Reduction of APOE accounts for neurobehavioral deficits in fetal alcohol spectrum disorders.

A hallmark of fetal alcohol spectrum disorders (FASD) is neurobehavioral deficits that still do not have effective treatment. Here, we present that reduction of Apolipoprotein E (APOE) is critically involved in neurobehavioral deficits in FASD. We show that prenatal alcohol exposure (PAE) changes chromatin accessibility of Apoe locus, and causes reduction of APOE levels in both the brain and peripheral blood in postnatal mice. Of note, postnatal administration of an APOE receptor agonist (APOE-RA) mitigates motor learning deficits and anxiety in those mice. Several molecular and electrophysiological properties essential for learning, which are altered by PAE, are restored by APOE-RA. Our human genome-wide association study further reveals that the interaction of PAE and a single nucleotide polymorphism in the APOE enhancer which chromatin is closed by PAE in mice is associated with lower scores in the delayed matching-to-sample task in children. APOE in the plasma is also reduced in PAE children, and the reduced level is associated with their lower cognitive performance. These findings suggest that controlling the APOE level can serve as an effective treatment for neurobehavioral deficits in FASD.

Datamining approaches for examining the low prevalence of N-acetylglutamate synthase deficiency and understanding transcriptional regulation of urea cycle genes.

Ammonia, which is toxic to the brain, is converted into non-toxic urea, through a pathway of six enzymatically catalyzed steps known as the urea cycle. In this pathway, N-acetylglutamate synthase (NAGS, EC 2.3.1.1) catalyzes the formation of N-acetylglutamate (NAG) from glutamate and acetyl coenzyme A. NAGS deficiency (NAGSD) is the rarest of the urea cycle disorders, yet is unique in that ureagenesis can be restored with the drug N-carbamylglutamate (NCG). We investigated whether the rarity of NAGSD could be due to low sequence variation in the NAGS genomic region, high NAGS tolerance for amino acid replacements, and alternative sources of NAG and NCG in the body. We also evaluated whether the small genomic footprint of the NAGS catalytic domain might play a role. The small number of patients diagnosed with NAGSD could result from the absence of specific disease biomarkers and/or short NAGS catalytic domain. We screened for sequence variants in NAGS regulatory regions in patients suspected of having NAGSD and found a novel NAGS regulatory element in the first intron of the NAGS gene. We applied the same datamining approach to identify regulatory elements in the remaining urea cycle genes. In addition to the known promoters and enhancers of each gene, we identified several novel regulatory elements in their upstream regions and first introns. The identification of cis-regulatory elements of urea cycle genes and their associated transcription factors holds promise for uncovering shared mechanisms governing urea cycle gene expression and potentially leading to new treatments for urea cycle disorders.

What clinic closure reveals about care for drug-resistant TB: a qualitative study.

BACKGROUND: There have been calls for "person-centered" approaches to drug-resistant tuberculosis (DR-TB) care. In 2020, Charles James Hospital in South Africa, which incorporated person-centered care, was closed. Patients were referred mid-course to a centralized, tertiary hospital, providing an opportunity to examine person-centered DR-TB and HIV care from the perspective of patients who lost access to it. METHODS: The impact of transfer was explored through qualitative interviews performed using standard methods. Analysis involved grounded theory; interviews were assessed for theme and content. RESULTS: After switching to the centralized site, patients reported being unsatisfied with losing access to a single clinic and pharmacy where DR-TB, HIV and chronic disease care were integrated. Patients also reported a loss of care continuity; at the decentralized site there was a single, familiar clinician whereas the centralized site had multiple, changing clinicians and less satisfactory communication. Additionally, patients reported more disease-related stigma and less respectful treatment, noting the loss of a "special place" for DR-TB treatment. CONCLUSION: By focusing on a DR-TB clinic closure, we uncovered aspects of person-centered care that were critical to people living with DR-TB and HIV. These perspectives can inform how care for DR-TB is operationalized to optimize treatment retention and effectiveness.

HIF-1α Regulation of Cytokine Production following TLR3 Engagement in Murine Bone Marrow-Derived Macrophages Is Dependent on Viral Nucleic Acid Length and Glucose Availability.

