SKF96365 modulates activity of CatSper channels in human sperm.

Exposure of human sperm to progesterone (P4) activates cation channel of sperm (CatSper) channels, inducing an intracellular Ca2+ concentration ([Ca2+]i) transient followed by repetitive [Ca2+]i activity (oscillations), which are believed to be functionally important. We investigated the potential significance of store-operated Ca2+-entry in these oscillations using the inhibitor SKF96365 (30 µM; SKF). Following pre-treatment of human sperm with 3 µM P4, exposure to SKF doubled the proportion of oscillating cells (P = 0.00004). In non-pre-treated cells, SKF had an effect similar to P4, inducing a [Ca2+]i transient in >80% of cells which was followed by oscillations in ≈50% of cells. The CatSper blocker RU1968 (11 µM) inhibited the SKF-induced [Ca2+]i increase and reversibly arrested [Ca2+]i oscillations. Using whole-cell patch clamp, we observed that SKF enhanced CatSper currents by 100% within 30 s, but amplitude then decayed to levels below control over the next minute. When cells were stimulated with P4, CatSper currents were stably increased (by 200%). Application of SKF then returned current amplitude to control level or less. When sperm were prepared in medium lacking bovine serum albumin (BSA), both P4 and SKF induced a [Ca2+]i transient in >95% of cells but the ability of SKF to induce oscillations was greatly reduced (P = 0.0009). We conclude that SKF, similar to a range of small organic molecules, activates CatSper channels, but that a secondary blocking action also occurs, which was detected only during patch-clamp recording. The failure of SKF to induce oscillations when cells were prepared without BSA emphasizes that the drug does not fully mimic the actions of P4.

Safe handling of hazardous drugs.

Background: This evidence-based practice guideline was developed to update and address new issues in the handling of hazardous drugs including being compliant with NAPRA (National Association of Pharmacy Regulatory Authorities) and USP 800 (United States Pharmacopeia) standards, the use of personal protective equipment and treatment in diverse settings including in the home setting. Methods: This guideline was developed from an adaptation and endorsement of existing guidelines and from three systematic reviews. Prior to publication, this guideline underwent a series of peer, patient, methodological and external reviews to gather feedback. All comments were addressed and the guideline was amended when required. This guideline applies to and is intended for all health care workers who may come into contact with hazardous drugs at any point in the medication circuit. Results: The recommendations represent a reasonable and practical set of procedures that the intended users of this guideline should implement to minimize the opportunity for accidental exposure. These recommendations are not limited to just the point of care, but cover the entire chain of handling of cytotoxics from the time they enter the institution until they leave in the patient or as waste. Conclusions: Decreasing the likelihood of accidental exposure to cytotoxic agents within the medication circuit is the main objective of this evidenced-based guideline. The recommendations differ slightly from previous guidelines due to new evidence.

Pain After Preoperative Ultrasound Guided Hip Injections for Total Hip Arthroplasty: A Pilot Randomized Controlled Trial.

Introduction. Hip replacement is a frequently performed and highly successful treatment for patients with end stage osteoarthritis. Advances in technique and pain management have allowed for rapid mobilization and early discharge after surgery. We hypothesize that pre-incision intra-articular injection of local anesthetic with epinephrine under image guidance combined with post incision peri-articular injection (PAI) may be more effective than PAI alone. Methods. A prospective, randomized, controlled, comparative investigation at a single institution of 41 patients undergoing THA who received standard 30 mL post-arthrotomy, PAI of ropivacaine with epinephrine under direct visualization after prosthesis implantation before closure or an equivalent dose divided into a 10 mL pre-incision, ultrasound guided intra-articular injection and a 20 mL post-arthrotomy PAI. Results. 42 patients were included in this study before its early conclusion with 22 patients in the treatment group and 20 in the control group. There were no significant differences in age, BMI or ASA scores. Additionally, there were no significant differences noted when comparing groups by postoperative outcome measures including OMME, EBL, OR time, PACU minutes, and first and last PACU pain score. Furthermore, there were no significant differences in the PROMs evaluated. Discussion. The addition of ultrasound guided pre-incision intra-articular injection to the standard PAI had no benefit when compared with standard PAI during a THA. Portable mobile phone based ultrasound devices provide a cost effective way to perform musculoskeletal blocks, and further studies on their use and comparative accuracy is warranted. A novel technique for confirmation of injection location is described.

Piecing together the eophytes - a new group of ancient plants containing cryptospores.

