Navigating the Gene Co-Expression Network and Drug Repurposing Opportunities for Brain Disorders Associated with Neurocognitive Impairment.

Neurocognitive impairment refers to a spectrum of disorders characterized by a decline in cognitive functions such as memory, attention, and problem-solving, which are often linked to structural or functional abnormalities in the brain. While its exact etiology remains elusive, genetic factors play a pivotal role in disease onset and progression. This study aimed to identify highly correlated gene clusters (modules) and key hub genes shared across neurocognition-impairing diseases, including Alzheimer's disease (AD), Parkinson's disease with dementia (PDD), HIV-associated neurocognitive disorders (HAND), and glioma. Herein, the microarray datasets AD (GSE5281), HAND (GSE35864), glioma (GSE15824), and PD (GSE7621) were used to perform Weighted Gene Co-expression Network Analysis (WGCNA) to identify highly preserved modules across the studied brain diseases. Through gene set enrichment analysis, the shared modules were found to point towards processes including neuronal transcriptional dysregulation, neuroinflammation, protein aggregation, and mitochondrial dysfunction, hallmarks of many neurocognitive disorders. These modules were used in constructing protein-protein interaction networks to identify hub genes shared across the diseases of interest. These hub genes were found to play pivotal roles in processes including protein homeostasis, cell cycle regulation, energy metabolism, and signaling, all associated with brain and CNS diseases, and were explored for their drug repurposing experiments. Drug repurposing based on gene signatures highlighted drugs including Dorzolamide and Oxybuprocaine, which were found to modulate the expression of the hub genes in play and may have therapeutic implications in neurocognitive disorders. While both drugs have traditionally been used for other medical purposes, our study underscores the potential of a combined WGCNA and drug repurposing strategy for searching for new avenues in the simultaneous treatment of different diseases that have similarities in gene co-expression networks.

COVision: convolutional neural network for the differentiation of COVID-19 from common pulmonary conditions using CT scans.

With the growing amount of COVID-19 cases, especially in developing countries with limited medical resources, it is essential to accurately and efficiently diagnose COVID-19. Due to characteristic ground-glass opacities (GGOs) and other types of lesions being present in both COVID-19 and other acute lung diseases, misdiagnosis occurs often - 26.6% of the time in manual interpretations of CT scans. Current deep-learning models can identify COVID-19 but cannot distinguish it from other common lung diseases like bacterial pneumonia. Concretely, COVision is a deep-learning model that can differentiate COVID-19 from other common lung diseases, with high specificity using CT scans and other clinical factors. COVision was designed to minimize overfitting and complexity by decreasing the number of hidden layers and trainable parameters while still achieving superior performance. Our model consists of two parts: the CNN which analyzes CT scans and the CFNN (clinical factors neural network) which analyzes clinical factors such as age, gender, etc. Using federated averaging, we ensembled our CNN with the CFNN to create a comprehensive diagnostic tool. After training, our CNN achieved an accuracy of 95.8% and our CFNN achieved an accuracy of 88.75% on a validation set. We found a statistical significance that COVision performs better than three independent radiologists with at least 10 years of experience, especially in differentiating COVID-19 from pneumonia. We analyzed our CNN's activation maps through Grad-CAMs and found that lesions in COVID-19 presented peripherally, closer to the pleura, whereas pneumonia lesions presented centrally.

Australian consumer perspectives on dialysis: first national census.

