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Pyoderma gangrenosum (PG) is a rare inflammatory dermatologic condition with neutrophilic infiltration of the skin that causes pustules and ulcerations. Janus kinase (JAK) inhibitors are immunomodulating agents that have been recently described in the literature as an effective treatment for PG. We describe a patient with PG on the lower extremities successfully treated with baricitinib. We also conducted a narrative review of the literature of PG patients treated with JAK inhibitors who were refractory to other treatments.
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Azetidinas , Inhibidores de las Cinasas Janus , Purinas , Piodermia Gangrenosa , Pirazoles , Sulfonamidas , Humanos , Piodermia Gangrenosa/tratamiento farmacológico , Piodermia Gangrenosa/diagnóstico , Inhibidores de las Cinasas Janus/uso terapéutico , Pirazoles/uso terapéutico , Sulfonamidas/uso terapéutico , Azetidinas/uso terapéutico , Purinas/uso terapéutico , Femenino , Resultado del Tratamiento , Piel/patología , Piel/efectos de los fármacos , Persona de Mediana Edad , MasculinoRESUMEN
WRN helicase is a promising target for treatment of cancers with microsatellite instability (MSI) due to its essential role in resolving deleterious non-canonical DNA structures that accumulate in cells with faulty mismatch repair mechanisms1-5. Currently there are no approved drugs directly targeting human DNA or RNA helicases, in part owing to the challenging nature of developing potent and selective compounds to this class of proteins. Here we describe the chemoproteomics-enabled discovery of a clinical-stage, covalent allosteric inhibitor of WRN, VVD-133214. This compound selectively engages a cysteine (C727) located in a region of the helicase domain subject to interdomain movement during DNA unwinding. VVD-133214 binds WRN protein cooperatively with nucleotide and stabilizes compact conformations lacking the dynamic flexibility necessary for proper helicase function, resulting in widespread double-stranded DNA breaks, nuclear swelling and cell death in MSI-high (MSI-H), but not in microsatellite-stable, cells. The compound was well tolerated in mice and led to robust tumour regression in multiple MSI-H colorectal cancer cell lines and patient-derived xenograft models. Our work shows an allosteric approach for inhibition of WRN function that circumvents competition from an endogenous ATP cofactor in cancer cells, and designates VVD-133214 as a promising drug candidate for patients with MSI-H cancers.
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Regulación Alostérica , Descubrimiento de Drogas , Inhibidores Enzimáticos , Proteómica , Helicasa del Síndrome de Werner , Animales , Femenino , Humanos , Masculino , Ratones , Regulación Alostérica/efectos de los fármacos , Línea Celular Tumoral , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/enzimología , Neoplasias Colorrectales/patología , Cisteína/efectos de los fármacos , Cisteína/metabolismo , Roturas del ADN de Doble Cadena/efectos de los fármacos , Descubrimiento de Drogas/métodos , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inestabilidad de Microsatélites , Modelos Moleculares , Helicasa del Síndrome de Werner/antagonistas & inhibidores , Helicasa del Síndrome de Werner/química , Helicasa del Síndrome de Werner/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Muerte Celular/efectos de los fármacos , Adenosina Trifosfato/metabolismoRESUMEN
Sick children often have a decreased appetite and experience vomiting and diarrhea; however, hypoglycemia (plasma glucose concentration ≤50 mg/dL or 2.8 mmol/L) is rare. Ketotic hypoglycemia (KH) is the most common cause of hypoglycemia presenting to an Emergency Department in a previously healthy child between 6 months and 6 years of age. Ketosis and hypoglycemia are now well understood to be normal physiologic responses of young children to prolonged fasting.There is now substantial evidence that the term KH describes a variety of conditions including both the lower end of the normal distribution of fasting tolerance in young children as well as numerous rare disorders that impair fasting adaptation. Recent advances in molecular genetic testing have led to the discovery of these rare disorders. Idiopathic pathological KH is a diagnosis of exclusion that describes rare children who have abnormally limited fasting tolerance, experience recurrent episodes of KH, or develop symptoms of hypoglycemia despite elevated ketone levels, and in whom an explanation cannot be found despite extensive investigation. This review provides an approach to distinguishing between physiological KH and pathological KH and includes recommendations for management.