The earliest evidence for land plants comes from dispersed cryptospores from the Ordovician, which dominated assemblages for 60 million years. Direct evidence of their parent plants comes from minute fossils in Welsh Borderland Upper Silurian to Lower Devonian rocks. We recognize a group that had forking, striated axes with rare stomata terminating in valvate sporangia containing permanent cryptospores, but their anatomy was unknown especially regarding conducting tissues. Charcoalified fossils extracted from the rock using HF were selected from macerates and observed using scanning electron microscopy. Promising examples were split for further examination and compared with electron micrographs of the anatomy of extant bryophytes. Fertile fossil axes possess central elongate cells with thick walls bearing globules, occasional strands and plasmodesmata-sized pores. The anatomy of these cells best matches desiccation-tolerant food-conducting cells (leptoids) of bryophytes. Together with thick-walled epidermal cells and extremely small size, these features suggest that these plants were poikilohydric. Our new data on conducting cells confirms a combination of characters that distinguish the permanent cryptospore-producers from bryophytes and tracheophytes. We therefore propose the erection of a new group, here named the Eophytidae (eophytes).

Earliest record of transfer cells in Lower Devonian plants.

Key sources of information on the nature of early terrestrial ecosystems are the fossilized remains of plants and associated organic encrustations, which are interpreted as either biofilms, biological soil crusts or lichens. The hypothesis that some of these encrustations might be the remains of the thalloid gametophytes of embryophytes provided the stimulus for this investigation. Fossils preserved in charcoal were extracted from Devonian Period (Lochkovian Stage, c. 410-419 Myr old) sediments at a geological site in Shropshire (UK). Scanning electron micrographs (SEMs) of the fossils were compared with new and published SEMs of extant bryophytes and tracheophytes, respectively. One specimen was further prepared and imaged by transmission electron microscopy. Fossils of thalloid morphology were composed almost entirely of cells with labyrinthine ingrowths; these also were present in fossils of axial morphology where they were associated with putative food-conducting cells. Comparison with modern embryophytes demonstrates that these distinctive cells are transfer cells (TCs). Our fossils provide by far the earliest geological evidence of TCs. They also show that some organic encrustations are the remains of thalloid land plants and that these are possibly part of the life cycle of a newly recognized group of plants called the eophytes.

Discrimination experiences, resilience, and cardiovascular disease risk factors among sexual minority women.

Resilience, or the process of adapting to adversity, may protect against the harmful effects of minority-related stressors on the cardiovascular health of sexual minority women (SMW). An online survey was conducted in a sample of cisgender, non-heterosexual women to evaluate resilience as a moderator of the association between discrimination experiences and key cardiovascular disease (CVD) risk factors: stress, tobacco-smoking, hazardous alcohol consumption, poor diet quality, physical inactivity, and sedentary behaviors. Overall, 191 women (mean age = 29.34, SD = 6.92; 84.5% White) completed the survey and met eligibility to be included in the data analysis. White race (b = - 6.71, SE = 2.49) and education (b = - 3.36, SE = 0.56) were each independently associated with fewer discrimination experiences. Latinx ethnicity was associated with more discrimination experiences (b = 9.34, SE = 2.61). Education was associated with greater resilience (b = 4.57, SE = 0.83). Multivariable regression models were adjusted for race, ethnicity, and education. Discrimination was associated with a higher likelihood of smoking in the past month (b = 0.04, SE = 0.02) and drinking at hazardous levels (b = 0.09, SE = 0.02). Resilience was associated with less stress (b = - 0.15, SE = 0.02), a lower likelihood of hazardous alcohol consumption (b = - 0.02, SE = 0.01) and less time spent engaging in sedentary behaviors (b = - 0.02, SE = 0.01). One moderation emerged, such that discrimination was negatively associated with stress for those low in resilience (b = - 1.75, SE = 0.58), and not associated with stress for those high in resilience. These findings may inform the development of CVD-risk reduction interventions for SMW, which could include both strategies to mitigate the effects of discrimination on substance use and coping skills to promote resilience.

Signatures of adaptation to a monocot host in the plant-parasitic cyst nematode Heterodera sacchari.