AIM: The percentage of people in Australia who undertake home dialysis has steadily decreased over the past 40 years and varies within Australia. Consumer factors related to this decline have not previously been determined. METHODS: A 78-question survey was developed and piloted in 2008 and 2009. Survey forms were distributed to all adult routine dialysis patients in all Australian states and territories (except Northern Territory) between 2009 and 2010. Of 9223 distributed surveys, 3250 were completed and returned. RESULTS: 49% of respondents indicated they had no choice in the type of dialysis and 48% had no choice in dialysis location. Respondents were twice as likely to receive information about haemodialysis (85%) than APD (39%) or CAPD (41%). The provision of education regarding home modalities differed significantly between states, and decreased with increasing patient age. Additional nursing support and reimbursement of expenses increased the proportion of those willing to commence dialysis at home, from 13% to 34%. State differences in the willingness to consider home dialysis, the degree of choice in dialysis location, the desire to change current dialysis type and/or location, and the provision of information about dialysis were identified. CONCLUSION: The delivery of pre-dialysis education is variable, and does not support all options of dialysis for all individuals. State variances indicate that local policy and health professional teams significantly influence the operation of dialysis programs.

Chronic kidney disease and automatic reporting of estimated glomerular filtration rate: new developments and revised recommendations.

The publication of the Australasian Creatinine Consensus Working Group's position statements in 2005 and 2007 resulted in automatic reporting of estimated glomerular filtration rate (eGFR) with requests for serum creatinine concentration in adults, facilitated the unification of units of measurement for creatinine and eGFR, and promoted the standardisation of assays. New advancements and continuing debate led the Australasian Creatinine Consensus Working Group to reconvene in 2010. The working group recommends that the method of calculating eGFR should be changed to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula, and that all laboratories should report eGFR values as a precise figure to at least 90 mL/min/1.73 m(2). Age-related decision points for eGFR in adults are not recommended, as although an eGFR < 60 mL/min/1.73 m(2) is very common in older people, it is nevertheless predictive of significantly increased risks of adverse clinical outcomes, and should not be considered a normal part of ageing.If using eGFR for drug dosing, body size should be considered, in addition to referring to the approved product information. For drugs with a narrow therapeutic index, therapeutic drug monitoring or a valid marker of drug effect should be used to individualise dosing. The CKD-EPI formula has been validated as a tool to estimate GFR in some populations of non-European ancestry living in Western countries. Pending publication of validation studies, the working group also recommends that Australasian laboratories continue to automatically report eGFR in Aboriginal and Torres Strait Islander peoples. The working group concluded that routine calculation of eGFR is not recommended in children and youth, or in pregnant women. Serum creatinine concentration (preferably using an enzymatic assay for paediatric patients) should remain as the standard test for kidney function in these populations.

Chronic kidney disease and measurement of albuminuria or proteinuria: a position statement.

Optimal detection and subsequent risk stratification of people with chronic kidney disease (CKD) requires simultaneous consideration of both kidney function (glomerular filtration rate [GFR]) and kidney damage (as indicated by albuminuria or proteinuria). Measurement of urinary albuminuria and proteinuria is hindered by a lack of standardisation regarding requesting, sample collection, reporting and interpretation of tests. A multidisciplinary working group was convened with the goal of developing and promoting recommendations that achieve consensus on these issues. The working group recommended that the preferred method for assessment of albuminuria in both diabetic and non-diabetic patients is urinary albumin-to-creatinine ratio (UACR) measurement in a first-void spot urine specimen. Where a first-void specimen is not possible or practical, a random spot urine specimen for UACR is acceptable. The working group recommended that adults with one or more risk factors for CKD should be assessed using UACR and estimated GFR every 1-2 years, depending on their risk-factor profile. Recommended testing algorithms and sex-specific cut-points for microalbuminuria and macroalbuminuria are provided. The working group recommended that all pathology laboratories in Australia should implement the relevant recommendations as a vital component of an integrated national approach to detection of CKD.

How Australian nephrologists view home dialysis: results of a national survey.

