Amyopathic dermatomyositis may be on the spectrum of autoinflammatory disease: A clinical review.

Systemic autoinflammatory diseases (SAIDs) are distinct from autoimmune diseases. The former primarily results from abnormal innate immune response and genetic testing is crucial for disease diagnosis. Similar cutaneous involvement is a main feature for both SAID and dermatomyositis (DM), so they can be confused with each other. A literature search of PubMed and MEDLINE was conducted for relevant articles. The similarities and differences between these two types of diseases were analyzed. We found phenotypic similarities between these two types of disorders. Accumulating data supports a major role of the innate immune system and a similar cytokine profile. Molecular testing using an autoinflammatory disease gene panel may help identify SAID patients from the DM population and may offer therapeutic benefit using interleukin-1 (IL-1) inhibitors. A subset of DM, notably amyopathic dermatomyositis in the absence of autoantibodies may be on the spectrum of autoinflammatory disease.

Patient characteristics of, and remedial interventions for, complaints and medico-legal claims against doctors: a rapid review of the literature.

BACKGROUND: It is uncertain if patient's characteristics are associated with complaints and claims against doctors. Additionally, evidence for the effectiveness of remedial interventions on rates of complaints and claims against doctors has not been synthesised. METHODS: We conducted a rapid review of recent literature to answer: Question 1 "What are the common characteristics and circumstances of patients who are most likely to complain or bring a claim about the care they have received from a doctor?" and Question 2 "What initiatives or interventions have been shown to be effective at reducing complaints and claims about the care patients have received from a doctor?". We used a systematic search (most recently in July 2023) of PubMed, Scopus, Web of Science and grey literature. Studies were screened against inclusion criteria and critically appraised in duplicate using standard tools. Results were summarised using narrative synthesis. RESULTS: From 8079 search results, we reviewed the full text of 250 studies. We included 25 studies: seven for Question 1 (6 comparative studies with controls and one systematic review) and 18 studies for Question 2 (14 uncontrolled pre-post studies, 2 comparative studies with controls and 2 systematic reviews). Most studies were set in hospitals across a mix of medical specialties. Other than for patients with mental health conditions (two studies), no other patient characteristics demonstrated either a strong or consistent effect on the rate of complaints or claims against their treating doctors. Risk management programs (6 studies), and communication and resolution programs (5 studies) were the most studied of 6 intervention types. Evidence for reducing complaints and medico-legal claims, costs or premiums and more timely management was apparent for both types of programs. Only 1 to 3 studies were included for peer programs, medical remediation, shared decision-making, simulation training and continuing professional development, with few generalisable results. CONCLUSION: Few patient characteristics can be reliably related to the likelihood of medico-legal complaints or claims. There is some evidence that interventions can reduce the number and costs of claims, the number of complaints, and the timeliness of claims. However, across both questions, the strength of the evidence is very weak and is based on only a few studies or study designs that are highly prone to bias.

The funnel-web spider venom derived single knot peptide Hc3a modulates acid-sensing ion channel 1a desensitisation.

Acid-sensing ion channel 1a (ASIC1a) is a proton-gated channel involved in synaptic transmission, pain signalling, and several ischemia-associated pathological conditions. The spider venom-derived peptides PcTx1 and Hi1a are two of the most potent ASIC1a inhibitors known and have been instrumental in furthering our understanding of the structure, function, and biological roles of ASICs. To date, homologous spider peptides with different pharmacological profiles at ASIC1a have yet to be discovered. Here we report the characterisation of Hc3a, a single inhibitor cystine knot peptide from the Australian funnel-web spider Hadronyche cerberea with sequence similarity to PcTx1. We show that Hc3a has complex pharmacology and binds different ASIC1a conformational states (closed, open, and desensitised) with different affinities, with the most prominent effect on desensitisation. Hc3a slows the desensitisation kinetics of proton-activated ASIC1a currents across multiple application pHs, and when bound directly to ASIC1a in the desensitised conformation promotes current inhibition. The solution structure of Hc3a was solved, and the peptide-channel interaction examined via mutagenesis studies to highlight how small differences in sequence between Hc3a and PcTx1 can lead to peptides with distinct pharmacology. The discovery of Hc3a expands the pharmacological diversity of spider venom peptides targeting ASIC1a and adds to the toolbox of compounds to study the intricacies of ASIC1 gating.

