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Background: Early non-infectious complications at initiation of peritoneal dialysis (PD) are a major burden with unknown long-term impacts on individuals. Methods: Prospective multicentre cohort study using univariable and multivariable Cox regression to identity mortality risk and PD discontinuation risk in those with and without non-infectious complications. All individuals commencing PD between 1 January 2014 and 31 December 2018, registered in the New Zealand Peritoneal Dialysis Registry (NZPDR) were followed up to 31 December 2020. Early non-infectious complications defined as functional, catheter-related, exit-site dialysate leak or anatomical leak complications occurring within 30 days of initiation of PD. Primary outcomes were patient survival and time on PD therapy. Secondary outcomes were peritonitis free survival, first PD catheter survival and catheter tunnel infection free survival. Results: Of 1596 individuals included in the study, 102 experienced an early non-infectious complication. Multivariable analysis demonstrated these complications were associated with higher risk of overall mortality (hazard ratio (HR) 1.71; 95% confidence interval (CI) 1.21–2.44), PD discontinuation (HR 1.84; 95% CI 1.41–2.41) and first catheter failure (HR 2.89; 95% CI 2.28–3.66). No difference was found for risk of development of first peritonitis episode or catheter tunnel infection. Mortality risk was associated with functional and exit-site dialysate leak complications and continued beyond 180 days. Risk of PD discontinuation and first catheter loss were associated with catheter and functional complications in the first 180 days. Conclusion: Early non-infectious complications are associated with long-term mortality risk. Further research in risk factors and causes of early non-infectious complications are required.

In general, fast-food organizations typically have distinctive ways of managing their business operations and achieving their corporate goals and objectives. The companies used marketing strategies to bring the organization’s mission and vision to life. Because these were influenced by the expanding population, trends, consumer behavior, internal and external factors in various situations, such as the most recent pandemic impact in 2020 continuing until 2021, many business models were introduced, adjusted, or replicated over the course of years. This study focuses on various business techniques and tactics that are crucial for the survival and sustainability of the fast-food industry and for competing against recently introduced rivals in the expanding food chain sector. This investigation will serve as a Quantitative Documentary Analysis through Data Mining. To sum it up, this research will offer suggestions on how to sell fast-food chains domestically, develop internationally, and, most importantly, ensure the survival of the company.

Under the rapid development of Phnom Penh, the pollutants control from different sources intothe main natural wetland, Tamouk lake is consequentially required for its ecosystem as well as thesustainable development. Therefore, this work aims to investigate the distribution of thepollutants from the urban canal and aquaculture farm to Tamouk lake through the analysis ofwater quality in both dry and rainy seasons. Twelve sampling sites, i.e., two from urban canals, onefrom aquaculture farm, and nine from the investigated lake, were selected for their water qualityassessment. As the results from both seasonal analyses, the maximum concentrations of totalsuspended solids (TSS), chemical oxygen demand (COD), and ammonia (NH3+) of the effluentfrom aquaculture farm and urban canal to the lake range of 107-134 mg l-1, 76-184 mg l-1, and 8.5-14.9mg l-1 in the dry season and 105-263mg l-1, 75-140 mg l-1, and 7.5-9.2 mg L-1in the rainy season,respectively. In addition, TSS and COD in the lake were only 72-93 mg l-1and 46-77mg l-1 of bothseasons, respectively, whereas NH3+ was estimated to be 7-14 times lower than that in urban canaland aquaculture farms. According to the result analysis, the lake’s water pollution was mainlycontributed by the discharge from the urban canal and aquaculture farm in both seasons. Higherrelease of pollutants from many sources during the rainy season could compensate for rainwater’sdilution effect, resulting in the high remaining of organic and nitrogen in lake water. Hence, toreduce the risk of the lake water to humans and ecosystems, the effluent from aquaculture farmsand urban water is highly suggested to have a proper treatment before discharging to the lake.

ispartof: IEEE Journal of Emerging and Selected Topics in Industrial Electronics vol:3 issue:3 pages:797-808 status: published