Hypoxia-inducible factor-1α (HIF-1α) is an important regulator of glucose metabolism and inflammatory cytokine production in innate immune responses. Viruses modulate HIF-1α to support viral replication and the survival of infected cells, but it is unclear if this transcription factor also plays an important role in regulating antiviral immune responses. In this study, we found that short and long dsRNA differentially engage TLR3, inducing distinct levels of proinflammatory cytokine production (TNF-α and IL-6) in bone marrow-derived macrophages from C57BL/6 mice. These responses are associated with differential accumulation of HIF-1α, which augments NF-κB activation. Unlike TLR4 responses, increased HIF-1α following TLR3 engagement is not associated with significant alterations in glycolytic activity and was more pronounced in low glucose conditions. We also show that the mechanisms supporting HIF-1α stabilization may differ following stimulation with short versus long dsRNA and that pyruvate kinase M2 and mitochondrial reactive oxygen species play a central role in these processes. Collectively, this work suggests that HIF-1α may fine-tune proinflammatory cytokine production during early antiviral immune responses, particularly when there is limited glucose availability or under other conditions of stress. Our findings also suggest we may be able to regulate the magnitude of proinflammatory cytokine production during antiviral responses by targeting proteins or molecules that contribute to HIF-1α stabilization.

Use of Baricitinib in Patients With Moderate to Severe Coronavirus Disease 2019.

Hyperinflammation is associated with increased mortality in coronavirus disease 2019 (COVID-19). In this retrospective, uncontrolled patient cohort with moderate -severe COVID-19, treatment with baricitinib plus hydroxychloroquine was associated with recovery in 11 of 15 patients. Baricitinib for the treatment of COVID-19 should be further investigated in randomized, controlled clinical trials.

Impact of pre-existing drug resistance on risk of virological failure in South Africa.

OBJECTIVES: There is conflicting evidence on the impact of pre-existing HIV drug resistance mutations (DRMs) in patients infected with non-B subtype virus. METHODS: We performed a case-cohort substudy of the AIDS Drug Resistance Surveillance Study, which enrolled South African patients initiating first-line efavirenz/emtricitabine/tenofovir. Pre-ART DRMs were detected by Illumina sequencing of HIV pol and DRMs present at <20% of the viral population were labelled as minority variants (MVs). Weighted Cox proportional hazards models estimated the association between pre-ART DRMs and risk of virological failure (VF), defined as confirmed HIV-1 RNA ≥1000 copies/mL after ≥5 months of ART. RESULTS: The evaluable population included 178 participants from a randomly selected subcohort (16 with VF, 162 without VF) and 83 additional participants with VF. In the subcohort, 16% of participants harboured ≥1 majority DRM. The presence of any majority DRM was associated with a 3-fold greater risk of VF (P = 0.002), which increased to 9.2-fold (P < 0.001) in those with <2 active drugs. Thirteen percent of participants harboured MV DRMs in the absence of majority DRMs. Presence of MVs alone had no significant impact on the risk of VF. Inclusion of pre-ART MVs with majority DRMs improved the sensitivity but reduced the specificity of predicting VF. CONCLUSIONS: In a South African cohort, the presence of majority DRMs increased the risk of VF, especially for participants receiving <2 active drugs. The detection of drug-resistant MVs alone did not predict an increased risk of VF, but their inclusion with majority DRMs affected the sensitivity/specificity of predicting VF.

The Impacts of Residential Location on the Risk of HIV Virologic Failure Among ART Users in Durban, South Africa.

Using a case-control study of patients receiving antiretroviral treatment (ART) in 2010-2012 at McCord Hospital in Durban, South Africa, we sought to understand how residential locations impact patients' risk of virologic failure (VF). Using generalized estimating equations to fit logistic regression models, we estimated the associations of VF with socioeconomic status (SES) and geographic access to care. We then determined whether neighborhood-level poverty modifies the association between individual-level SES and VF. Automobile ownership for men and having non-spouse family members pay medical care for women remained independently associated with increased odds of VF for patients dwelling in moderately and severely poor neighborhoods. Closer geographic proximity to medical care was positively associated with VF among men, while higher neighborhood-level poverty was positively associated with VF among women. The programmatic implications of our findings include developing ART adherence interventions that address the role of gender in both the socioeconomic and geographical contexts.

Caregiver Use of the Core Components of Technology-Enhanced Helping the Noncompliant Child: A Case Series Analysis of Low-Income Families.

Children from low-income families are more likely to develop early-onset disruptive behavior disorders (DBDs) compared to their higher income counterparts. Low-income families of children with early-onset DBDs, however, are less likely to engage in the standard-of-care treatment, behavioral parent training (BPT), than families from other sociodemographic groups. Preliminary between-group findings suggested technology-enhanced BPT was associated with increased engagement and boosted treatment outcomes for low-income families relative to standard BPT. The current study used a case series design to take this research a step further by examining whether there was variability in use of, and reactions to, the smartphone enhancements within technology-enhanced BPT and the extent to which this variability paralleled treatment outcome. Findings provide a window into the uptake and use of technology-enhanced service delivery methods among low-income families, with implications for the broader field of children's mental health.