Emergency Department Take-Home Naloxone Improves Access Compared with Pharmacy-Dispensed Naloxone.

BACKGROUND: Opioid overdose is a major cause of mortality in the United States. In spite of efforts to increase naloxone availability, distribution to high-risk populations remains a challenge. OBJECTIVE: To assess the effects of multiple different naloxone distribution methods on patient obtainment of naloxone in the emergency department (ED) setting. METHODS: Naloxone was provided to patients in three 12-month phases between February 2020 and February 2023. In Phase 1, physicians could offer patients electronic prescriptions, which were filled in a nearby in-hospital discharge pharmacy. In Phase 2, physicians directly provided patients with take-home naloxone at discharge. In Phase 3, distribution was expanded to allow ED staff to hand patients take-home naloxone at time of discharge. The total number of prescriptions, rate of prescription filling, and amount of take-home naloxone kits provided to patients were then statistically analyzed using 95% confidence intervals (CI) and chi-squared testing. RESULTS: In Phase 1, 348 naloxone prescriptions were written, with 133 (95% CI 112.5-153.5) filled. In Phase 2, 327 (95% CI 245.5-408.5) take-home naloxone kits were given to patients by physicians. In Phase 3, 677 (95% CI 509.5-844.5) take-home naloxone kits were provided to patients by ED staff. There were statistically significant increases in naloxone distribution from Phase 1 to Phase 2, and Phase 2 to Phase 3. CONCLUSIONS: Take-home naloxone increases access when compared with naloxone prescriptions in the ED setting. A multidisciplinary approach combined with the removal of regulatory and administrative barriers allowed for further increased distribution of no-cost naloxone to patients.

Adulterants present in the San Diego county fentanyl supply: a laboratory analysis of seized law enforcement samples.

BACKGROUND: The opioid overdose crisis is one of the worst public health crises ever to face the US and emerging evidence suggests its effects are compounded by the presence of drug adulterants. Here we report our efforts to characterize the adulterants present within the local fentanyl supply of San Diego County, obtained from undifferentiated drug samples seized by local law enforcement over the calendar year 2021. METHODS: Thirty-two participating local law enforcement agencies across San Diego submitted 4838 unknown individual illicit drug samples (total of 312 kg) to the San Diego County Sheriff's Department Regional Crime Laboratory for identification. RESULTS: Qualitative analysis of these samples via FTIR and GC-MS identified methamphetamine (38.7%), fentanyl (20.8%), diacetylmorphine (heroin) (10.2%), codeine (5.8%) and alprazolam (4.3%) as the most common illicit substances and the presence of 52 unique adulterants. The most common adulterants included 4-methylaminoantipyrine (4-MAAP) (10.9%), mannitol (9%), acetaminophen (8.5%), methamphetamine (4.2%), diacetylmorphine (heroin) (3.6%), tramadol (1.9%), and xylazine (1.7%). Several additional pharmacologically active adulterants and contaminants of interest were also identified. CONCLUSION: This analysis is vital for public health use and harm reduction efforts at the level of the individual consumer. Continued direct surveillance of the drug supply is necessary for the detection of potentially harmful adulterants that may pose serious threats to the public.

Cell-intrinsic C5a synergizes with Dectin-1 in macrophages to mediate fungal killing.

The complement factor C5a is a core effector product of complement activation. C5a, acting through its receptors C5aR1 and C5aR2, exerts pleiotropic immunomodulatory functions in myeloid cells, which is vital for host defense against pathogens. Pattern-recognition receptors (PRRs) are similarly expressed by immune cells as detectors of pathogen-associated molecular patterns. Although there is evidence of cross talk between complement and PRR signaling pathways, knowledge of the full potential for C5a-PRR interaction is limited. In this study, we comprehensively investigated how C5a signaling through C5a receptors can modulate diverse PRR-mediated cytokine responses in human primary monocyte-derived macrophages and observed a powerful, concentration-dependent bidirectional effect of C5a on PRR activities. Unexpectedly, C5a synergized with Dectin-1, Mincle, and STING in macrophages to a much greater extent than TLRs. Notably, we also identified that selective Dectin-1 activation using depleted zymosan triggered macrophages to generate cell-intrinsic C5a, which acted on intracellular and cell surface C5aR1, to help sustain mitochondrial ROS generation, up-regulate TNFα production, and enhance fungal killing. This study adds further evidence to the holistic functions of C5a as a central immunomodulator and important orchestrator of pathogen sensing and killing by phagocytes.