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OBJECTIVES: We evaluate the potential clinical and cost impacts of discontinuing disease-modifying therapy (DMT) in people with multiple sclerosis (PwMS) when age-related immunosenescence can reduce DMT efficacy while increasing associated risks. METHODS: A Markov model simulated clinical and cost impacts to the patient and payers when a proportion of eligible patients with relapsing remitting multiple sclerosis (RRMS) discontinue DMT. Eligibility was defined as age >55 years, an RRMS diagnosis of >5 years, and no history of relapses for 5 years. Increasing the proportion of eligible patients willing to discontinue therapy was also modeled. Clinical and cost inputs were from published literature. RESULTS: Difference in EDSS progression between eligible patients who did and did not attempt discontinuation was not significant. After 1 year of eligibility, per-patient costs were $96k lower in the cohort that attempted discontinuation; however a higher proportion of relapses were seen in this group. When the proportion of patients willing to discontinue DMT increased, clinical findings remained consistent while the average cost per patient decreased. CONCLUSION: While there are increased clinical and cost benefits as more eligible patients attempt discontinuation, the risk of relapses can increase. Timely disease monitoring is required to manage safe DMT discontinuation.
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Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Humanos , Persona de Mediana Edad , Progresión de la Enfermedad , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Modelos Económicos , RecurrenciaRESUMEN
CONTEXT: Glycogen storage disease type Ia (GSDIa) is an inborn metabolic disorder characterized by impaired endogenous glucose production (EGP). Monitoring of patients with GSDIa is prioritized because of ongoing treatment developments. Stable isotope tracers may enable reliable EGP monitoring. OBJECTIVE: The aim of this study was to prospectively assess the rate of appearance of endogenous glucose into the bloodstream (Ra) in patients with GSDIa after a single oral D-[6,6-2H2]-glucose dose. METHODS: Ten adult patients with GSDIa and 10 age-, sex-, and body mass index-matched healthy volunteers (HVs) were enrolled. For each participant, 3 oral glucose tracer tests were performed: (1) preprandial/fasted, (2) postprandial, and (3) randomly fed states. Dried blood spots were collected before D-[6,6-2H2]-glucose administration and 10, 20, 30, 40, 50, 60, 75, 90, and 120 minutes thereafter. RESULTS: Glucose Ra in fasted HVs was consistent with previously reported data. The time-averaged glucose Ra was significantly higher in (1) preprandial/fasted patients with GSDIa than HV and (2) postprandial HV compared with fasted HV(P < .05). A progressive decrease in glucose Ra was observed in preprandial/fasted patients with GSDIa; the change in glucose Ra time-course was directly correlated with the change in capillary glucose (P < .05). CONCLUSION: This is the first study to quantify glucose Ra in patients with GSDIa using oral D-[6,6-2H2] glucose. The test can reliably estimate EGP under conditions in which fasting tolerance is unaffected but does not discriminate between relative contributions of EGP (eg, liver, kidney) and exogenous sources (eg, dietary cornstarch). Future application is warranted for longitudinal monitoring after novel genome based treatments in patients with GSDIa in whom nocturnal dietary management can be discontinued.