Interactions between plant-parasitic nematodes and their hosts are mediated by effectors, i.e. secreted proteins that manipulate the plant to the benefit of the pathogen. To understand the role of effectors in host adaptation in nematodes, we analysed the transcriptome of Heterodera sacchari, a cyst nematode parasite of rice (Oryza sativa) and sugarcane (Saccharum officinarum). A multi-gene phylogenetic analysis showed that H. sacchari and the cereal cyst nematode Heterodera avenae share a common evolutionary origin and that they evolved to parasitise monocot plants from a common dicot-parasitic ancestor. We compared the effector repertoires of H. sacchari with those of the dicot parasites Heterodera glycines and Globodera rostochiensis to understand the consequences of this transition. While, in general, effector repertoires are similar between the species, comparing effectors and non-effectors of H. sacchari and G. rostochiensis shows that effectors have accumulated more mutations than non-effectors. Although most effectors show conserved spatiotemporal expression profiles and likely function, some H. sacchari effectors are adapted to monocots. This is exemplified by the plant-peptide hormone mimics, the CLAVATA3/EMBRYO SURROUNDING REGION-like (CLE) effectors. Peptide hormones encoded by H. sacchari CLE effectors are more similar to those from rice than those from other plants, or those from other plant-parasitic nematodes. We experimentally validated the functional significance of these observations by demonstrating that CLE peptides encoded by H. sacchari induce a short root phenotype in rice, whereas those from a related dicot parasite do not. These data provide a functional example of effector evolution that co-occurred with the transition from a dicot-parasitic to a monocot-parasitic lifestyle.

TERMINAL FLOWER-1/CENTRORADIALIS inhibits tuberisation via protein interaction with the tuberigen activation complex.

Potato tuber formation is a secondary developmental programme by which cells in the subapical stolon region divide and radially expand to further differentiate into starch-accumulating parenchyma. Although some details of the molecular pathway that signals tuberisation are known, important gaps in our knowledge persist. Here, the role of a member of the TERMINAL FLOWER 1/CENTRORADIALIS gene family (termed StCEN) in the negative control of tuberisation is demonstrated for what is thought to be the first time. It is shown that reduced expression of StCEN accelerates tuber formation whereas transgenic lines overexpressing this gene display delayed tuberisation and reduced tuber yield. Protein-protein interaction studies (yeast two-hybrid and bimolecular fluorescence complementation) demonstrate that StCEN binds components of the recently described tuberigen activation complex. Using transient transactivation assays, we show that the StSP6A tuberisation signal is an activation target of the tuberigen activation complex, and that co-expression of StCEN blocks activation of the StSP6A gene by StFD-Like-1. Transcriptomic analysis of transgenic lines misexpressing StCEN identifies early transcriptional events in tuber formation. These results demonstrate that StCEN suppresses tuberisation by directly antagonising the function of StSP6A in stolons, identifying StCEN as a breeding marker to improve tuber initiation and yield through the selection of genotypes with reduced StCEN expression.

The timescale of early land plant evolution.

Establishing the timescale of early land plant evolution is essential for testing hypotheses on the coevolution of land plants and Earth's System. The sparseness of early land plant megafossils and stratigraphic controls on their distribution make the fossil record an unreliable guide, leaving only the molecular clock. However, the application of molecular clock methodology is challenged by the current impasse in attempts to resolve the evolutionary relationships among the living bryophytes and tracheophytes. Here, we establish a timescale for early land plant evolution that integrates over topological uncertainty by exploring the impact of competing hypotheses on bryophyte-tracheophyte relationships, among other variables, on divergence time estimation. We codify 37 fossil calibrations for Viridiplantae following best practice. We apply these calibrations in a Bayesian relaxed molecular clock analysis of a phylogenomic dataset encompassing the diversity of Embryophyta and their relatives within Viridiplantae. Topology and dataset sizes have little impact on age estimates, with greater differences among alternative clock models and calibration strategies. For all analyses, a Cambrian origin of Embryophyta is recovered with highest probability. The estimated ages for crown tracheophytes range from Late Ordovician to late Silurian. This timescale implies an early establishment of terrestrial ecosystems by land plants that is in close accord with recent estimates for the origin of terrestrial animal lineages. Biogeochemical models that are constrained by the fossil record of early land plants, or attempt to explain their impact, must consider the implications of a much earlier, middle Cambrian-Early Ordovician, origin.

Cefepime Pharmacokinetics in Critically Ill Pediatric Patients Receiving Continuous Renal Replacement Therapy.