Computational Design of α-Conotoxins to Target Specific Nicotinic Acetylcholine Receptor Subtypes.

Nicotinic acetylcholine receptors (nAChRs) are drug targets for neurological diseases and disorders, but selective targeting of the large number of nAChR subtypes is challenging. Marine cone snail α-conotoxins are potent blockers of nAChRs and some have been engineered to achieve subtype selectivity. This engineering effort would benefit from rapid computational methods able to predict mutational energies, but current approaches typically require high-resolution experimental structures, which are not widely available for α-conotoxin complexes. Herein, five mutational energy prediction methods were benchmarked using crystallographic and mutational data on two acetylcholine binding protein/α-conotoxin systems. Molecular models were developed for six nAChR subtypes in complex with five α-conotoxins that were studied through 150 substitutions. The best method was a combination of FoldX and molecular dynamics simulations, resulting in a predictive Matthews Correlation Coefficient (MCC) of 0.68 (85 % accuracy). Novel α-conotoxin mutants designed using this method were successfully validated by experimental assay with improved pharmaceutical properties. This work paves the way for the rapid design of subtype-specific nAChR ligands and potentially accelerated drug development.

Epidemiology and management of ankle sprain injuries over seven seasons in an elite professional ballet company.

OBJECTIVES: To investigate the epidemiology and management of ankle ligament sprains over seven seasons in a professional ballet company. DESIGN: Descriptive epidemiology study. METHODS: Medical attention injury, time-loss injury, and exposure data pertaining to 140 professional ballet dancers were prospectively recorded by Chartered Physiotherapists over seven seasons (2015/16-2021/22); a period including the COVID-19 global pandemic. RESULTS: Sixty-nine ankle sprains (46 time-loss) in 45 dancers (32 %) were recorded: 51 sprains were classified as grade I, 15 were classified as grade II, and three were classified as grade III; 53 sprains affected only one ligament, whilst 16 were multi-ligament sprains. For time-loss injuries, median time-loss durations varied by grading (I - 31 days, II - 54 days, and III - 147 days) and the number of ligaments affected (one - 31 days, two - 54 days, three - 134 days, four - 137 days), with time-loss ranging from 1 to 188 days. Of the 46 time-loss ankle sprains, eight were mild, nine were moderate, and 29 were severe. The incidence rate (injuries·1000 h-1) of medical attention ankle sprains was 0.073 (95 % CI: 0.046 to 0.117) in male dancers and 0.101 (95 % CI: 0.069 to 0.148) in female dancers, and the incidence of time-loss ankle sprains was 0.044 (95 % CI: 0.024 to 0.080) in male dancers and 0.064 (95 % CI: 0.040 to 0.103) in female dancers. No significant effect of sex was observed on either medical attention (p = .304) or time-loss (p = .327) ankle sprain incidence rates. Ten percent of dancers sustained multiple sprains across the seven seasons. Fifty and 39 % of ankle sprains in female and male dancers, respectively, were preceded by a history of ankle sprains. Jumping and landing (30 sprains) and non-dance movements (16 sprains) were the most common inciting movements. Bone bruising and synovitis were the most common concurrent pathologies. CONCLUSIONS: Ankle sprains placed a considerable burden on the ballet company studied. These time-loss durations specified by number and grade of ligament sprain, injury history, and secondary pathologies can guide return-to-dance rehabilitation pathways.

A ten-year retrospective California Poison Control System experience with possible amatoxin mushroom calls.