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Glucosa , Enfermedad del Almacenamiento de Glucógeno Tipo I , Adulto , Humanos , Glucosa/metabolismo , Enfermedad del Almacenamiento de Glucógeno Tipo I/metabolismo , Hígado/metabolismo , Glucosa-6-Fosfatasa/metabolismo , Glucemia/metabolismoRESUMEN
Catatonia is a psychomotor syndrome resulting from an underlying psychiatric or medical disorder commonly observed in inpatient psychiatric units. While benzodiazepines and electroconvulsive therapy (ECT) are effective treatment options, the unavailability of ECT in many community psychiatric hospitals in the United States negatively affects patient outcomes. We present a 25-year-old African American male with a psychiatric diagnosis of schizophrenia complicated by malignant catatonia who was admitted to a community psychiatric hospital. He required intensive medical stabilization with supportive management, and transfer requests to ECT-equipped hospitals were initiated. While awaiting transfer for 148 days, the patient's symptoms did not fully remit with lorazepam (even with 36 mg daily in divided doses) and other psychotropic medication trials, including antipsychotics and mood stabilizers. After nearly 5 months of inpatient stay, he was successfully transferred, received ECT treatment, and experienced rapid resolution of catatonia. After discharge, to obtain three monthly sessions of maintenance ECT, he had 5-h one-way ground transportation arranged to an out-of-county ECT-equipped facility. There was no relapse in catatonia by the 2-year follow-up. This report highlights a significant healthcare disparity when attempting to manage severe catatonia within community hospital settings without access to ECT in the United States. Alternative treatments, including antipsychotics, had minimal impact on symptoms and possibly increased morbidity in this case while awaiting ECT. Treatment at our designated safety net hospital still required referral to 14 ECT-equipped hospitals before successful transfer. This case highlights the urgent need for ECT availability in more community hospitals to treat patients with refractory psychiatric conditions, including catatonia. ECT is an essential psychiatric treatment that, for certain conditions, has no appropriate alternatives. We propose that access to ECT be considered in the determination of safety net hospital systems, with improved ability to transfer patients who are suffering from treatable life-threatening mental health conditions.
Challenges of Treating Catatonia without Access to Electroconvulsive Therapy Catatonia is a complex psychiatric condition characterized by abnormal movements, behaviors, and withdrawal from regular activities. Electroconvulsive therapy (ECT) and benzodiazepines are first-line treatments for catatonia. However, ECT is not widely available, particularly in community mental health centers. We present a case of benzodiazepine-resistant catatonia that was initially treated at a community hospital that did not have access to ECT. We made a substantial number of referrals to ECT-equipped hospitals to transfer the patient; however, he was not able to be transferred until hospital day 148. The patient received ECT and experienced rapid resolution of symptoms. This report highlights a significant healthcare disparity when attempting to manage catatonia within community hospital settings without access to ECT in the United States. ECT is an essential psychiatric treatment that, for certain conditions, has no appropriate alternatives. We propose that access to ECT be considered in the determination of safety net hospital systems, with improved ability to transfer patients who are suffering from treatable life-threatening mental health conditions.
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BACKGROUND: Prior authorization review (PAR), in the United States, is a process that was initially intended to focus on hospital admissions and costly high-acuity care. Over time, payors have broadened the scope of PAR to include imaging studies, prescriptions, and routine treatment. The potential detrimental effect of PAR on health care has recently been brought into the limelight, but its impact on orthopedic subspecialty care remains unclear. This study investigated the denial rate, the duration of care delay, and the administrative burden of PAR on orthopedic subspecialty care. METHODS: A prospective, multicenter study was performed analyzing the PAR process. Orthopedic shoulder and/or sports subspecialty practices from 6 states monitored payor-mandated PAR during the course of providing routine patient care. The insurance carrier (traditional Medicare, managed Medicare, Medicaid, commercial, worker's compensation, or government payor [ie, Tricare, Veterans Affairs]), location of service, rate of approval or denial, time to approval or denial, and administrative time required to complete process were all recorded and evaluated. RESULTS: Of 1065 total PAR requests, we found a 1.5% (16/1065) overall denial rate for advanced imaging or surgery when recommended by an orthopedic subspecialist. Commercial and Medicaid insurance resulted in a small but statistically significantly higher rate of denial compared to traditional Medicare, managed Medicare, worker's compensation, or governmental insurance (P < .001). The average administrative time spent on a single PAR was 19.5 minutes, and patients waited an average of 2.2 days to receive initial approval. Managed Medicare, commercial insurance, worker's compensation, and Medicaid required approximately 3-4 times more administrative time to process a PAR than to traditional Medicare or other governmental insurance (P < .001). After controlling for the payor, we identified a significant difference in approval or denial based on geographic location (P < .001). An appeal resulted in a relatively low rate of subsequent denial (20%). However, approximately a third of all appeals remained in limbo for 30 days or more after the initial request. CONCLUSIONS: This is the largest prospective analysis to date of the impact of PAR on orthopedic subspecialty care in the United States. Nearly all PAR requests are eventually approved when recommended by orthopedic subspecialists, despite requiring significant resource use and delaying care. Current PAR practices constitute an unnecessary process that increases administrative burden and negatively impacts access to orthopedic subspecialty care. As health care shifts to value-based care, PAR should be called into question, as it does not seem to add value but potentially negatively impacts cost and timeliness of care.
