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Congenital nephrogenic diabetes insipidus (CNDI) is a rare disease that results in polyuria due to decreased responsiveness to the antidiuretic hormone in the collecting ducts of the kidney. Without compensation by drinking large amounts of water, dehydration and hypernatremia can rapidly develop. We present a case of a patient originally diagnosed with CNDI who required surgery and a fasting period due to adhesive bowel obstruction. The patient was a 46-year-old man who was originally diagnosed with CNDI. He was prescribed trichlormethiazide but self-discontinued treatment in the process. His normal urine output was about 7,000–8,000 mL/day. He underwent robot-assisted radical cystectomy and uretero-cutaneostomy for bladder cancer. Two years later, he was hospitalized due to adhesive bowel obstruction. A 5% glucose solution was infused, and the dose was adjusted according to the urine volume and electrolytes. An adhesiotomy was performed due to recurrent bowel obstruction in a short period of time. A 5% glucose solution was used as the main infusion during the perioperative period. Once drinking water was resumed after surgery, urinary output and electrolytes were easily controlled. In conclusion, patients with CNDI should be given a 5% glucose solution as the primary infusion, and the infusion volume should be adjusted by monitoring daily urine output, electrolytes, and blood glucose levels. Infusion management is easier if oral intake is initiated as early as possible.

BackgroundThe addition of calcium to resuscitation fluids is a common practice in horses, but studies evaluating the effects of calcium supplementation are limited. In healthy horses, decreases in heart rate and changes in serum electrolyte concentrations have been reported.HypothesisCalcium gluconate administration at a rate of 0.4 mg/kg/min to eliminated endurance horses with metabolic problems will affect heart rate, gastrointestinal sounds, and serum electrolyte concentrations.AnimalsEndurance horses eliminated from the Tevis Cup 100-mile (160 km) endurance ride for metabolic problems and requiring IV fluid therapy were eligible.MethodsSixteen horses were randomly assigned to receive 0.4 mg/kg/min of calcium (23% calcium gluconate solution) over 1 hour diluted in 10 L of a non-calcium containing isotonic crystalloid (CAL group) or 10 L of a non-calcium containing isotonic crystalloid (CON group). Staff members administering the fluids were blinded to treatment group. Blood samples were collected and physical examinations performed before and after treatment. Heart rates were recorded every 15 min during fluid administration. Data were compared using 2-way analysis of variance (ANOVA) with repeated measures for continuous variables and Fisher's exact test for categorical variables.ResultsCalcium was associated with lower heart rates 45 min after starting the infusion (P = .002). Gastrointestinal sounds were less likely to improve in the calcium group compared with the control group (P = .005). An increase in plasma phosphorus concentration (P = .03) was associated with calcium administration.ConclusionsIntravenous calcium supplementation to endurance horses eliminated from competition after development of metabolic problems may decrease heart rate but impairs improvement in gastrointestinal sounds.

We recently demonstrated that prostaglandin production in brain endothelial cells is both necessary and sufficient for the generation of fever during systemic immune challenge. I here discuss this finding in light of the previous literature and point to some unresolved issues. Funding Agencies|Swedish Research Council [2020-00881]; Swedish Cancer Foundation [22 2338 Pj]; Swedish Brain Foundation [FO2121-0010]; County Council of Ostergotland [LIO-4818]

Food insecurity (FI) impacts people with HIV (PWH) and those who use substances (i.e. drugs and alcohol). We evaluated the longitudinal association between FI and HIV transmission risks (unprotected sexual contacts and shared needles/syringes). Among 351 PWH who use substances in Russia, 51.6% reported FI and 37.0% past month injection drug use. The mean number of unprotected sexual contacts in the past 90days was 13.4 (SD 30.1); 9.7% reported sharing needles/syringes in the past month. We did not find a significant association between mild/moderate FI (adjusted IRR = 0.87, 95% CI 0.47, 1.61) or severe FI (aIRR = 0.84, 95% CI 0.46, 1.54; global p = 0.85) and unprotected sexual contacts. We observed a significant association between severe FI and sharing needles/syringes in the past month (adjusted OR = 3.27, 95% CI 1.45, 7.39; p = 0.004), but not between mild/moderate FI and sharing needles/syringes in the past month (aOR = 1.40,95% CI 0.58, 3.38; p = 0.45). These findings suggest that severe FI could be a potential target for interventions to lower HIV transmission.

Refereed/Peer-reviewed Purpose: Map existing research and describe the consumer/caregiver experience of community-based intravenous treatment, central venous access devices (CVADs), supportive care needs, and information preferences. Design: Scoping review. Methods: Five databases (Joanna Briggs Institute, Cochrane library, Emcare, Embase, and Medline) were searched. Screening and data extraction were performed independently by two reviewers. Findings: Forty-eight studies were included. Conclusions: Although community-based intravenous treatment and CVADs have a significant impact on consumers and caregivers, there is scant research on their supportive care needs and information preferences. Clinical Evidence: Some consumers and caregivers may require additional support while undergoing community-based intravenous treatment.

