at many hospitals across the United States. OBJECTIVE: We hypothesized that an educational program designed to teach optimal alphanumeric paging behavior in conjunction with providing nurses with alphanumeric pagers would improve the quality and efficiency of nurse pages. METHODS: We implemented an educational program to teach nurses about optimal alphanumeric paging, defined as including four important components-patient identification, clinical scenario, sender identification, and callback number. We also provided each nurse with their own unique pager. Alphanumeric paging logs were reviewed prior to the intervention (baseline study period), and again following implementation of the intervention (intervention study period). Questionnaires were also completed by resident-physicians and nurses before and after implementation. RESULTS: During the intervention period, the percentage of ideal pages increased, and the percentage of suboptimal pages decreased. Compared to baseline, pages during the intervention period more often included patient identity, clinical scenario, and page-sender. Resident-physicians rated the paging-system's impact on patient care and job satisfaction more highly, and reported that disruptions and nurse accessibility were less of a problem during the intervention period compared to baseline. Nurses reported less problems with disruptions, ignored pages, miscommunication, and contentious relationships with resident-physicians. CONCLUSIONS: This study underscores the importance of two-way communication, which can be achieved without expensive technology. Creative use of old technology, such as providing nurses with traditional pagers, can improve communication and workflow, and potentially quality of care and patient safety.

Leiomyosarcoma of maxilla: a case report with review of literature.

OBJECTIVE: One challenging feature of head and neck pathology is that a dizzying array of spindle cell lesions occurs here which ranges all the way from reactive, very aggressive forms to malignant lesions. Leiomyosarcoma is one such malignant tumour of mesenchymal origin exhibiting smooth muscle differentiation; presenting generally nonspecific signs and symptoms. Here we present a case of leiomyosarcoma in a 21 year old female patient associated with single reddish pink swelling present in the posterior right maxillary tuberosity region with moderate facial asymmetry. On histopathological analysis, all the classic features were noted and diagnosis of a spindle cell neoplasm was made without any obscurity. There are many lesions like rhabdomyosarcoma, fibrosarcoma, liposarcoma, multiple peripheral nerve sheath tumour, angiosarcomas, melanomas, kaposi sarcoma, solitary fibrous tumors, etc., which mimic leiomyosarcoma clinically and histopathologically and therefore immunohistochemical staining with specific markers plays a vital role in arriving at a conclusive diagnosis.

Coculturing with endothelial cells promotes in vitro maturation and electrical coupling of human embryonic stem cell-derived cardiomyocytes.

BACKGROUND: Pluripotent human embryonic stem cells (hESC) are a promising source of repopulating cardiomyocytes. We hypothesized that we could improve maturation of cardiomyocytes and facilitate electrical interconnections by creating a model that more closely resembles heart tissue; that is, containing both endothelial cells (ECs) and cardiomyocytes. METHODS: We induced cardiomyocyte differentiation in the coculture of an hESC line expressing the cardiac reporter NKX2.5-green fluorescent protein (GFP), and an Akt-activated EC line (E4+ECs). We quantified spontaneous beating rates, synchrony, and coordination between different cardiomyocyte clusters using confocal imaging of Fura Red-detected calcium transients and computer-assisted image analysis. RESULTS: After 8 days in culture, 94% ± 6% of the NKX2-5GFP+ cells were beating when hESCs embryonic bodies were plated on E4+ECs compared with 34% ± 12.9% for controls consisting of hESCs cultured on BD Matrigel (BD Biosciences) without ECs at Day 11 in culture. The spatial organization of beating areas in cocultures was different. The GFP+ cardiomyocytes were close to the E4+ECs. The average beats/min of the cardiomyocytes in coculture was faster and closer to physiologic heart rates compared with controls (50 ± 14 [n = 13] vs 25 ± 9 [n = 8]; p < 0.05). The coculture with ECs led to synchronized beating relying on the endothelial network, as illustrated by the loss of synchronization upon the disruption of endothelial bridges. CONCLUSIONS: The coculturing of differentiating cardiomyocytes with Akt-activated ECs but not EC-conditioned media results in (1) improved efficiency of the cardiomyocyte differentiation protocol and (2) increased maturity leading to better intercellular coupling with improved chronotropy and synchrony.

Lin28 and let-7 in the Metabolic Physiology of Aging.