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INTRODUCTION: Neurodegenerative diseases cause developmental delays and loss of milestones in infants and children. However, scalable outcome measures that quantify features meaningful to parents/caregivers (P/CGs) and have regulatory precedence are lacking for assessing the effectiveness of treatments in clinical trials of neurodegenerative disorders. To address this gap, we developed an innovative, blinded strategy for single-arm trials with external controls using expert panel review of home video. METHOD: We identified meaningful, observable, and objective developmental milestones from iterative interviews with P/CGs and clinical experts. Subsequently, we standardized video recording procedures and instructions to ensure consistency in how P/CGs solicited each activity. In practice, videos would be graded by an expert panel blinded to treatment. To ensure blinding and quality control, video recordings from interim time points would be randomly interspersed. We conducted a pilot study and a pretest of grading to test feasibility and improve the final strategy. RESULTS: The five P/CGs participating in the pilot study found the instructions clear, selected activities important and reflective of their children's abilities, and recordings at-home preferrable to in-clinic assessments. The three grading experts found the videos easy to grade and the milestones clinically meaningful. CONCLUSION: Our standardized strategy enables expert panel grading of developmental milestone achievements using at-home recordings, blinded to treatment and post-baseline time points. This rigorous and objective scoring system has broad applicability in various disease contexts, with or without external controls. Moreover, our strategy facilitates flexible, continued data collection and the videos can be archived for future analyses.
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Evaluación de Resultado en la Atención de Salud , Padres , Niño , Lactante , Humanos , Proyectos Piloto , Grabación en Video , Recolección de DatosRESUMEN
Efforts directed at improving potency and preparing structurally different TYK2 JH2 inhibitors from the first generation of compounds such as 1a led to the SAR study of new central pyridyl based analogs 2-4. The current SAR study resulted in the identification of 4h as a potent and selective TYK2 JH2 inhibitor with distinct structural differences from 1a. In this manuscript, the in vitro and in vivo profiles of 4h are described. The hWB IC50 of 4h was shown as 41 nM with 94% bioavailability in the mouse PK study.
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Piridinas , TYK2 Quinasa , Ratones , Animales , Relación Estructura-Actividad , Piridinas/farmacologíaRESUMEN
OBJECTIVES: Ketone production is a physiological phenomenon that occurs during beta-oxidation of free fatty acids. Distinguishing physiologic ketosis from pathologic over-production/underutilization of ketones is critical as part of the diagnostic evaluation of disorders of carbohydrate metabolism, but there is limited literature on normal ketone production with fasting. Our aim is to measure fasting serum beta-hydroxybutyrate (BHB) concentrations in healthy children after an overnight fast. METHODS: Children ≤18 years of age were prospectively recruited from elective procedures through our surgery centers. Exclusion criteria included a history of diabetes, hypopituitarism, adrenal, metabolic or inflammatory disorders, dietary restrictions, trauma, or use of medications that might affect blood glucose. Serum glucose, cortisol, and BHB were assessed after an overnight fast. RESULTS: Data from 94 participants (mean 8.3 ± 5.7â¯years, 54â¯% male, 46â¯% female, were analyzed. Children ≤3â¯years of age (19) have significantly higher mean (0.40 ± 0.06â¯mmol/L) and median (0.4, IQR 0.2-0.6â¯mmol/L) BHB concentrations compared to children >3 years of age (75) with mean (0.21 ± 0.02â¯mmol/L) and median BHB (0.1, IQR 0.1-0.2â¯mmol/L) (p<0.0001). Fasting BHB levels of >1.0â¯mmol/L was rare (2â¯%, N=2) and 74â¯% (N=70) of participants had BHB levels <0.3â¯mmol/L. CONCLUSIONS: BHB concentrations are significantly higher in young children (≤3 years of age) compared to older children. Fasting BHB levels >1.0â¯mmol/L are rare within our population and therefore may identify a value above which there may a greater concern for pathologic ketotic hypoglycemia. It is imperative to establish the normative range in children to differentiate physiological from pathological ketotic hypoglycemia.