Keratinocyte growth factor promotes epithelial survival and resolution in a human model of lung injury.

RATIONALE: Increasing epithelial repair and regeneration may hasten resolution of lung injury in patients with the acute respiratory distress syndrome (ARDS). In animal models of ARDS, keratinocyte growth factor (KGF) reduces injury and increases epithelial proliferation and repair. The effect of KGF in the human alveolus is unknown. OBJECTIVES: To test whether KGF can attenuate alveolar injury in a human model of ARDS. METHODS: Volunteers were randomized to intravenous KGF (60 µg/kg) or placebo for 3 days, before inhaling 50 µg LPS. Six hours later, subjects underwent bronchoalveolar lavage (BAL) to quantify markers of alveolar inflammation and cell-specific injury. MEASUREMENTS AND MAIN RESULTS: KGF did not alter leukocyte infiltration or markers of permeability in response to LPS. KGF increased BAL concentrations of surfactant protein D, matrix metalloproteinase (MMP)-9, IL-1Ra, granulocyte-macrophage colony-stimulating factor (GM-CSF), and C-reactive protein. In vitro, BAL fluid from KGF-treated subjects inhibited pulmonary fibroblast proliferation, but increased alveolar epithelial proliferation. Active MMP-9 increased alveolar epithelial wound repair. Finally, BAL from the KGF-pretreated group enhanced macrophage phagocytic uptake of apoptotic epithelial cells and bacteria compared with BAL from the placebo-treated group. This effect was blocked by inhibiting activation of the GM-CSF receptor. CONCLUSIONS: KGF treatment increases BAL surfactant protein D, a marker of type II alveolar epithelial cell proliferation in a human model of acute lung injury. Additionally, KGF increases alveolar concentrations of the antiinflammatory cytokine IL-1Ra, and mediators that drive epithelial repair (MMP-9) and enhance macrophage clearance of dead cells and bacteria (GM-CSF). Clinical trial registered with ISRCTN 98813895.

An acute increase in the stress hormone corticosterone is associated with mating behavior in both male and female red-spotted newts, Notophthalmus viridescens.

Hormones play key, functional roles in mediating the tradeoff between survival and reproduction. Glucocorticoid hormones can inhibit reproduction and improve chances of survival during periods of stress. However, glucocorticoid hormones are, at times, also associated with successfully engaging in energetically costly courtship and mating behaviors. Corticosterone (CORT), a primary glucocorticoid hormone in amphibians, reptiles and birds, may be important in activating or sustaining energetically costly mating behaviors. We used a non-invasive, water-borne hormone assay to measure CORT release rates of male and female red-spotted newts (Notophthalmus viridescens) collected when either engaged in amplexus or when not engaged in amplexus. Because amplexus is energetically costly for males, we predicted that males would have higher CORT release rates than females. We also predicted that females in amplexus would have elevated CORT release rates because the restraint of amplexus prevents foraging and breathing and may be costly. Here we show that an acute increase in CORT is associated with amplexus behavior in both male and female red-spotted newts. Additionally we demonstrate that males have higher overall CORT release rates both in and out of amplexus than do females. Our results support the hypothesis that glucocorticoid hormones are associated with energetically costly courtship and mating behaviors for both sexes.

Longitudinal tracking of hemocyte populations in vivo indicates lineage relationships and supports neural progenitor identity in adult neurogenesis.