The Lin28/let-7 molecular switch has emerged as a central regulator of growth signaling pathways and metabolic enzymes. Initially discovered to regulate developmental timing in the nematode, the Lin28/let-7 pathway of RNA regulation has gained prominence for its role in mammalian stem cells, cancer cells, tissue development, and aging. By regulating RNAs, the pathway coordinates cellular growth and cellular metabolism to influence metabolic physiology. Here, we review this regulatory mechanism and its impact on cancers, which reactivate Lin28, cardiovascular diseases, which implicate let-7, human genome-wide association studies (GWAS) of growth, and metabolic diseases, which implicate the Lin28/let-7 pathway. We also highlight questions relating to Barker's Hypothesis and the potential actions of the Lin28/let-7 pathway on programming long-lasting epigenetic effects.

Microparticles mediated cross-talk between tumoral and endothelial cells promote the constitution of a pro-metastatic vascular niche through Arf6 up regulation.

The tumor stroma plays an essential role in tumor growth, resistance to therapy and occurrence of metastatic phenotype. Tumor vessels have been considered as passive conducts for nutrients but several studies have demonstrated secretion of pro-tumoral factors by endothelial cells. The failure of anti-angiogenic therapies to meet expectations raised by pre-clinical studies prompt us to better study the cross-talk between endothelial and cancer cells. Here, we hypothesized that tumor cells and the endothelium secrete bio-active microparticles (MPs) participating to a functional cross-talk. We characterized the cancer cells MPs, using breast and ovarian cancer cell lines (MCF7, MDA-MB231, SKOV3, OVCAR3 and a primary cell lines, APOCC). Our data show that MPs from mesenchymal-like cell lines (MDA-MB231, SKOV3 and APOCC) were able to promote an activation of endothelial cells through Akt phosphorylation, compared to MPs from epithelial-like cell lines (OVCAR3 and MCF7). The MPs from mesenchymal-like cells contained increased angiogenic molecules including PDGF, IL8 and angiogenin. The endothelial activation was associated to increased Arf6 expression and MPs secretion. Endothelial activation functionalized an MP dependent pro-tumoral vascular niche promoting cancer cells proliferation, invasiveness, stem cell phenotype and chemoresistance. MPs from cancer and endothelial cells displayed phenotypic heterogeneity, and participated to a functional cross-talk where endothelial activation by cancer MPs resulted in increased secretion of EC-MPs sustaining tumor cells. Such cross-talk may play a role in perfusion independent role of the endothelium.

Surface-active solid lipid nanoparticles as Pickering stabilizers for oil-in-water emulsions.

Oil-in-water (O/W) emulsions solely stabilized by surface-active solid lipid nanoparticles (SLNs) were developed. The SLNs were generated by quench-cooling hot O/W nanoemulsions consisting of 7.5% glyceryl stearyl citrate (GSC) dispersed in water. Their initial volume-weighted mean particle diameter (∼152 nm) and zeta potential (ca.-49 mV) remained unchanged for 24 weeks. O/W emulsions (oil phase volume fraction: 0.2) containing 7.5% (w/w) GSC SLNs in the aqueous phase were kinetically-stable for 12 weeks and did not visually phase-separate over 24 weeks. The O/W emulsions generated with solid-state GSC SLNs had a volume-weighted mean oil droplet diameter of ∼459 nm and a zeta potential of ca.-43 mV. Emulsion microstructure evaluated with TEM revealed dispersed oil droplets sparsely covered with adsorbed Pickering-type SLNs as well aggregated SLNs present in the continuous phase. Gradual emulsion destabilization resulted from GSC SLN dissolution during the experimental timeframe. Overall, surface-active SLNs developed via nanoemulsions effectively kinetically stabilized O/W emulsions.

Optimization of cow dung spiked pre-consumer processing vegetable waste for vermicomposting using Eisenia fetida.

This paper reports the optimization of cow dung (CD) spiked pre-consumer processing vegetable waste (PPVW) for vermicomposting using Eisenia fetida in a laboratory scale study. Vermicomposting process decreased carbon and organic matter concentration and increased N, P and K content in the vermicompost. The C:N ratio was decreased by 45-69% in different vermireactors indicating stabilization of the waste. The heavy metal content was within permissible limits of their application in agricultural soils. It has been concluded from the results that addition of PPVW up to 40% with CD can produce a good quality vermicompost. Whereas, growth and fecundity of E. fetida was best when reared in 20% PPVW+80% CD feed mixture. However, higher percentages of PPVW in different vermireactors significantly affected the growth and fecundity of worms.