Purpose of reviewPatients, providers, and trainees should understand the current types of asynchronous technologies that can be used to enhance the delivery and accessibility of mental health care. Asynchronous telepsychiatry (ATP) removes the need for real time communication between the clinician and patient, which improves efficiency and enables quality specialty care. ATP can be applied as distinct consultative and supervisory models in clinician-to-clinician, clinician-to-patient, and patient-to-mobile health settings.Recent findingsThis review is based on research literature and the authors' clinical and medical training, using experiences with asynchronous telepsychiatry from before, during, and after the COVID-19 pandemic. Our studies demonstrate that ATP provides positive outcomes in the clinician-to-patient model with demonstrated feasibility, outcomes and patient satisfaction. One author's medical education experience in the Philippines during COVID-19 highlights the potential to utilize asynchronous technology in areas with limitations to online learning. We emphasize the need to teach media skills literacy around mental health to students, coaches, therapists, and clinicians when advocating for mental well-being. Several studies have demonstrated the feasibility of incorporating asynchronous e-tools such as self-guided multimedia and artificial intelligence for data collection at the clinician-to-clinician and patient-to-mobile health level. In addition, we offer fresh perspectives on recent trends in asynchronous telehealth in wellness, applying concepts such as "tele-exercise" and "tele-yoga."SummaryAsynchronous technologies continue to be integrated into mental health care services and research. Future research must ensure that the design and the usability of this technology puts the patient and provider first.

Myelin repair is an unrealized therapeutic goal in the treatment of multiple sclerosis (MS). Uncertainty remains about the optimal techniques for assessing therapeutic efficacy and imaging biomarkers are required to measure and corroborate myelin restoration. We analyzed myelin water fraction imaging from ReBUILD, a double-blind, randomized placebo-controlled (delayed treatment) remyelination trial, that showed a significant reduction in VEP latency in patients with MS. We focused on brain regions rich in myelin. Fifty MS subjects in two arms underwent 3T MRI at baseline and months 3 and 5. Half of the cohort was randomly assigned to receive treatment from baseline through 3 mo, whereas the other half received treatment from 3 mo to 5 mo post-baseline. We computed myelin water fraction changes occurring in normal-appearing white matter of corpus callosum, optic radiations, and corticospinal tracts. An increase in myelin water fraction was documented in the normal-appearing white matter of the corpus callosum, in correspondence with the administration of the remyelinating treatment clemastine. This study provides direct, biologically validated imaging-based evidence of medically induced myelin repair. Moreover, our work strongly suggests that significant myelin repair occurs outside of lesions. We therefore propose myelin water fraction within the normal-appearing white matter of the corpus callosum as a biomarker for clinical trials looking at remyelination.

The Nrf2-KEAP1 pathway plays an important role in the cellular response to oxidative stress and confers protection in diseases associated with chronic inflammation. However, chronic activation of the Nrf2 pathway may contribute to metabolic changes and disease progression in cancer. We investigated the activation of Nrf2 in human cancers and fibroblast cells through KEAP1 inhibition and cancer associated KEAP1/Nrf2 mutations. We define a core set of 14 upregulated Nrf2 target genes from seven RNA-Sequencing databases that we generated and analyzed. Additionally, we validated this universal Nrf2 target gene set through analyses of published databases. An Nrf2 activity score based on expression of these core target genes correlates with resistance to drugs such as PX-12 and necrosulfonamide but not to paclitaxel or bardoxolone methyl. We validated these findings and found Nrf2 activation also led to radioresistance in cancer cell lines. Finally, our Nrf2 score is prognostic for survival for a variety of cancers, an observation validated in additional independent cohorts. These analyses define a core Nrf2 gene set that is robust, versatile, and useful for predicting drug resistance and cancer prognosis.SIGNIFICANCEThe frequent activation of Nrf2 observed in cancer cells confers protection from oxidative stress, cytotoxic chemotherapeutic agents and radiation. We define a ‘Nrf2 gene signature’ that is comprised of 14 target genes and faithfully predicts increased Nrf2 activity, selective drug and radiation resistance in cancer cell lines, and a worse clinical prognosis in a variety of human cancers.