Adult neurogenesis, which takes place in both vertebrate and invertebrate species, is the process by which new neurons are born and integrated into existing functional neural circuits, long after embryonic development. Most studies in mammals suggest that self-renewing stem cells are the source of the new neurons, although the extent of self-renewal is a matter of debate. In contrast, research in the crayfish Procambarus clarkii has demonstrated that the neural progenitors producing adult-born neurons are capable of both self-renewing and consuming (non-self-renewing) divisions. However, self-renewing divisions are relatively rare, and therefore the production of adult-born neurons depends heavily on progenitors that are not replenishing themselves. Because the small pool of neural progenitors in the neurogenic niche is never exhausted throughout the long lives of these animals, we hypothesized that there must also be an extrinsic source of these cells. It was subsequently demonstrated that the neural progenitors originate in hemocytes (blood cells) produced by the immune system that travel in the circulation before ultimately integrating into niches where the neural lineage begins. The current study examines the developmental lineage of the three hemocyte types - hyaline (HC), semigranular (SGC) and granular (GC) cells - with the goal of understanding the origins of the progenitor cells that produce adult-born neurons. Longstanding qualitative metrics for hemocyte classification were validated quantitatively. Then, in a longitudinal study, proliferation markers were used to label the hemocytes in vivo, followed by sampling the circulating hemocyte population over the course of two months. Hemolymph samples were taken at intervals to track the frequencies of the different hemocyte types. These data reveal sequential peaks in the relative frequencies of HCs, SGCs and GCs, which were identified using qualitative and quantitative measures. These findings suggest that the three hemocyte types comprise a single cellular lineage that occurs in the circulation, with each type as a sequential progressive stage in hemocyte maturation beginning with HCs and ending with GCs. When combined with previously published data, this timeline provides additional evidence that HCs serve as the primary neural progenitor during adult neurogenesis in P. clarkii.

Performance of screening tools for cervical neoplasia among women in low- and middle-income countries: A systematic review and meta-analysis.

OBJECTIVE: To evaluate the performance of visual inspection with acetic acid (VIA) testing, visual inspection with Lugol's iodine (VILI), primary HPV testing, and conventional Pap smear in detecting CIN2+ among non-pregnant women aged 30-65 in LMICs between 1990 and 2020. DESIGN: Systematic review and meta-analysis. SETTING AND PARTICIPANTS: Low- and middle-income countries, non-pregnant women aged 30-65. METHODS: CENTRAL (Cochrane Library), CINAHL, Embase, Global Health, PubMed, and Web of Science databases were systematically searched to identify studies evaluating the performance of cervical cancer screening methods in LMICs. A diagnostic test accuracy meta-analysis was conducted to evaluate the performance of 4 screening methods in detecting CIN2+ relative to biopsy or cytology reference standards. Pooled statistics for sensitivity, specificity, diagnostic odds ratios, and summary receiver operating characteristic curves were determined for each method. Subgroup analyses were performed to examine whether there was variation in performance based on different reference standards for defining CIN2+, specifically: colposcopy-directed biopsy, biopsy alone, colposcopy alone, or liquid-based cytology. RESULTS: Eighteen studies were identified through systematic review. Twelve studies were included in meta-analysis; 11 were cross-sectional and 1 was a randomized controlled clinical trial. The remaining six of the eighteen studies were inclided in a narrative syntehsis. Pooled estimates for sensitivity for VIA, VILI, primary HPV testing, and conventional Pap smear were 72.3%, 64.5%, 79.5%, and 60.2%, respectively; pooled estimates for specificity were 74.5%, 68.5%, 72.6%, and 97.4%, respectively; the diagnostic odds ratios were 7.31, 3.73, 10.42, 69.48, respectively; and the area under the summary receiver operating characteristic curves were 0.766, 0.647, 0.959, and 0.818, respectively. Performance of the screening method varied based on the reference standard used; pooled estimates using either colposcopy-directed biopsy or biopsy alone as the reference standard generally reported lower estimates; pooled estimates using either colposcopy alone or liquid-based cytology as references reported higher estimates. CONCLUSIONS AND IMPLICATIONS: This meta-analysis found primary HPV testing to be the highest performing cervical cancer screening method in accurately identifying or excluding CIN2+. Further evaluation of performance at different CIN thresholds is warranted.

Amphibian diversity across three adjacent ecosystems in Área de Conservación Guanacaste, Costa Rica.

Amphibians are the most threatened species-rich vertebrate group, with species extinctions and population declines occurring globally, even in protected and seemingly pristine habitats. These 'enigmatic declines' are generated by climate change and infectious diseases. However, the consequences of these declines are undocumented as no baseline ecological data exists for most affected areas. Like other neotropical countries, Costa Rica, including Área de Conservación Guanacaste (ACG) in north-western Costa Rica, experienced rapid amphibian population declines and apparent extinctions during the past three decades. To delineate amphibian diversity patterns within ACG, a large-scale comparison of multiple sites and habitats was conducted. Distance and time constrained visual encounter surveys characterised species richness at five sites-Murciélago (dry forest), Santa Rosa (dry forest), Maritza (mid-elevation dry-rain forest intersect), San Gerardo (rainforest) and Cacao (cloud forest). Furthermore, species-richness patterns for Cacao were compared with historic data from 1987-8, before amphibians declined in the area. Rainforests had the highest species richness, with triple the species of their dry forest counterparts. A decline of 45% (20 to 11 species) in amphibian species richness was encountered when comparing historic and contemporary data for Cacao. Conservation efforts sometimes focus on increasing the resilience of protected areas, by increasing their range of ecosystems. In this sense ACG is unique containing many tropical ecosystems compressed in a small geographic space, all protected and recognised as a UNESCO world heritage site. It thus provides an extraordinary platform to understand changes, past and present, and the resilience of tropical ecosystems and assemblages, or lack thereof, to climate change.