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Hipoglucemia , Cetosis , Niño , Humanos , Masculino , Femenino , Adolescente , Preescolar , Lactante , Cetonas , Hipoglucemia/diagnóstico , Cetosis/diagnóstico , Ácido 3-Hidroxibutírico/metabolismo , AyunoRESUMEN
BACKGROUND: Local anesthesia administration is frequently the most painful step of dermatologic surgery. Identification of an anesthetic that minimizes infiltration pain and toxicity while maximizing duration of action would improve both patient satisfaction and procedural safety. This study compared eight local anesthetic solutions to identify the composition that minimizes infiltration pain, maximizes duration of effect, and minimizes amount of local anesthetic needed. METHODS: In a double-blinded study, thirty subjects were injected with eight local anesthetic solutions of varied concentrations of lidocaine, epinephrine, benzyl alcohol, and sodium bicarbonate. Infiltration pain was rated by subjects using a visual analog scale and duration of anesthesia was assessed by needle prick sensation every 15 minutes. RESULTS: Solutions 2, 7, and 8, were significantly less painful (P<0.001), though not statistically different from each other. Two of the three solutions were buffered 10:1 with sodium bicarbonate. Additionally, two of the three contained notably decreased concentrations of lidocaine, 0.091% and 0.083%, than traditionally used in practice. The use of benzyl alcohol did not result in a reduction of reported pain. The duration of action was equal among the solutions regardless of anesthetic concentration. CONCLUSIONS: A solution of 0.091% lidocaine with epinephrine 1:1,100,000 and 0.82% benzyl alcohol reduces medication dose while ensuring maximum patient comfort and, theoretically, increases shelf life. While considered off-label, clinically effective dermal anesthesia may be obtained at a lower concentration of lidocaine and epinephrine than is commonly used, aiding conservative use of local anesthetic, particularly during times of national shortage. J Drugs Dermatol. 2023;22(4): doi:10.36849/JDD.5183 Citation: Moses A, Klager S, Weinstein A, et al. A comparative analysis of local anesthetics: Injection associated pain and duration of anesthesia. J Drugs Dermatol. 2023;22(4):364-368. doi:10.36849/JDD.5183.
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Anestésicos Locales , Bicarbonato de Sodio , Humanos , Anestésicos Locales/efectos adversos , Lidocaína/efectos adversos , Dolor/tratamiento farmacológico , Dolor/etiología , Epinefrina/efectos adversos , Alcohol Bencilo , Anestesia Local , Método Doble CiegoRESUMEN
Buspirone is commonly used to treat generalized anxiety disorder and demonstrates a limited side-effect profile compared to other anxiolytics. Buspirone is considered generally safe, and neuropsychiatric adverse reactions are uncommon. There are rare clinical case reports that suggest buspirone-induced psychosis. We present a case of buspirone worsening psychosis for a patient psychiatrically hospitalized for an episode of decompensated schizoaffective disorder. The patient had a primary diagnosis of schizoaffective disorder and was treated with antipsychotics during this hospitalization, but his symptoms worsened when buspirone was administered on two separate occasions. During the first trial of buspirone, the patient exhibited traits of increased aggression, odd behaviors, and paranoia. The buspirone was discontinued after the patient admitted to hiding his pills to later consume through nasal ingestion. The second trial resulted in repeated exacerbated symptoms of paranoia related to food and substantially decreased oral intake. Considering its complex mechanism of action, buspirone is suggested to derive its neuropharmacological effects through 5-HT1A receptors. However, the drug also has been found to mediate dopamine neurotransmission. Buspirone acts as an antagonist at presynaptic dopamine D2, D3, and D4 receptors. Yet, contrary to expected outcomes, it was unable to produce antipsychotic effects and instead resulted in a substantial increase in dopaminergic metabolites. The route of administration may also play a role in the enhancement of the buspirone's effects, particularly considering that after first-pass metabolism, buspirone has approximately 4% oral bioavailability. Intranasal administration of buspirone leads to faster drug absorption by direct transport from the nasal mucosa to the brain and increased bioavailability.