AIM: Australia's commitment to home dialysis therapies has been significant. However, there is marked regional variation in the uptake of home haemodialysis (HD) and peritoneal dialysis (PD) suggesting further scope for the expansion of these modalities. METHODS: Between 1 April and 5 August 2009, Australian nephrologists were invited to complete an online survey. Seventy-six questions were asked covering characteristics of the dialysis units, responders' experience, adequacy of facilities and support structures, attitudes to the use of home HD and PD and issues impeding the increased uptake of home dialysis. RESULTS: Completed surveys were received and analysed from 71 respondents; 27 from Heads of Units (35% response rate) and 44 (16%) from other nephrologists. There was strong agreement that HD with long hours was advantageous and that this was most easily accomplished in the home. PD was not considered to be an inferior therapy. A 'PD first' policy existed in 34% of Renal Units. The most commonly reported impediments to expanding home dialysis services were financial disadvantage for home HD patients, and lack of physical infrastructure for training, support and education. Areas of concern for expanding home dialysis programmes included psychiatry support, access to respite care and home visits, and lack of support from medical administration and government. The majority of nephrologists would recommend home dialysis to more patients if these impediments could be overcome. CONCLUSION: This survey identified support from nephrologists for the expansion of home dialysis in Australia and highlighted important barriers to improving access to these therapies.

Assessment of the Nova StatSensor whole blood point-of-care creatinine analyzer for the measurement of kidney function in screening for chronic kidney disease.

BACKGROUND: Point-of-care testing for creatinine using a fingerprick sample and resultant estimated glomerular filtration rate has potential for screening for chronic kidney disease in community settings. This study assessed the applicability of the Nova StatSensor creatinine analyzer for this purpose. METHODS: Fingerprick samples from 100 patients (63 renal, 37 healthy volunteers; range 46-962 micromol/L) were assayed using two StatSensor analyzers. Lithium heparin venous plasma samples collected simultaneously were assayed in duplicate using the isotope dilution mass spectrometry-aligned Roche Creatinine Plus enzymatic assay on a Hitachi Modular P unit. Method comparison statistics and the ability of the StatSensor to correctly categorise estimated glomerular filtration rate above or below 60 mL/min were calculated pre- and post-alignment with the laboratory method. RESULTS: StatSensor 1 creatinine results (y) were much lower than the laboratory (y=0.75x+10.2, average bias -47.3, 95% limits of agreement -208 to +113 micromol/L). For estimated glomerular filtration rates above or below 60 mL/min, 100% and 87% of results respectively agreed with the laboratory estimated glomerular filtration rate (79% and 96% post-alignment). StatSensor 2 statistics were similar. The 95% limits of agreement between StatSensor creatinine results were -35 to +34 micromol/L. CONCLUSIONS: Isotope dilution mass spectrometry alignment of the StatSensor will identify most patients with estimated glomerular filtration rate <60 mL/min, but there will be many falsely low estimated glomerular filtration rate results that require laboratory validation. Creatinine results need improvement.

Home haemodialysis in Australia - is the wheel turning full circle?

In the mid 1970s, home haemodialysis accounted for nearly half of all patients on dialysis, both in Australia and elsewhere. The advent of both peritoneal dialysis (itself a home therapy) and satellite haemodialysis resulted in a gradual attrition in the use of home haemodialysis. Since 2000, the introduction of nocturnal home haemodialysis has begun to change this pattern in Australia, with a sharp growth in the uptake of home haemodialysis. Home haemodialysis, which enables longer hours and more frequent treatments than facility-based (hospital or satellite centre) dialysis, appears to offer improved patient outcomes in observational studies; randomised studies are necessary to confirm these findings. Home haemodialysis is also a cheaper form of therapy than facility-based dialysis. As newer, simpler and more user-friendly equipment is emerging that will make home haemodialysis even more accessible and attractive to the consumer, we believe that this trend toward a greater uptake of home haemodialysis should and will continue.

Screening for chronic kidney disease in Australia: a pilot study in the community and workplace.