INTRODUCTION: Mushrooms containing amatoxin are found worldwide and represent a challenging poisoning for the clinician and consulting poison center. This study evaluates the experience of a large poison system with possible amatoxin-containing mushroom ingestion calls. METHODS: A 10-year retrospective review of the California Poison Control System database was performed for amatoxin mushroom ingestion calls resulting in hospitalization. Cases found were abstracted and data statistically analyzed for association with a composite endpoint of death, liver transplant, and/or the need for dialysis. RESULTS: Amatoxin-containing mushroom calls are infrequent with the vast majority (98.4 percent) coming from Northern California during the rainier first and fourth quarters (October through March) of the year. Elevated initial aminotransferase activities and international normalized ratios were predictive of the composite negative outcome. The mortality plus liver transplant and hemodialysis composite rate was 8.2 percent, consistent with current literature. CONCLUSION: The California Poison Control System has relatively few amatoxin-containing mushroom ingestion calls that result in hospitalization but those that are reported mostly occur in Northern California. Treatment bias towards the sickest patients may explain the association of intravenous fluid use or treatment with acetylcysteine or silibinin with meeting the composite outcome. The initial presence of elevated hepatic aminotransferase activity and international normalized ratios are poor prognostic indicators and are likely reflective of late presentation, an advanced toxic phase of amatoxin poisoning, and/or delays in time to obtain poison center consultation.

Taking the bait: Strychnine poisoning.

A 48-year-old male intentionally ingested "gopher killer" containing strychnine as a, suicide attempt. He rapidly developed generalized muscle spasms with opisthotonos followed by cardiovascular collapse. He was resuscitated, treated with 24 h of, neuromuscular paralysis, and was discharged on hospital day 10 without sequelae. A blood strychnine concentration obtained five hours post ingestion was 2.2 mg/L. Strychnine poisoning is exceedingly rare in the modern United States and this report contains a video recording of the classic exam findings.

Transient Complete Atrioventricular Block Associated With Herbal Supplement Use.

INTRODUCTION: Increasing and easy availability of so-called natural/herbal supplements pose the unique challenge of identifying associated side effects, including arrhythmias in otherwise-healthy individuals. CASE PRESENTATION: A 25-year-old female patient presented to the emergency department with fatigue and lightheadedness. The electrocardiogram showed complete AV block with a junctional escape rhythm at 55 beats per minute with QT prolongation (542ms). One week ago, she started to use a herbal medication (Muscle Eze Advanced) for muscle cramps after workouts. Extensive cardiac testing, including complete blood count, complete metabolic panel, TSH, transthoracic echocardiography, urine drug analysis, Lyme antibody were negative. Normal sinus rhythm was restored spontaneously within 1 day of discontinuing the herbal medication. PR and corrected QT intervals returned to baseline over the next two weeks. CONCLUSION: Muscle Eze Advanced consists of seven ingredients, including Melissa officinalis and Valeriana officinalis that have negative chronotropic, negative dromotrophic and QT prolonging effects. Recognizing the association between certain over-the-counter supplements and brady-arrhythmias may circumvent need for permanent pacemakers - an important consideration especially in the young.

Pediatric Rattlesnake Envenomations Treated With Crotalidae Equine Immune F(Ab') 2 Antivenom : A 3-Year Retrospective Observational Analysis.

OBJECTIVES: Rattlesnake envenomations are uncommon, and the majority occur in adults. Although Crotalidae equine immune F(ab') 2 antivenom (F(ab') 2 AV; trade name ANAVIP) was introduced in 2018, no pediatric specific studies of F(ab') 2 AV have been reported to date. The objective of this study was to evaluate the clinical performance and adverse effects of F(ab') 2 AV in children. METHODS: A single-center, retrospective chart review was performed on patients with rattlesnake envenomation presenting to a children's hospital between October 2018 and August 2022. Inclusion criteria were age younger than 18 years and F(ab') 2 AV use. Exclusion criteria were other antivenom use at any time and presentation beyond 24 hours postenvenomation.Demographic characteristics, hemoglobin, platelet count, fibrinogen, international normalized ratio, number of F(ab') 2 AV vials used, infusion-related complications, and clinical outcomes were collected. RESULTS: Twenty-six patients, 19 males and 7 females, with a mean age of 7.7 years (0.67 to 16 years) met inclusion criteria. Fourteen (54%) were treated with only the initial 10 vial F(ab') 2 AV doses. Twelve patients were given additional doses with a median additional vials of 10 (4-34 vials; interquartile range, 8.75-12 vials). The median total vials given for all patients was 10 (10-44 vials; interquartile range, 10-20 vials).Two patients developed acute infusion reactions. Both were treated by slowing the infusion rate and with medications (diphenhydramine, corticosteroids). No delayed reactions were noted. No patients required blood products or surgical interventions.After discharge, no complications, recurrent symptoms, return visits, or readmissions were reported. Follow-up by chart review or phone was obtained for 18 patients, and no postdischarge complications were noted. Seven patients had postdischarge hematologic laboratory evaluations and all were normal. CONCLUSIONS: Although limited by small sample size and postdischarge follow-up, F(ab') 2 AV was well tolerated in our series of pediatric patients, consistent with prior studies of all age groups.