This retrospective study included pediatric intensive care unit patients receiving continuous veno-venous hemodiafiltration (CVVHDF) being treated with cefepime. The free drug concentration above one time the MIC (fT>1×MIC) and four times a presumed MIC (fT>4×MIC) of 8 µg/ml were calculated. Four patients received doses ranging from 48 to 64 mg/kg of body weight every 6 to 12 h. Three patients achieved 100% fT>1×MIC, with the fourth patient achieving 98% fT>1×MIC. Therapeutic drug monitoring should be considered for critically ill patients receiving cefepime on CVVHDF.

Population Pharmacokinetic Assessment of Vancomycin Dosing in the Large Pediatric Patient.

The most appropriate vancomycin dosing strategy in pediatric patients weighing ≥70 kg (weight based versus non-weight based) to achieve an area under the concentration-time curve (AUC) of ≥400 mg·liter/h and a trough concentration of <20 mg/liter is not known. Population pharmacokinetic analysis determined that dosing of vancomycin should be weight based using fat-free mass, with appropriate adjustment for kidney dysfunction.

Identification of TIMING OF CAB EXPRESSION 1 as a temperature-sensitive negative regulator of tuberization in potato.

For many potato cultivars, tuber yield is optimal at average daytime temperatures in the range 14-22 °C. Above this range, tuber yield is reduced for most cultivars. We previously reported that moderately elevated temperature increases steady-state expression of the core circadian clock gene TIMING OF CAB EXPRESSION 1 (StTOC1) in developing tubers, whereas expression of the StSP6A tuberization signal is reduced, along with tuber yield. In this study we provide evidence that StTOC1 links environmental signalling with potato tuberization by suppressing StSP6A autoactivation in the stolons. We show that transgenic lines silenced in StTOC1 expression exhibit enhanced StSP6A transcript levels and changes in gene expression in developing tubers that are indicative of an elevated sink strength. Nodal cuttings of StTOC1 antisense lines displayed increased tuber yields at moderately elevated temperatures, whereas tuber yield and StSP6A expression were reduced in StTOC1 overexpressor lines. Here we identify a number of StTOC1 binding partners and demonstrate that suppression of StSP6A expression is independent of StTOC1 complex formation with the potato homolog StPIF3. Down-regulation of StTOC1 thus provides a strategy to mitigate the effects of elevated temperature on tuber yield.

Population pharmacokinetic analysis of vancomycin in pediatric continuous renal replacement therapy.

BACKGROUND AND OBJECTIVES: Dosing of vancomycin in pediatric patients undergoing continuous venous-venous hemodiafiltration (CVVHDF) is challenging. Characterization of vancomycin pharmacokinetics can assist with dosing and attainment of goal serum concentrations. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: Patients less than 19 years of age who received vancomycin and had post-dose vancomycin concentrations while undergoing CVVHDF were identified. Data collection included the following: patient demographics, vancomycin dosing and serum concentrations, CVVHDF variables, serum creatinine (SCR), blood urea nitrogen (BUN), albumin, hematocrit, and urine output. Fat-free mass was calculated. Data were summarized with descriptive statistical methods, and population pharmacokinetic analysis was performed with NONMEM 7.2 and PDx-Pop 5.2. Simulation was performed to identify dosing regimens with the highest percentage of goal serum concentration < 20 mg/L and AUC0-24:MIC ≥ 400 attainment. RESULTS: A total of 138 patients met study criteria (45.6% male, median age 4.9 years (IQR (1.0, 14.5))). Mean vancomycin dose was 14.3 ± 1.6 mg/kg/dose (19.5 ± 3.0 mg/kg/dose by FFM). Patients had a median of six (IQR 2, 12) vancomycin serum concentrations sampled 13.6 ± 8.4 h after the dose, and the mean vancomycin serum concentration was 11.3 ± 3.4 mg/L. Vancomycin pharmacokinetics were characterized by a two-compartment model with allometric scaling on fat-free mass and significant covariates of SCR, BUN, dialysate flow rate, and ultrafiltration rate on clearance. Simulation identified doses of 40-50 mg/kg/day that divided every 8-12 h had the highest percentage of patients with a serum concentration < 20 mg/L and an AUC0-24:MIC ≥ 400. CONCLUSIONS: Vancomycin pharmacokinetics are characterized by fat-free mass, serum creatinine, blood urea nitrogen, dialysate flow rate, and ultrafiltration rate in the pediatric CVVHDF population. Dosing of 40-50 mg/kg/day on fat-free mass divided every 8-12 h with frequent vancomycin serum sampling is recommended.

Population Pharmacokinetic Analysis of Gentamicin in Pediatric Extracorporeal Membrane Oxygenation.