Many biomarkers in clinical neuroscience lack pathological certification. This issue is potentially a significant contributor to the limited success of neuroprotective and neurorestorative therapies for human neurological disease—and is evident even in areas with therapeutic promise such as myelin repair. Despite the identification of promising remyelinating candidates, biologically validated methods to demonstrate therapeutic efficacy or provide robust preclinical evidence of remyelination in the CNS are lacking. Therapies with potential to remyelinate the CNS constitute one of the most promising and highly anticipated therapeutic developments in the pipeline to treat multiple sclerosis and other demyelinating diseases. The optic nerve has been proposed as an informative pathway to monitor remyelination in animals and human subjects. Recent clinical trials using visual evoked potential have had promising results, but without unequivocal evidence about the cellular and molecular basis for signal changes on visual evoked potential, the interpretation of these trials is constrained. The visual evoked potential was originally developed and used in the clinic as a diagnostic tool but its use as a quantitative method for assessing therapeutic response requires certification of its biological specificity. Here, using the tools of experimental pathology we demonstrate that quantitative measurements of myelination using both histopathological measures of nodal structure and ultrastructural assessments correspond to visual evoked potential latency in both inflammatory and chemical models of demyelination. Visual evoked potential latency improves after treatment with a tool remyelinating compound (clemastine), mirroring both quantitative and qualitative myelin assessment. Furthermore, clemastine does not improve visual evoked potential latency following demyelinating injury when administered to a transgenic animal incapable of forming new myelin. Therefore, using the capacity for therapeutic enhancement and biological loss of function we demonstrate conclusively that visual evoked potential measures myelin status and is thereby a validated tool for preclinical verification of remyelination.

Global migration trends are accelerating population admixture. Increasing population diversity met with minority health disparities necessitates thoughtful training of health professional students. Health professional accreditation standards emphasize pharmacogenomics and clinical cultural competency (CCC); however, published studies focus on students’ knowledge in pharmacogenomics alone. This report reviews considerations for integrating CCC into required pharmacogenomic education in pharmacy and other health disciplines. By coupling both topics during didactic training and active learning exercises repeated throughout the existing curriculum, students can become adept at these individualized patient care skills and retain their knowledge into their careers. Moving beyond race as a proxy for healthcare decision-making, the CCC of clinicians coupled with patients’ genetic test results could empower clinicians to address health disparities and facilitate discussions about the role of race in clinical practice. Ultimately, an integrated approach of teaching pharmacogenomics and CCC could dismantle race-norming or race-based clinical practices.

There is currently a lack of precise predictive biomarkers for patient selection in clinical trials of inhibitors targeting replication stress (RS) response proteins ATR and CHK1. The objective of this study was to identify novel predictive biomarkers for the response to these agents in treating non–small cell lung cancer (NSCLC). A genome-wide loss-of-function screen revealed that tumor suppressor PPP2R2A, a B regulatory subunit of protein phosphatase 2 (PP2A), determines sensitivity to CHK1 inhibition. A synthetic lethal interaction between PPP2R2A deficiency and ATR or CHK1 inhibition was observed in NSCLC in vitro and in vivo and was independent of p53 status. ATR and CHK1 inhibition resulted in significantly increased levels of RS and altered replication dynamics, particularly in PPP2R2A-deficient NSCLC cells. Mechanistically, PPP2R2A negatively regulated translation of oncogene c-Myc protein. c-Myc activity was required for PPP2R2A deficiency-induced alterations of replication initiation/RS and sensitivity to ATR/CHK1 inhibitors. We conclude that PPP2R2A deficiency elevates RS by upregulating c-Myc activity, rendering cells reliant on the ATR/CHK1 axis for survival. Our studies show a novel synthetic lethal interaction and identify PPP2R2A as a potential new predictive biomarker for patient stratification in the clinical use of ATR and CHK1 inhibitors.Significance:This study reveals new approaches to specifically target PPP2R2A-deficient lung cancer cells and provides a novel biomarker that will significantly improve treatment outcome with ATR and CHK1 inhibitors.

Supplementary Materials and Methods.

Background/ObjectiveThe most significant adverse events following SARS-CoV-2 vaccination are myocarditis and pericarditis. Myositis and dermatomyositis have been reported following SARS-CoV-2 infection, but vaccine-induced dermatomyositis (DM) has not been reported. Our case series aimed to characterize new onset dermatomyositis or disease-related flares following SARS-CoV-2 vaccination.Materials and methodsA total of 53 patients from our institution with a new or pre-existing diagnosis of DM were recruited and consented. Phone interviews were conducted to obtain vaccination status and symptoms following vaccination. Electronic medical records were reviewed to extract age, sex, autoantibody profiles, comorbidities, immunomodulatory therapies, creatine kinase (CK) values, and SARS-CoV-2 vaccination dates from the provincial vaccination registry. For patients who reported disease flares, records were reviewed for the onset and nature of symptoms, extent of organ involvement and changes in immunomodulation.ResultsOn average, patients received 2.62 vaccine doses (range 1–3 doses). A total of 3 of 51 patients (5.88%) experienced dermatomyositis symptoms following vaccination. Two patients were newly diagnosed with dermatomyositis, one requiring hospitalization. Reported symptom onset following vaccination ranged from 1 to 30 days. Of note, all of these patients had normal CK values, even though there was muscle biopsy-confirmed myositis in one patient. Eight patients in the cohort (15.1%) had asymptomatic CK elevation (ConclusionNew onset dermatomyositis or flare up of pre-existing dermatomyositis may be a rare complication in SARS-CoV-2 vaccination although no studies can support a true correlation. Several pathophysiologic mechanisms are proposed.