A nuclear receptor HR96-related gene underlies large trans-driven differences in detoxification gene expression in a generalist herbivore.

The role, magnitude, and molecular nature of trans-driven expression variation underlying the upregulation of detoxification genes in pesticide resistant arthropod populations has remained enigmatic. In this study, we performed expression quantitative trait locus (eQTL) mapping (n = 458) between a pesticide resistant and a susceptible strain of the generalist herbivore and crop pest Tetranychus urticae. We found that a single trans eQTL hotspot controlled large differences in the expression of a subset of genes in different detoxification gene families, as well as other genes associated with host plant use. As established by additional genetic approaches including RNAi gene knockdown, a duplicated gene with a nuclear hormone receptor HR96-related ligand-binding domain was identified as causal for the expression differences between strains. The presence of a large family of HR96-related genes in T. urticae may enable modular control of detoxification and host plant use genes, facilitating this species' known and rapid evolution to diverse pesticides and host plants.

Spectrophotometric analysis of purple urine secondary to methylene blue and hydroxocobalamin co-administration.

BACKGROUND: The development of purple urine after methylene blue (methylthioninium chloride) and hydroxocobalamin co-administration is a rare clinical entity that has not been fully elucidated. A 47-year-old male presented to the emergency department with hypotension, cyanosis, and depressed mental status. The patient was noted to have profound peripheral and central cyanosis, as well as chocolate-colored arterial blood. He was treated with both methylene blue and hydroxocobalamin and developed purple urine for approximately 1 week. METHODS: Color chromatography was performed by placing the patient's urine directly onto absorbent filter paper. Urine spectrophotometry was performed utilizing the NanoDrop One/One C UV-Vis Spectrophotometer. RESULTS: Color chromatography of the urine was demonstrated clear separation of distinct red and blue phases. Urine spectrophotometry demonstrated near perfect overlap between the methylene blue + hydroxocobalamin absorbance spectrum and the patient's purple urine absorbance spectrum. CONCLUSION: Purple urine secondary to methylene blue and hydroxocobalamin co-administration is due to combined urinary excretion of methylene blue (blue) and hydroxocobalamin (red), and not a novel purple metabolite. We anticipate that this is going to be an increasingly common clinical entity as the roles of both hydroxocobalamin and methylene blue expand from toxicologic antidotes to adjunct therapies for vasoplegia, poor cardiac output, and sepsis.

Severe arsenic poisoning due to Ayurvedic supplements.

Patients that are taking Ayurvedic supplements have an increased risk of heavy metal toxicity. Lead, arsenic, and mercury are frequently identified in these supplements and can cause clinically significant toxicity. Clinicians should screen patients routinely for use of non-pharmaceutical medications and supplements.

Cardiovascular risk in chronic myeloid leukaemia: A multidisciplinary consensus on screening and management.

INTRODUCTION: Tyrosine kinase inhibitors (TKIs) have become the mainstay of treatment for chronic myeloid leukaemia (CML), but cardiovascular (CV) risk and exacerbation of underlying risk factors associated with TKIs have become widely debated. Real-world evidence reveals little application of CV risk factor screening or continued monitoring within UK CML management. This consensus paper presents practical recommendations to assist healthcare professionals in conducting CV screening/comorbidity management for patients receiving TKIs. METHODS: We conducted a multidisciplinary panel meeting and two iterative surveys involving 10 CML specialists: five haematologists, two cardio-oncologists, one vascular surgeon, one haemato-oncology pharmacist and one specialist nurse practitioner. RESULTS: The panel recommended that patients commencing second-/third-generation TKIs undergo formal CV risk assessment at baseline, with additional investigations and involvement of cardiologists/vascular surgeons for those with high CV risk. During treatment, patients should undergo CV monitoring, with the nature and frequency of testing dependent on TKI and baseline CV risk. For patients who develop CV adverse events, decision-making around TKI interruption, cessation or change should be multidisciplinary and balance CV and haematological risk. CONCLUSION: The panel anticipates these recommendations will support healthcare professionals in implementing CV risk screening and monitoring, broadly and consistently, and thereby help optimise TKI treatment for CML.