Adult neurogenesis in crayfish: Identity and regulation of neural progenitors produced by the immune system.

Adult-born neurons are incorporated into brain circuits in the crayfish Procambarus clarkii, as in many vertebrate and invertebrate species. Adult neurogenesis depends on several conserved features, including the presence of neurogenic niches housing progenitor cells and the expansion, migration, and differentiation of their daughters, the neural precursor cells. However, in contrast to mammalian species, the progenitors initiating the neurogenic lineage in P. clarkii do not undergo long-term self-renewal. A central question is the mode of replenishment of these cells. Experiments have shown that hemocytes generated by the immune system, and not other cell types, are attracted to and incorporated into the niche. The present studies highlight the interdependency of the immune and nervous systems in the generation of adult-born neurons, by demonstrating that hyaline hemocytes are the probable neural progenitor cells, and that serotonin and the cytokine astakine 1 regulate both immune function and adult neurogenesis.

A feasibility trial of acupuncture in cancer patients undergoing radiotherapy treatment.

OBJECTIVE: We conducted a feasibility trial of acupuncture in cancer patients undergoing radiotherapy treatment. The trial included training radiographers to deliver acupuncture within patients' routine NHS care. METHODS: Mixed methods pragmatic randomized parallel-group exploratory feasibility trial comparing standard care to standard care plus acupuncture. RESULTS: Most aspects of the research design and acupuncture intervention were acceptable to the 101 participants. Participants' valued the opportunity to receive acupuncture within their NHS care, perceived the treatment as eliciting a number of beneficial effects, and had a positive impact on their NHS cancer treatment. However, quantitative analysis of outcome measure data revealed no consistent significant differences between those receiving standard care and those receiving standard care plus acupuncture. CONCLUSION: It is feasible to implement acupuncture in a busy radiotherapy unit provided by specially trained radiographers. The methodology employed appears acceptable for the evaluation of acupuncture for radiotherapy patients.

Experience of a surgeon at the emergency department during COVID-19 pandemic.

INTRODUCTION: The COVID pandemic, which started on 11th March as per the World Health Organization, has resulted in a drastic change in health care delivery, including emergency services. Most health workers have deviated towards COVID care delivery; only a few were available for non-COVID conditions. All elective and non-essential services were postponed resulting in the increased burden of the emergency department. The emergency department had to provide essential emergency care with available staff without exposing them to the virus. Triaging of the patients was modified according to the needs. METHODS: The statistics of the emergency department of this period (April and May 2020) are compared with the same period of previous years (2018-2019) with the number of patients, indications, and complications. The methods of triaging and preparation were discussed. DISCUSSION: The number of patients admitted to the emergency department (ED) was low during the COVID pandemic. Nevertheless, they got admitted with complications due to delay in accessing the health care facility. Patients with diabetic foot ulcers were also presenting late, leading to an increased number of the forefoot and below knee amputations. In trauma, the emergency department has maintained the same death rate as previous years by giving great care. The indications for tracheostomy were worrisome because it would have been prevented if the patients presented early. Pediatric patients were also presented late, resulting in increased mortality. Some cancer patients also presented with a complication in the emergency department because of the postponement of elective surgeries. CONCLUSION: There is a delay in accessing the health care delivery for non-COVID conditions resulting in more amputations of limbs and resections of the bowel. So the type of care in the emergency department was changed due to atypical presentation and complicated cases. It is necessary to ensure the provision of high quality health care delivery to non-COVID patients also.

Ghrelin Receptor Signaling Is Not Required for Glucocorticoid-Induced Obesity in Male Mice.