The pilot program Kidney Evaluation for You (KEY) was conducted in Australia to screen for chronic kidney disease (CKD). Targeting people at high risk (those with diabetes, hypertension, a first-degree relative with kidney failure, or age >50 years), KEY aimed to establish community-based screening protocols, assess efficacy in promoting changes in risk-factor management, and explore participant CKD awareness. KEY offered free cardiovascular and kidney checks using point-of-care testing for on-site pathology measurements (estimated glomerular filtration rate, hemoglobin A1c, cholesterol, hemoglobin, albuminuria), lifestyle assessment, and exit interviews. Participants were telephoned at 3 months to ascertain whether KEY advice had been followed. Community and health professional support was strong; 99% of participants rated involvement as beneficial. Of 402 high-risk individuals recruited, findings were suggestive of CKD in 20.4%. Of these, 69% had hypertension, 30% diabetes, and 40% elevated total cholesterol. All participants with CKD stage 3b or higher were aged >61 years. Overall, 58% of participants were referred to their primary care providers for further action; of these, 82% saw their doctors in the next 3 months and 94% discussed KEY results. Follow-up telephone contact was successful for 82% of participants. A change in management occurred for 67%. Thus, the KEY approach to early detection of CKD and selected referral of participants was largely successful.

Review article: Early detection of chronic kidney disease in Australia: which way to go?

Early detection of chronic kidney disease (CKD) followed by appropriate clinical management appears the only means by which the increasing burden on the health-care system and affected individuals will be reduced. The asymptomatic nature of CKD means that early detection can only occur through testing of individuals. The World Health Organization principles of screening for chronic disease can now be largely fulfilled for CKD. The risk groups to be targeted, the expected yield and the tests to be performed are reviewed. For a screening programme to be sustainable it must carry a greater benefit than risk of harm for the participant and be shown to be cost-effective from the community point of view. Whole population screening for CKD is impractical and is not cost-effective. Screening of those at increased risk of CKD could occur either through special events run in the community, workplace or in selected locations such as pharmacies or through opportunistic screening of high-risk people in general practice. Community screening programmes targeted at known diabetics, hypertensives and those over 55 years have been described to detect 93% of all CKD in the community. The yield of CKD stages 3-5 from community screening has been found to vary from 10% to 20%. The limitations of screening programmes including the cost and recruitment bias are discussed. The most sustainable and likely the most cost-efficient model appears to be opportunistic general practice screening. The changing structure of general practice in Australia lends itself well to the requirements for early detection of CKD.

Automated reporting of eGFR: a useful tool for identifying and managing kidney disease.

Estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease formula has been shown to provide unbiased and acceptably accurate estimates of measured GFR across a broad range of individuals with impaired kidney function. eGFR is superior to measuring serum creatinine (SCr) concentration alone, more accurate than other prediction formulas (such as Cockcroft-Gault) in the setting of reduced kidney function, and more practical and reliable under most circumstances than measuring urinary creatinine clearance. Routine eGFR reporting with requests for SCr, in concert with clinician education, has been shown to enhance the detection of chronic kidney disease (CKD), resulting in improved cardiac and renal outcomes for patients. eGFR has been shown to effectively identify individuals at increased risk of adverse drug reactions (even when SCr concentration is in the normal range). For most drugs prescribed in primary care and for most patients of average age and body size, drug dosage adjustments based on eGFR should be similar to those based on Cockcroft-Gault. eGFR should not replace Cockcroft-Gault for determining dosage adjustments for critical-dose drugs that have a narrow therapeutic index. eGFR has resulted in important spin-off benefits, such as standardisation of laboratory creatinine assays and enhanced public and clinician awareness of CKD. Clinicians should be aware of the strengths, weaknesses and appropriate use of eGFR. Considerable research effort is being directed towards further refinement of eGFR.

How do the Australian guidelines for lipid-lowering drugs perform in practice? Cardiovascular disease risk in the AusDiab Study, 1999-2000.