BACKGROUND: Gentamicin pharmacokinetics may be altered in pediatric patients undergoing extracorporeal membrane oxygenation (ECMO). Description of gentamicin pharmacokinetics and relevant variables can improve dosing. METHODS: A retrospective population pharmacokinetic study was designed, and pediatric patients who received gentamicin while undergoing ECMO therapy over a period of 6 1/2 years were included. Data collection included the following: patient demographics, serum creatinine, albumin, hematocrit, gentamicin dosing and serum concentrations, urine output, and ECMO circuit parameters. Descriptive statistics were used to characterize the patient population. Population pharmacokinetic analysis was performed with NONMEM, and simulation was performed to identify empiric doses to achieve therapeutic serum concentrations. RESULTS: A total of 37 patients met study criteria (75.7% male patients), with a median age of 0.17 [interquartile range (IQR) 0.12-0.82] years. Primary indications for ECMO included the following: congenital diaphragmatic hernia (n = 17), persistent pulmonary hypertension (n = 5), and septic shock (n = 4). Patients received a total of 117 gentamicin doses [median 1.8 (IQR 1.4-2.9) mg/kg/dose] and had 125 serum concentrations measured at a median of 22.8 (IQR 15.8-25.5) hours after a dose. Population pharmacokinetic analysis identified a 2-compartment model with additive error as the best fit. Covariates included the following: allometrically scaled fat-free mass on clearance, central and peripheral volume of distribution (VDcentral and VDperipheral), and intercompartmental clearance; serum creatinine on clearance; ultrafiltration rate on central volume of distribution. Simulation identified dosage of 4-5 mg/kg/dose every 24 hours for neonates and infants as an acceptable empiric dosing regimen. Children and adolescents had elevated trough concentrations when dosed according to traditional dosing methods. CONCLUSIONS: Fat-free mass should be used to dose gentamicin in pediatric ECMO patients. Serum creatinine is a marker of gentamicin clearance and should be used to adjust gentamicin dosing in pediatric ECMO patients.

Population Pharmacokinetics of Vancomycin in Pediatric Extracorporeal Membrane Oxygenation.

OBJECTIVES: Describe the pharmacokinetics of vancomycin in pediatric patients undergoing extracorporeal membrane oxygenation and provide dosing recommendations to attain an area under the curve for 24 hours greater than 400 in this population. DESIGN: Retrospective, population pharmacokinetic analysis. SETTING: PICU of a large tertiary care children's hospital. INTERVENTIONS: Population pharmacokinetic analysis and simulation were performed with NONMEM v7.3 (Icon, PLC, Dublin, Ireland). PATIENTS: Patients less than 19 years old who received IV vancomycin and had serum vancomycin concentration monitoring while undergoing extracorporeal membrane oxygenation from January 1, 2011, to June 30, 2017. MEASUREMENTS AND MAIN RESULTS: A total of 93 patients met study criteria (male 51%, median age 0.64 yr [interquartile range 0.07-6.7 yr]). Mean estimated creatinine clearance was 65 ± 47 mL/min/1.73 m. Patients received 1,116 vancomycin doses (14.6 ± 1.9 mg/kg/dose) and had 433 vancomycin serum concentrations (13.6 ± 6.9 mg/L) at 13.2 ± 10.7 hours after a dose. A two-compartment pharmacokinetic model with allometrically scaled weight on clearance (0.75) and volumes of distribution (1) was developed. Serum creatinine, postmenstrual age were significant covariates for clearance, patient age for central volume of distribution, and albumin for peripheral volume of distribution. Simulation identified a doses of 25-30 mg/kg/dose every 12-24 hours as having the highest percentage of patients with an area under the curve for 24 hours greater than 400 with the highest percentage trough concentrations in the less than 15 mg/L range. CONCLUSIONS: A vancomycin dose of 25-30 mg/kg/dose every 12-24 hours with serum concentration monitoring is a reasonable empiric dosing strategy to obtain an area under the curve for 24 hours greater than 400 in pediatric extracorporeal membrane oxygenation patients.

Relationships between mammographic density, tissue microvessel density, and breast biopsy diagnosis.

