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This book focuses on reinforcing core concepts, improving exam technique and developing confidence in answering the style of questions used in the examinations.

The On-Off direction-selective ganglion cell (DSGC) in mammalian retinas responds most strongly to a stimulus moving in a specific direction. The DSGC initiates spikes in its dendritic tree, which are thought to propagate to the soma with high probability. Both dendritic and somatic spikes in the DSGC display strong directional tuning, whereas somatic PSPs (postsynaptic potentials) are only weakly directional, indicating that spike generation includes marked enhancement of the directional signal. We used a realistic computational model based on anatomical and physiological measurements to determine the source of the enhancement. Our results indicate that the DSGC dendritic tree is partitioned into separate electrotonic regions, each summing its local excitatory and inhibitory synaptic inputs to initiate spikes. Within each local region the local spike threshold nonlinearly amplifies the preferred response over the null response on the basis of PSP amplitude. Using inhibitory conductances previously measured in DSGCs, the simulation results showed that inhibition is only sufficient to prevent spike initiation and cannot affect spike propagation. Therefore, inhibition will only act locally within the dendritic arbor. We identified the role of three mechanisms that generate directional selectivity (DS) in the local dendritic regions. First, a mechanism for DS intrinsic to the dendritic structure of the DSGC enhances DS on the null side of the cell's dendritic tree and weakens it on the preferred side. Second, spatially offset postsynaptic inhibition generates robust DS in the isolated dendritic tips but weak DS near the soma. Third, presynaptic DS is apparently necessary because it is more robust across the dendritic tree. The pre- and postsynaptic mechanisms together can overcome the local intrinsic DS. These local dendritic mechanisms can perform independent nonlinear computations to make a decision, and there could be analogous mechanisms within cortical circuitry.

The hippocampus, a structure essential for spatial navigation and memory undergoes anatomical and functional changes during chronic stress. Here, we investigate the effects of chronic stress on the ability of place cells to encode the neural representation of a linear track. To model physiological conditions of chronic stress on hippocampal function, transgenic mice expressing the genetically encoded calcium indicator GCaMP6f in CA1 pyramidal neurons were chronically administered with 40 μg/ml of cortisol for 8 weeks. Cortisol-treated mice exhibited symptoms typically observed during chronic stress, including diminished reward seeking behavior and reduced adrenal gland and spleen weights. imaging of hippocampal cellular activity during linear track running behavior revealed a reduced number of cells that could be recruited to encode spatial position, despite an unchanged overall number of active cells, in cortisol-treated mice. The properties of the remaining place cells that could be recruited to encode spatial information, however, was unperturbed. Bayesian decoders trained to estimate the mouse's position on the track using single neuron activity data demonstrated reduced performance in a cue richness-dependent fashion in cortisol-treated animals. The performance of decoders utilizing data from the entire neuronal ensemble was unaffected by cortisol treatment. Finally, to test the hypothesis that an antidepressant drug could prevent the effects of cortisol, we orally administered a group of mice with 10 mg/kg citalopram during cortisol administration. Citalopram prevented the cortisol-induced decrease in single-neuron decoder performance but failed to significantly prevent anhedonia and the cortisol-induced reduction in the proportion place cells. The dysfunction observed at the single-neuron level indicates that chronic stress may impair the ability of the hippocampus to encode individual neural representations of the mouse's spatial position, a function pivotal to forming an accurate navigational map of the mouse's external environment; however, the hippocampal ensemble as a whole is resilient to any cortisol-induced insults to single neuronal place cell function on the linear track.

Increased levels of uric acid are associated with cardiovascular disease and the metabolic syndrome. They may predict clinical outcomes and also the onset of hypertension, though it is less clear that hyperuricaemia can be regarded as an independent risk factor given its clustering with other well-recognised factors. Uric acid may increase as a result of pathophysiological processes such as impaired renal sodium handling but may also contribute to renal and vascular damage, particularly endothelial dysfunction. It is notable that the synthesis of uric acid may be associated with the generation of reactive oxygen species if the enzyme xanthine oxidorectase is converted to the oxidase, as may occur in ischaemia. It has been suggested that uric acid may play a role in the pathogenesis of early-onset hypertension but evidence for this is limited. There is also very limited data to suggest that in some circumstances lowering uric acid can lower blood pressure. In the metabolic syndrome, the presence of elevated uric acid concentrations is closely associated with raised triglyceride levels, for reasons that have not been clearly defined. It remains to be seen whether uric acid could or should be considered a specific therapeutic target in cardiovascular disease and especially in hypertension and if so what should be the optimal pharmacological approach to lowering serum urate levels.