OBJECTIVE: To determine how well the current Pharmaceutical Benefits Scheme (PBS) eligibility criteria for subsidy of lipid-lowering drugs compare with current national guidelines for determining the population at high risk of developing cardiovascular disease (CVD). DESIGN AND PARTICIPANTS: Analyses of the population-based, cross-sectional Australian Diabetes, Obesity and Lifestyle (AusDiab) study, conducted in 1999-2000. The 1991 Framingham risk prediction equation was used to compute 5-year risk of developing first-time CVD in 8286 participants aged 30-74 years with neither CVD nor diabetes. Based on the National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand guidelines, people with either 5-year CVD risk > or = 15% or with 5-year CVD risk of 10%-< 15% and the metabolic syndrome were defined as having estimated high absolute CVD risk. MAIN OUTCOME MEASURES: 5-year CVD risk; estimated population with high CVD risk. RESULTS: Among participants without prevalent CVD or diabetes, 7.9% of men and 1.5% of women had a 5-year CVD risk > or = 15%. Of the estimated residential Australian population in 2000 aged 30-74 years without CVD or diabetes, 717 000 people were considered to be at high absolute CVD risk. Among the high-risk AusDiab participants without CVD or diabetes, only 16.9% of men and 15.4% of women were being treated with lipid-lowering drugs. Of the 9.6% of participants free of CVD and diabetes who were untreated but eligible for subsidy under PBS criteria, only 27.4% had an estimated high absolute CVD risk. CONCLUSION: Strategies for CVD prevention using lipid-lowering medications can be improved by adoption of the absolute-risk approach.

Implementation of the routine reporting of eGFR in Australia and New Zealand.

The reporting of an eGFR (estimated glomerular filtration rate) with every requested serum creatinine concentration measurement has been successfully introduced as routine practice in Australia and New Zealand. This change in laboratory practice has been linked with a major educational initiative in the diagnosis and management of chronic kidney disease as well as standardization of a range of laboratory measurement and reporting issues. The process has been collaborative between renal physicians, chemical pathologists and laboratory scientists and their respective professional bodies, and the relevant decisions have been made collectively on the best available evidence. The initial guidelines were released in August 2005 and these have been followed up in 2007 with further recommendations to address issues arising since that time.

Analgesic nephropathy and renal replacement therapy in Australia: trends, comorbidities and outcomes.

BACKGROUND AND OBJECTIVES: This study examined age-specific incidence and prevalence of renal replacement therapy attributed to analgesic nephropathy from 1971 through 2005 and adjusted comorbidity prevalence and survival of patients who had analgesic nephropathy and were on renal replacement therapy (compared with control subjects without diabetes). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This retrospective cohort study, using data from the Australia and New Zealand Dialysis and Transplant registry, included all patients who were aged 35 to 84 yr and started long-term renal replacement therapy in Australia from 1971 through 2006. RESULTS: Of 31,654 incident renal replacement therapy patients, 10.2% had analgesic nephropathy. Incidence and prevalence of renal replacement therapy attributed to analgesic nephropathy decreased earlier and faster among younger (age <55 yr) patients. Prevalence of analgesic nephropathy among 75- to 84-yr-old renal replacement therapy patients is still increasing. Compared with control subjects without diabetes, comorbidities (coronary artery, cerebrovascular, peripheral vascular, and chronic lung diseases) were more prevalent among patients with analgesic nephropathy at renal replacement therapy start. All-cause, cardiovascular, infection, and cancer mortality were higher among patients who had analgesic nephropathy and were on renal replacement therapy. For both comorbidities and mortality, the associations were stronger in younger patients. CONCLUSIONS: Trends in renal replacement therapy attributed to analgesic nephropathy differed by age. Patients with analgesic nephropathy have more comorbidities and poorer survival on renal replacement therapy, especially among younger patients.

Chronic kidney disease and automatic reporting of estimated glomerular filtration rate: revised recommendations.