BACKGROUND: Women with high levels of mammographic density (MD) have a four- to six-fold increased risk of developing breast cancer; however, most neither have a prevalent tumor nor will they develop one. Magnetic resonance imaging (MRI) studies suggest that background parenchymal enhancement, an indicator of vascularity, is related to increased breast cancer risk. Correlations of microvessel density (MVD) in tissue, MD and biopsy diagnosis have not been defined, and we investigated these relationships among 218 women referred for biopsy. METHODS: MVD was determined by counting CD31-positive vessels in whole sections of breast biopsies in three representative areas; average MVD was transformed to approximate normality. Using digital mammograms, we quantified MD volume with single X-ray absorptiometry. We used linear regression to evaluate associations between MVD and MD adjusted for age and body mass index (BMI) overall, and stratified by biopsy diagnosis: cases (in situ or invasive cancer, n = 44) versus non-cases (non-proliferative or proliferative benign breast disease, n = 174). Logistic regression adjusted for age, BMI, and MD was used to calculate odds ratios (ORs) and 95 % confidence intervals (CIs) for associations between MVD and biopsy diagnosis. We also assessed whether the MVD-breast cancer association varied by MD. RESULTS: MVD and MD were not consistently associated. Higher MVD was significantly associated with higher odds of in situ/invasive disease (ORAdjusted = 1.69, 95 % CI = 1.17-2.44). MVD-breast cancer associations were strongest among women with greater non-dense volume. CONCLUSIONS: Increased MVD in tissues is associated with breast cancer, independently of MD, consistent with MRI findings suggestive of its possible value as a radiological cancer biomarker.

WHIRLY1 Functions in the Control of Responses to Nitrogen Deficiency But Not Aphid Infestation in Barley.

WHIRLY1 is largely targeted to plastids, where it is a major constituent of the nucleoids. To explore WHIRLY1 functions in barley (Hordeum vulgare), RNA interference-knockdown lines (W1-1, W1-7, and W1-9) that have very low levels of HvWHIRLY1 transcripts were characterized in plants grown under optimal and stress conditions. The WHIRLY1-1 (W1-1), W1-7, and W1-9 plants were phenotypically similar to the wild type but produced fewer tillers and seeds. Photosynthesis rates were similar in all lines, but W1-1, W1-7, and W1-9 leaves had significantly more chlorophyll and less sucrose than the wild type. Transcripts encoding specific subsets of chloroplast-localized proteins, such as ribosomal proteins, subunits of the RNA polymerase, and thylakoid nicotinamide adenine dinucleotide (reduced) and cytochrome b6/f complexes, were much more abundant in the W1-7 leaves than the wild type. Although susceptibility of aphid (Myzus persicae) infestation was similar in all lines, the WHIRLY1-deficient plants showed altered responses to nitrogen deficiency, maintaining higher photosynthetic CO2 assimilation rates than the wild type under limiting nitrogen. Although all lines showed globally similar low nitrogen-dependent changes in transcripts and metabolites, the increased abundance of FAR-RED IMPAIRED RESPONSE1-like transcripts in nitrogen-deficient W1-7 leaves infers that WHIRLY1 has a role in communication between plastid and nuclear genes encoding photosynthetic proteins during abiotic stress.

Reporting of health practitioners by their treating practitioner under Australia's national mandatory reporting law.

OBJECTIVE: To describe the frequency, nature and outcomes of reports about health practitioners made by their treating practitioners under Australia's new mandatory reporting system. DESIGN AND SETTING: Retrospective case file review and analysis of treating practitioner reports received by the Australian Health Practitioner Regulation Agency between 1 November 2011 and 31 January 2013, and of the outcomes of the completed investigations of these reports to November 2014. MAIN OUTCOME MEASURES: Characteristics of treating practitioners and reported practitioners; nature of the care relationship; grounds for report; regulatory action taken in response to report. RESULTS: Of 846 mandatory reports about medical practitioners, 64 (8%) were by treating practitioners. A minority of reports (14 of 64) were made by a practitioner-patient's regular care provider; most (50 of 64) arose from an encounter during an acute admission, first assessment or informal corridor consultation. The reported practitioner-patients were typically being treated for mental illness (28 of 64) or substance misuse (25 of 64). In 80% of reports (50 of 64), reporters described practitioner-patients who exhibited diminished insight, dishonesty, disregard for patient safety, or an intention to self-harm. CONCLUSIONS: The nature and circumstances of the typical treating practitioner report challenge assumptions expressed in policy debates about the merits of the new mandatory reporting law. Mandatory reports by treating practitioners are rare. The typical report is about substance misuse or mental illness, is made by a doctor who is not the patient's regular care provider, and identifies an impediment to safely managing the risk posed by the practitioner-patient within the confines of the treating relationship.