ObjectiveSystem-level safety measures do not exist to ensure that patients with iron deficiency anaemia (IDA) undergo proper diagnostic evaluations. We sought to determine if a set of EHR (electronic health record) tools and an expedited referral workflow increase short-term completion of bidirectional endoscopy in higher risk patients with IDA.Materials and methodsWe conducted a pragmatic, cluster-randomised trial randomised by primary care physician (PCP) that included 16 PCPs and 316 patients with IDA. Physicians were randomised to intervention or control groups. Intervention components included a patient registry visible within the EHR, point-of-care alert and expedited diagnostic evaluation workflow for IDA. Outcomes were assessed at 120 days. The primary outcome was completion of bidirectional endoscopy. Secondary outcomes were any endoscopy completed or scheduled, gastroenterology consultation completed, and gastroenterology referral or endoscopy ordered or completed.ResultsThere were no differences in the primary or secondary outcomes. At 120 days, the primary outcome had occurred for 7 (4%) of the intervention group and 5 (3.5%) of the control group. For the three secondary outcomes, rates were 15 (8.6%), 12 (6.9%) and 39 (22.4%) for the immediate intervention group and 10 (7.0%), 9 (6.3%) and 25 (17.6%) for the control group, respectively, p>0.2. Lack of physician time to use the registry tools was identified as a barrier.Discussion and conclusionProviding PCPs with lists of patients with IDA and a pathway for expedited evaluation did not increase rates of completing endoscopic evaluation in the short term.Trial registration numberNCT05365308.

Schachter explores the improvisatory style of jazz musician Keith Jarrett, and considers if current analytical tools are sufficient to account for it. He examines these topics through a close analysis of Jarrett's approach to the jazz standard, focusing mostly on his recording of \"Autumn Leaves\" on the 1995 album Keith Jarrett at the Blue Note.

Rationale: Vaccines remain central to the management of COVID-19 pandemic, including the need for repeat doses of vaccines to boost immunity. There has been an accumulating case count of glomerulopathies temporally associated with COVID-19 vaccination. This case series presents 4 patients who developed double-positive anti–glomerular basement membrane antibody (anti-GBM) and myeloperoxidase (MPO) antineutrophil cytoplasmic autoantibody (ANCA)-associated glomerulonephritis after COVID-19 mRNA vaccination. This report contributes to our collective knowledge about the pathophysiology and clinical outcomes associated with this rare complication. Presenting Concerns of the Patient: Four patients developed nephritic syndrome within 1 to 6 weeks after receiving a COVID-19 mRNA vaccine (3 post Pfizer-BioNTech and 1 post Moderna vaccination). Three of the 4 patients also had hemoptysis. Diagnosis: Three of the 4 patients had double-positive serology, whereas the fourth patient had renal biopsy findings consistent with double-positive disease, although anti-GBM serology was negative. All patients had renal biopsy findings consistent with double-positive anti-GBM and ANCA-associated glomerulonephritis. Interventions: All 4 patients were treated with pulse steroids, cyclophosphamide, and plasmapheresis. Outcomes: Of the 4 patients, 1 demonstrated complete remission, 2 remained dialysis-dependent, and the fourth is deceased. Of the 2 patients who received repeat vaccination with COVID-19 mRNA vaccine, 1 patient had second serologic flare of anti-GBM in response to the vaccine. Novel Findings: This case series reinforces growing evidence that COVID-19 mRNA vaccine-induced glomerulonephritis is a rare but real phenomenon. Dual ANCA and anti-GBM nephritis can present after the first dose of COVID-19 mRNA vaccine or after several administrations of the vaccine. We are the first to report cases of double-positive MPO ANCA and anti-GBM nephritis after Pfizer-BioNTech vaccination. To our knowledge, we are also the first to report outcomes of repeat COVID-19 vaccination in patients with de novo flare of ANCA and anti-GBM nephritis temporally associated with COVID-19 vaccination.