Since publication of the Australasian Creatinine Consensus Working Group's position statement in 2005, most Australasian laboratories now automatically report an estimated glomerular filtration rate (eGFR) (based on the Modification of Diet in Renal Disease [MDRD] formula) with results of serum creatinine tests in adults. Anecdotal evidence suggests that automatic reporting of eGFR helps to identify asymptomatic kidney dysfunction at an earlier stage and to develop rational and appropriate management plans. Changes to the measurement and calibration of serum creatinine assays and issues regarding implementation of eGFR in clinical practice led the Australasian Creatinine Consensus Working Group to reconvene in 2007. The recommendations contained here build on the original 2005 position statement and consolidate the role of eGFR in clinical practice. The Working Group recommends that the eGFR upper reporting limit be extended to 90 mL/min/1.73 m2, with eGFR values above this amount being reported as "> 90 mL/min/1.73 m2", rather than as a precise figure. The Working Group has concluded that it is currently premature to recommend age-related decision points for eGFR. However, it is appropriate to advise medical practitioners that, in people aged >/= 70 years, an eGFR in the range 45-59 mL/min/1.73 m2, if stable over time and unaccompanied by other evidence of kidney damage, may be interpreted as consistent with a typical eGFR for this age group and is unlikely to be associated with chronic kidney disease-related complications. Pending publication of validation studies, the Working Group recommends that Australasian laboratories continue to automatically report eGFR in Aboriginal and Torres Strait Islander peoples and other ethnic groups. The Working Group supports the use of eGFR to assist drug dosing decision making in general practice.

A comparative study of sirolimus tablet versus oral solution for prophylaxis of acute renal allograft rejection.

This multicenter, open-label study compared the efficacy, safety, and pharmacokinetic parameters of sirolimus (rapamycin) tablet and liquid formulations for prevention of efficacy failure. A total of 477 renal allograft recipients were randomly assigned (1:1) to receive either tablet or solution formulations of sirolimus for 12 months, plus cyclosporine (CsA) and steroids. Pharmacokinetic parameters were analyzed based on trough concentrations and 24-hour pharmacokinetic profiles. There were no significant differences in efficacy failure at 3 or 12 months between tablet and solution groups. Graft survival, patient survival, rate of first biopsy-confirmed acute rejection, time to and severity of acute rejection, and laboratory parameters were not significantly different between groups. Mean steady-state sirolimus and CsA pharmacokinetic parameters on days 30 and 90 were not significantly different by formulation, except for longer sirolimus t(max) after tablet administration. Multivariate logistic regression analysis indicated that low sirolimus C(min,TN) and more human leukocyte antigen mismatches were predictors of acute rejection. The tablet and solution formulations of sirolimus demonstrated therapeutic equivalence.

Chronic kidney disease and automatic reporting of estimated glomerular filtration rate: a position statement.

The systematic staging of chronic kidney disease (CKD) by glomerular filtration measurement and proteinuria has allowed the development of rational and appropriate management plans. One of the barriers to early detection of CKD is the lack of a precise, reliable and consistent measure of kidney function. The most common measure of kidney function is currently serum creatinine concentration. It varies with age, sex, muscle mass and diet, and interlaboratory variation between measurements is as high as 20%. The reference interval for serum creatinine concentration includes up to 25% of people (particularly thin, elderly women) who have an estimated glomerular filtration rate (eGFR) that is significantly reduced (< 60 mL/min/1.73 m2). The recent publication of a validated formula (MDRD) to estimate GFR from age, sex, race and serum creatinine concentration, without any requirement for measures of body mass, allows pathology laboratories to "automatically" generate eGFR from data already acquired. Automatic laboratory reporting of eGFR calculated from serum creatinine measurements would help to identify asymptomatic kidney dysfunction at an earlier stage. eGFR correlates well with complications of CKD and an increased risk of adverse outcomes such as cardiovascular morbidity and mortality. We recommend that pathology laboratories automatically report eGFR each time a serum creatinine test is ordered in adults. As the accuracy of eGFR is suboptimal in patients with normal or near-normal renal function, we recommend that calculated eGFRs above 60 mL/min/1.73 m2 be reported by laboratories as "> 60 mL/min/1.73 m2", rather than as a precise figure.