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Task-based functional magnetic resonance imaging (tfMRI) has developed as a common alternative in epilepsy surgery to the intracarotid amobarbital procedure, also known as the Wada procedure. Prior studies have implicated tfMRI as a comparable predictor of postsurgical cognitive outcomes. However, the predictive validity of tfMRI has not been established. This preregistered systematic review and meta-analysis (CRD42020183563) synthesizes the literature predicting postsurgical cognitive outcomes in temporal lobe epilepsy (TLE) using tfMRI. The PubMed and PsycINFO literature databases were queried for English-language articles published between January 1, 2009 and December 31, 2020 associating tfMRI laterality indices or symmetry of task activation with outcomes in TLE. Their references were reviewed for additional relevant literature, and unpublished data from our center were incorporated. Nineteen studies were included in the meta-analysis. tfMRI studies predicted postsurgical cognitive outcomes in left TLE ( ρ Ì = -.27, 95% confidence interval [CI] = -.32 to -.23) but not right TLE ( ρ Ì = -.02, 95% CI = -.08 to .03). Among studies of left TLE, language tfMRI studies were more robustly predictive of postsurgical cognitive outcomes ( ρ Ì = -.27, 95% CI = -.33 to -.20) than memory tfMRI studies ( ρ Ì = -.27, 95% CI = -.43 to -.11). Further moderation by cognitive outcome domain indicated language tfMRI predicted confrontation naming ( ρ Ì = -.32, 95% CI = -.41 to -.22) and verbal memory ( ρ Ì = -.26, 95% CI = -.35 to -.17) outcomes, whereas memory tfMRI forecasted only verbal memory outcomes ( ρ Ì = -.37, 95% CI = -.57 to -.18). Surgery type, birth sex, level of education, age at onset, disease duration, and hemispheric language dominance moderated study outcomes. Sensitivity analyses suggested the interval of postsurgical follow-up, and reporting and methodological practices influenced study outcomes as well. These findings intimate tfMRI is a modest predictor of outcomes in left TLE that should be considered in the context of a larger surgical workup.
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Epilepsia del Lóbulo Temporal , Epilepsia , Humanos , Epilepsia del Lóbulo Temporal/diagnóstico por imagen , Epilepsia del Lóbulo Temporal/cirugía , Imagen por Resonancia Magnética/métodos , Memoria/fisiología , Epilepsia/cirugía , Lateralidad Funcional/fisiología , Cognición , Pruebas NeuropsicológicasRESUMEN
Background: Kratom (Mitragyna speciosa) use in the United States is becoming increasingly popular and its legal status varies widely from state to state. Multiple reports of adverse events associated with kratom use have ranged from liver injury, seizures, psychiatric disturbance, and rarely death. Methods: This study investigated coroner autopsy reports from Kern County in California for the year 2020 which included qualitative data on substances from blood toxicological reports. Of the 214 opioid-associated accidental overdoses reported, 4 subjects (1.9%) had mitragynine (kratom) exposure on the autopsy report and were included in the study. We reported available demographic information and comorbid substance findings from the associated autopsy reports. Results: All 4 individuals with mitragynine (kratom) toxicology had accidental opioid overdose deaths noted in autopsy reports. Each subject also had toxicology positive for at least one other substance. Fentanyl was found in 3 (75%) of the cases and suspected to be the primary contributor to opioid-related deaths in those cases. However, one fatality was without fentanyl, but instead had tested positive for benzodiazepines, cannabis, and other psychiatric medications. Discussion: The findings of this brief report provide insight into the role that mitragynine (kratom) may have in modulating risk of opioid-related deaths. The combined use of kratom with opioids such as fentanyl appears most likely to increase the risk of a fatal overdose, but it may also occur with other medications such as benzodiazepines and psychiatric medications. It is a serious concern that in the midst of the opioid overdose epidemic there is a growing presence of kratom use in the U.S. population with a largely unregulated status.