Background: Long-duration (7-8 hours) hemodialysis provides benefits compared with conventional thrice-weekly, 4-hour sessions. Nurse-administered, in-center nocturnal hemodialysis (INHD) may expand the population to whom an intensive dialysis schedule can be offered. Objective: The primary objective of this study was to determine predictors of INHD technique failure, disruptions, and technique survival. Design: This study used retrospective chart and database review methodology. Setting: This study was conducted at a single Canadian INHD program operating in Victoria, British Columbia, within a tertiary care hospital. Our program serves a catchment population of approximately 450 000 people. Patients/Sample/Participants: Forty-three consecutive incident INHD patients took part in the INHD program of whom 42 provided informed consent to participate in this study. Methods: We conducted a retrospective observational study including incident INHD patients from 2015 to 2017. The primary outcome was technique failure ≤6 months (TF ≤6). Secondary outcomes included technique survival and reasons for/predictors of INHD discontinuation or temporary disruption. Predictors of each outcome included demographics, comorbidities, and Clinical Frailty Scale (CFS) scoring. Results: Among 42 patients, mean (SD) age, dialysis vintage, CFS score, and follow-up were 63 (16) years, 46 (55) months, 4 (1), and 11 (9) months, respectively. 52% were aged ≥65 years. TF ≤6 occurred in 12 (29%) patients. One-year technique survival censored for transplants and home dialysis transitions was 60%. Discontinuation related to insomnia (32%), medical status change (27%), and vascular access (23%). In unadjusted Cox survival analysis, 1-point increases in CFS score associated with a higher risk of technique failure (hazard ratio: 2.04, 95% confidence interval [CI]: 1.26-3.31). In an adjusted analysis, higher frailty severity also associated with temporary INHD disruptions (incidence rate ratio: 2.64, 95% CI: 1.55-4.50, comparing CFS of ≥4 to 1-3). Limitations: The retrospective, observational design of this study resulted in limited ability to control for confounding factors. In addition, the relatively small number of events observed owing to a small sample size diminished statistical power to inform study conclusions. Use of a single physician to determine the clinical frailty score is another limitation. Finally, the use of a single center for this study limits generalizability to other programs and clinic settings. Conclusions: INHD is a sustainable modality, even among older patients. Higher frailty associates with INHD technique failure and greater missed treatments. Inclusion of a CFS threshold of ≤4 into INHD inclusion criteria may help to identify individuals most likely to realize the long-term benefits of INHD. Trial Registration: Due to the retrospective and observational design of this study, trial registration was not necessary.

Background Early referral and management of high-risk chronic kidney disease may prevent or delay the need for dialysis. Automatic eGFR reporting has increased demand for out-patient nephrology consultations and in some cases, prolonged queues. In Canada, a national task force suggested the development of waiting time targets, which has not been done for nephrology. Methods We sought to describe waiting time for outpatient nephrology consultations in British Columbia (BC). Data collection occurred in 2 phases: 1) Baseline Description (Jan 18-28, 2010) and 2) Post Waiting Time Benchmark-Introduction (Jan 16-27, 2012). Waiting time was defined as the interval from receipt of referral letters to assessment. Using a modified Delphi process, Nephrologists and Family Physicians (FP) developed waiting time targets for commonly referred conditions through meetings and surveys. Rules were developed to weigh-in nephrologists’, FPs’, and patients’ perspectives in order to generate waiting time benchmarks. Targets consider comorbidities, eGFR, BP and albuminuria. Referred conditions were assigned a priority score between 1-4. BC nephrologists were encouraged to centrally triage referrals to see the first available nephrologist. Waiting time benchmarks were simultaneously introduced to guide patient scheduling. A post-intervention waiting time evaluation was then repeated. Results In 2010 and 2012, 43/52 (83%) and 46/57 (81%) of BC nephrologists participated. Waiting time decreased from 98(IQR44,157) to 64(IQR21,120) days from 2010 to 2012 (p = <.001), despite no change in referral eGFR, demographics, nor number of office hrs/wk. Waiting time improved most for high priority patients. Conclusions An integrated, Provincial initiative to measure wait times, develop waiting benchmarks, and engage physicians in active waiting time management associated with improved access to nephrologists in BC. Improvements in waiting time was most marked for the highest priority patients, which suggests that benchmarks had an influence on triaging behavior. Further research is needed to determine whether this effect is sustainable.

Objective Rheumatoid arthritis (RA) confers a 1.5‐ to 2.0‐fold increased risk of cardiovascular disease (CVD). A prior multifaceted quality improvement approach to improving CVD preventive care increased CVD risk factor assessments, but there was no significant effect on the management of risk factors. We tested the impact of adding a proactive outreach strategy promoting primary care treatment of CVD risk factors among patients with RA through their rheumatology practice. Methods Through electronic health record searches, we identified patients with RA who were potential candidates for hypertension treatment initiation or intensification, statin therapy, or a smoking‐cessation intervention. A nonclinician care manager contacted patients by phone and mail on behalf of the rheumatologists, provided information about the identified risk factor(s), recommend follow‐up with primary care physicians (PCPs), sent correspondence to PCPs, and followed up with patients to see what actions had been taken. We measured preventive cardiology quality indicators and compared preintervention and intervention time periods using interrupted time series methods. Results During the 6‐month intervention period, the proportion of patients prescribed at least moderate‐intensity statin treatment for primary prevention rose from 18.4% to 23.8%. The rate of increase was 1.06% greater per month than during the preceding period (P < 0.001). Rates of increase in hypertension diagnosis and control improved more rapidly during this phase (P < 0.001 for each) and reversed preceding negative trends. Conclusion Implementing proactive nonclinician outreach to encourage primary care–based treatment of CVD risk factors was associated with increases in statin prescribing and in hypertension diagnosis and control. Smoking was not affected.