We report that the neurotrophin receptor p75 contributes to sensory neuron survival through the regulation of cholesterol metabolism in Schwann cells. Selective deletion of p75 in mouse Schwann cells of either sex resulted in a 30% loss of dorsal root ganglia (DRG) neurons and diminished thermal sensitivity. P75 regulates Schwann cell cholesterol biosynthesis in response to BDNF, forming a co-receptor complex with ErbB2 and activating ErbB2-mediated stimulation of sterol regulatory element binding protein 2 (SREBP2), a master regulator of cholesterol synthesis. Schwann cells lacking p75 exhibited decreased activation of SREBP2 and a reduction in 7-dehydrocholesterol (7-DHC) reductase (DHCR7) expression, resulting in accumulation of the neurotoxic intermediate, 7-dehyrocholesterol in the sciatic nerve. Restoration of DHCR7 in p75 null Schwann cells in mice significantly attenuated DRG neuron loss. Together, these results reveal a mechanism by which the disruption of lipid metabolism in glial cells negatively influences sensory neuron survival, which has implications for a wide range of peripheral neuropathies.SIGNIFICANCE STATEMENTAlthough expressed in Schwann cells, the role of p75 in myelination has remained unresolved in part because of its dual expression in sensory neurons that Schwann cells myelinate. When p75 was deleted selectively among Schwann cells, myelination was minimally affected, while sensory neuron survival was reduced by 30%. The phenotype is mainly due to dysregulation of cholesterol biosynthesis in p75-deficient Schwann cells, leading to an accumulation of neurotoxic cholesterol precursor, 7-dehydrocholesterol (7-DHC). Mechanism-wise, we discovered that in response to BDNF, p75 recruits and activates ErbB2 independently of ErbB3, thereby stimulating the master regulator, sterol regulatory element binding protein 2 (SREBP2). These results together highlight a novel role of p75 in Schwann cells in regulating DRG neuron survival by orchestrating proper cholesterol metabolism.

Brachiocephalic arteriovenous fistulas (AVF) makeup approximately one third of prevalent dialysis vascular accesses. The most common cause of malfunction with this access is cephalic arch stenosis (CAS). The accepted requirement for treatment of a venous stenosis lesion is ⩾50% stenosis associated with hemodynamically abnormalities. However, the correlation between percentage stenosis and a clinically significant decrease in access blood flow (Qa) is low. The critical parameter is the absolute minimal luminal diameter (MLD) of the lesion. This is the parameter that exerts the key restrictive effect on Qa and results in hemodynamic and functional implications for the access. CAS is the result of low wall shear stress (WSS) resulting from the effects of increased blood flow and the unique anatomical configuration of the CAS. Decrease in WSS has a linear relationship to increased blood flow velocity and neointimal hyperplasia exhibits an inverse relationship with WSS. The result is a stenotic lesion. The presence of downstream venous stenosis causes an inflow-outflow mismatch resulting in increased pressure within the access. Qa in this situation may be decreased, increased, or within a normal range. Over time, the increased intraluminal pressure can result in marked aneurysmal changes within the AVF, difficulties with cannulation and the dialysis treatment, and ultimately, increasing risk of access thrombosis. Complete characterization of the lesion both hemodynamically and anatomically should be the first step in developing a strategy for management. This requires both access flow measurement and angiographic imaging. Patients with CAS present a relatively broad spectrum as relates to both of these parameters. These data should be used to determine whether primary treatment of CAS should be directed toward the anatomical lesion (small MLD and low Qa) or the pathophysiology (large MLD and high Qa).