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Glycogen storage disease type IX (GSD-IX) constitutes nearly a quarter of all GSDs. This ketotic form of GSD is caused by mutations in phosphorylase kinase (PhK), which is composed of four subunits (α, ß, γ, δ). PhK is required for the activation of the liver isoform of glycogen phosphorylase (PYGL), which generates free glucose-1-phosphate monomers to be used as energy via cleavage of the α -(1,4) glycosidic linkages in glycogen chains. Mutations in any of the PhK subunits can negatively affect the regulatory and catalytic activity of PhK during glycogenolysis. To understand the pathogenesis of GSD-IX-beta, we characterized a newly created PHKB knockout (Phkb−/−) mouse model. In this study, we assessed fasting blood glucose and ketone levels, serum metabolite concentrations, glycogen phosphorylase activity, and gene expression of gluconeogenic genes and fibrotic genes. Phkb−/− mice displayed hepatomegaly with lower fasting blood glucose concentrations. Phkb−/− mice showed partial liver glycogen phosphorylase activity and increased sensitivity to pyruvate, indicative of partial glycogenolytic activity and upregulation of gluconeogenesis. Additionally, gene expression analysis demonstrated increased lipid metabolism in Phkb−/− mice. Gene expression analysis and liver histology in the livers of old Phkb−/− mice (>40 weeks) showed minimal profibrogenic features when analyzed with age-matched wild-type (WT) mice. Collectively, the Phkb−/− mouse recapitulates mild clinical features in patients with GSD-IX-beta. Metabolic and molecular analysis confirmed that Phkb−/− mice were capable of sustaining energy homeostasis during prolonged fasting by using partial glycogenolysis, increased gluconeogenesis, and potentially fatty acid oxidation in the liver.
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Enfermedad del Almacenamiento de Glucógeno , Glucogenólisis , Fosforilasa Quinasa/metabolismo , Animales , Glucemia/metabolismo , Modelos Animales de Enfermedad , Enfermedad del Almacenamiento de Glucógeno/genética , Enfermedad del Almacenamiento de Glucógeno/metabolismo , Hígado/metabolismo , Ratones , Fosforilasa Quinasa/genéticaRESUMEN
Clozapine-induced constipation is an increasingly recognized adverse reaction that frequently impairs optimal management of treatment-resistant schizophrenia. The Food and Drug Administration recently strengthened an existing warning for clozapine, citing constipation as an adverse effect that can progress to serious bowel complications. Evidence-based guidelines for laxatives in the management of clozapine-induced constipation remain scarce, and there is a general need for improved algorithms in the management of this common condition. Lubiprostone is a relatively new laxative that has labeled indications for opioid-induced constipation, irritable bowel syndrome with constipation, and chronic idiopathic constipation. This case series describes clinical pearls associated with four cases of treatment-resistant schizophrenia who underwent treatment of clozapine-induced constipation with lubiprostone. The findings of this case series suggest that there may be significant therapeutic potential in the utilization of lubiprostone for the management of clozapine-induced constipation with a low risk of adverse reactions. The study of lubiprostone benefit (i.e., without coadministration of other laxatives) continues to be of prominent interest in understanding its ability to manage clozapine-induced constipation.
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Background: Multiple sclerosis (MS) is a progressive autoimmune disorder of the central nervous system characterized by symptoms including reduced mobility, pain, fatigue, and spasticity. MS affects nearly 1 million people in the United States, with significant negative impact on a patient's quality of life, and an average lifetime cost of care in excess of $4 million. The cost-effective management of patients with MS faces several challenges. Objective: To review the challenges to the cost-effective management of patients with MS, and to offer healthcare stakeholders a roadmap to address them. Discussion: The cost-effective management of patients with MS, which is driven largely by how quickly a patient receives effective medication therapy, is challenged by a paucity of between-office-visit clinical data, variability of provider expertise with magnetic resonance imaging (MRI), MRI machine quality, lack of standards for MRI machines and reports, misaligned financial incentives, the limited number of available Current Procedural Terminology (CPT) codes for brain MRI, the complexity of disease-modifying therapy (DMT) selection, poor patient adherence to treatment plans, poor communication among providers, and a lack of objective measures of disease progression. Conclusion: Insurers, neurologists, researchers, and patient advocacy groups must address the needs of patients with MS holistically. These efforts should include establishing standards for MRI machines and reports, matching patients with MS specialists, aligning financial incentives, including creating a new CPT code for complex brain MRI, streamlining prior authorization processes of DMTs, using technology to gather patient data and improve coordination of care, and developing better measurement tools of disease activity.