Chronically elevated levels of glucocorticoids increase food intake, weight gain, and adiposity. Similarly, ghrelin, a gut-secreted hormone, is also associated with weight gain, adiposity, and increased feeding. Here we sought to determine if corticosterone-induced metabolic and behavioral changes require functional ghrelin receptors (GHSR). To do this, we treated male C57BL mice with chronic corticosterone (CORT) mixed in their drinking water for 28 days. Half of these mice received the GHSR antagonist JMV2959 via osmotic minipumps while treated with CORT. In a second experiment, we gave the same CORT protocol to mice with a targeted mutation to the GHSR or their wild-type littermates. As expected, CORT treatment increased food intake, weight gain, and adiposity, but contrary to expectations, mice treated with a GHSR receptor antagonist or GHSR knockout (KO) mice did not show attenuated food intake, weight gain, or adiposity in response to CORT. Similarly, the effects of CORT on the liver were the same or more pronounced in GHSR antagonist-treated and GHSR KO mice. Treatment with JMV2959 did attenuate the effects of chronic CORT on glycemic regulation as determined by the glucose tolerance test. Finally, disruption of GHSR signaling resulted in behavioral responses associated with social withdrawal, potentially due to neuroprotective effects of GHSR activation. In all, we propose that blocking GHSR signaling helps to moderate glucose concentrations when CORT levels are high, but blocking GHSR signaling does not prevent increased food intake, weight gain, or increased adiposity produced by chronic CORT.

The clinical role of VeriStrat testing in patients with advanced non-small cell lung cancer considered unfit for first-line platinum-based chemotherapy.

PURPOSE: We previously demonstrated that the median survival of patients with poor prognosis non-small cell lung cancer (NSCLC) considered unfit for first-line platinum chemotherapy was <4 months. We evaluated whether VeriStrat could be used as a prognostic or predictive biomarker in this population. EXPERIMENTAL DESIGN: We conducted a randomised double-blind trial among patients with untreated advanced NSCLC considered unfit for platinum chemotherapy because of poor performance status (PS) or multiple comorbidities. All patients received active supportive care (ASC) and were treated with either oral erlotinib or placebo daily. Five hundred twenty-seven patients had plasma samples for VeriStrat classification: good (VeriStrat Good [VSG]) or poor (VeriStrat Poor [VSP]). Main end-point was overall survival. RESULTS: Fifty-five percent patients had VSG, and 83% had Eastern Cooperative Oncology Group (ECOG) 2-3 at baseline. VeriStrat was strongly associated with survival. Among patients managed with ASC only, the adjusted hazard ratio (HR) was 0.54 (p < 0.001) for VSG versus VSP. The association was consistent across patient factors: HR = 0.25 (p = 0.004) and HR = 0.56 (p < 0.001) for ECOG 0-1 and 2-3, respectively, HR = 0.49 (0070 < 0.001) for age≥75 years and HR = 0.59 (p = 0.007) for stage IV. Several ECOG 2-3 patients had long survival: 2-year survival was 8% for VSG patients who had ASC, compared with 0% for VSP. VeriStrat status did not predict benefit from erlotinib treatment because the HRs for erlotinib versus placebo were similar between VSG and VSP patients. CONCLUSIONS: VeriStrat was not a predictive marker for survival when considering first-line erlotinib for patients with NSCLC who had poor PS and were not recommended for platinum doublet therapies. However, VeriStrat was an independent prognostic marker of survival. It represents an objective measurement that could be considered alongside other patient factors to provide a more refined assessment of prognosis for this particular patient group. VSG patients could be selected for treatment trials because of better survival, while VSP patients can continue to be treated conservatively or offered trials of less toxic agents. TRIAL REGISTRATION ISRCTN NUMBER: ISRCTN02370070.

Inter-rater reliability of case-note audit: a systematic review.

OBJECTIVE: The quality of clinical care is often assessed by retrospective examination of case-notes (charts, medical records). Our objective was to determine the inter-rater reliability of case-note audit. METHODS: We conducted a systematic review of the inter-rater reliability of case-note audit. Analysis was restricted to 26 papers reporting comparisons of two or three raters making independent judgements about the quality of care. RESULTS: Sixty-six separate comparisons were possible, since some papers reported more than one measurement of reliability. Mean kappa values ranged from 0.32 to 0.70. These may be inflated due to publication bias. Measured reliabilities were found to be higher for case-note reviews based on explicit, as opposed to implicit, criteria and for reviews that focused on outcome (including adverse effects) rather than process errors. We found an association between kappa and the prevalence of errors (poor quality care), suggesting alternatives such as tetrachoric and polychoric correlation coefficients be considered to assess inter-rater reliability. CONCLUSIONS: Comparative studies should take into account the relationship between kappa and the prevalence of the events being measured.