CAGE sequencing reveals CFTR-dependent dysregulation of type I IFN signaling in activated cystic fibrosis macrophages.

An intense, nonresolving airway inflammatory response leads to destructive lung disease in cystic fibrosis (CF). Dysregulation of macrophage immune function may be a key facet governing the progression of CF lung disease, but the underlying mechanisms are not fully understood. We used 5' end centered transcriptome sequencing to profile P. aeruginosa LPS-activated human CF macrophages, showing that CF and non-CF macrophages deploy substantially distinct transcriptional programs at baseline and following activation. This includes a significantly blunted type I IFN signaling response in activated patient cells relative to healthy controls that was reversible upon in vitro treatment with CFTR modulators in patient cells and by CRISPR-Cas9 gene editing to correct the F508del mutation in patient-derived iPSC macrophages. These findings illustrate a previously unidentified immune defect in human CF macrophages that is CFTR dependent and reversible with CFTR modulators, thus providing new avenues in the search for effective anti-inflammatory interventions in CF.

"Campfire corrosive: Isolated gastrointestinal injury following ingestion of copper salts".

Human exposures to "fire color changing" agents containing copper salts (CS) are rare. We report the case of an intentional mixed CS ingestion with resulting corrosive gastrointestinal injury absent classic laboratory abnormalities. A 23-year-old male with a history of bipolar disorder presented to the emergency department two hours after intentional ingesting an unknown quantity of the fire colorant "Mystical Fire," which contains cupric sulfate (CuSO4) and cupric chloride (CuCl2). He subsequently developed nausea and abdominal pain and had several episodes of vomiting. Physical examination was notable for diffuse abdominal tenderness without peritoneal signs. Laboratory evaluation was without signs of hemolysis, metabolic derangements, or acute kidney or liver injury. He was noted to have a methemoglobin concentration of 2.2%, which did not require treatment. Serum copper testing was within normal limits. Abdominal CT imaging showed no significant findings. Endoscopy was performed and revealed diffuse esophagitis and gastritis. The patient was started on a proton pump inhibitor and discharged. In this case, the absence of classic laboratory findings of copper did not rule out the presence of gastrointestinal injury. Further investigation is needed to determine the most effective means of ruling out clinically significant CS ingestions.

Improving the annotation of the cattle genome by annotating transcription start sites in a diverse set of tissues and populations using Cap Analysis Gene Expression sequencing.

Understanding the genomic control of tissue-specific gene expression and regulation can help to inform the application of genomic technologies in farm animal breeding programs. The fine mapping of promoters [transcription start sites (TSS)] and enhancers (divergent amplifying segments of the genome local to TSS) in different populations of cattle across a wide diversity of tissues provides information to locate and understand the genomic drivers of breed- and tissue-specific characteristics. To this aim, we used Cap Analysis Gene Expression (CAGE) sequencing, of 24 different tissues from 3 populations of cattle, to define TSS and their coexpressed short-range enhancers (<1 kb) in the ARS-UCD1.2_Btau5.0.1Y reference genome (1000bulls run9) and analyzed tissue and population specificity of expressed promoters. We identified 51,295 TSS and 2,328 TSS-Enhancer regions shared across the 3 populations (dairy, beef-dairy cross, and Canadian Kinsella composite cattle from 2 individuals, 1 of each sex, per population). Cross-species comparative analysis of CAGE data from 7 other species, including sheep, revealed a set of TSS and TSS-Enhancers that were specific to cattle. The CAGE data set will be combined with other transcriptomic information for the same tissues to create a new high-resolution map of transcript diversity across tissues and populations in cattle for the BovReg project. Here we provide the CAGE data set and annotation tracks for TSS and TSS-Enhancers in the cattle genome. This new annotation information will improve our understanding of the drivers of gene expression and regulation in cattle and help to inform the application of genomic technologies in breeding programs.