Sanja Horvat,1 Bas Staffhorst,2 Jan-Hein MG Cobben2 1Department of Anesthesiology and Pain Medicine, University Medical Centre Groningen, Groningen, The Netherlands; 2Department of Anesthesiology and Pain Medicine, Deventer Ziekenhuis, Deventer, The NetherlandsCorrespondence: Sanja Horvat, Email shorvat88@gmail.comIntroduction: Neuropathic pain is a widespread problem with a big impact on quality of life. The currently used drug regimens are often insufficiently effective or cause – sometimes unacceptable – side effects. Intravenous lidocaine could be an alternative treatment, by blocking spontaneous depolarization and hyperexcitability in upregulated sodium channels in nociceptors. Research so far has shown varying results but the treatment protocols differed a lot and follow-up was usually short. In our hospital, lidocaine infusions have been applied for many years in a unique treatment protocol consisting of a relatively high dose of lidocaine (1000 mg) administered over 25 hours. Our aim is to share information on both the efficacy and safety of this treatment schedule.Methods: We conducted a retrospective cohort study in all patients who received a lidocaine infusion between January 2014 and January 2018. The standard infusion protocol consists of a total of 1000 mg lidocaine administered intravenously during 25 hours (40 mg/hour). Pain diagnoses were stratified into 15 groups, in agreement with diagnoses used in daily practice. Effectiveness of the treatment was classified as effect or no effect based on the description found in the chart.Results: We included 282 patients, with a median age of 58 years and 64% of whom were female. Patients with myofascial pain syndrome, peripheral (mono)neuropathy, small fiber neuropathy and vascular disease benefited most. Patients with cancer pain, postherpetic neuralgia, chemotherapy-induced neuropathy and radicular pain showed the least pain improvement. There were no serious adverse events.Conclusion: In selected patients, lidocaine infusions may be a safe and efficacious treatment for chronic neuropathic pain. More prospective research is needed to further determine the optimal dosing, duration and interval of lidocaine infusion therapy, and to better understand in which specific patient categories this treatment is most beneficial.Keywords: chronic pain, neuropathic pain, intravenous, lidocaine

Background and ObjectivesMyasthenia gravis (MG) is an autoimmune disease characterized by dysfunction at the neuromuscular junction. Treatment frequently includes corticosteroids (CSs) and IV immunoglobulin (IVIG). This study was conducted to determine whether immune globulin (human), 10% caprylate/chromatography purified (IGIV-C) could facilitate CS dose reduction in CS-dependent patients with MG.MethodsIn this randomized double-blind placebo-controlled trial, CS-dependent patients with MG (Myasthenia Gravis Foundation of America Class II–Iva; AChR+) received a loading dose of 2 g/kg IGIV-C over 2 days (maximum 80 g/d) or placebo at week 0 (baseline). Maintenance doses (1 g/kg IGIV-C or placebo) were administered every 3 weeks through week 36. Tapering of CS was initiated at week 9 and continued through week 36 unless the patient worsened (quantitative MG score ≥4 points from baseline). CS doses were increased (based on the current CS dose) in patients who worsened. Patients were withdrawn if worsening failed to improve within 6 weeks or if a second CS increase was required. The primary efficacy end point (at week 39) was a ≥50% reduction in CS dose. Secondary and safety end points were assessed throughout the study and follow-up (weeks 42 and 45). The study results and full protocol are available atclinicaltrials.gov/ct2/show/NCT02473965.ResultsThe primary end point (≥50% reduction in CS dose) showed no significant difference between the IGIV-C treatment (60.0% of patients) and placebo (63.3%). There were no significant differences for secondary end points. Safety data indicated that IGIV-C was well tolerated.DiscussionIn this study, IGIV-C was not more effective than placebo in reducing daily CS dose. These results suggest that the effects of IGIV-C and CS are not synergistic and may be mechanistically different.Trial Registration InformationThe trial was registered on clinicaltrialsregister.eu (EudraCT #: 2013-005099-17) andclinicaltrials.gov(identifierNCT02473965).Classification of EvidenceThis study provides Class II evidence that IVIG infusions in adult patients with MG do not increase the percentage of patients achieving a ≥50% reduction in corticosteroid dose compared with placebo.

Introduction Two phase 3 studies demonstrated superior efficacy of intravenous daratumumab (DARA IV) plus bortezomib/melphalan/prednisone (ALCYONE) or lenalidomide/dexamethasone (Rd; MAIA) versus standard-of-care regimens for transplant-ineligible newly diagnosed multiple myeloma. In these studies, patients could switch from DARA IV to subcutaneous daratumumab (DARA SC) while receiving daratumumab monotherapy in ALCYONE (as of Cycle 11) or daratumumab plus Rd in MAIA. The phase 3 COLUMBA study demonstrated noninferiority of DARA SC to DARA IV. DARA SC reduced administration time, allowing patients to spend less time in healthcare settings, a relevant practical consideration for patient care in the COVID-19 pandemic/settings of limited healthcare resources. Methods DARA SC 1800 mg was administered every 4 weeks, per approved dosing schedules. We evaluated safety and patient-reported experience (ALCYONE only) among patients who switched from DARA IV to DARA SC. Results Fifty-seven patients in ALCYONE and 135 in MAIA switched to DARA SC. Three (2.2%; MAIA) patients reported injection-site reactions, all of which were mild. No infusion-related reactions occurred with DARA SC. In ALCYONE, >80% of patients preferred DARA SC over DARA IV. Grade 3/4 treatment-emergent adverse events (TEAEs) occurred in 5.3% of patients in ALCYONE and 25.9% in MAIA; one (0.7%; MAIA) patient experienced a TEAE with an outcome of death. Conclusion For transplant-ineligible newly diagnosed multiple myeloma, DARA SC (monotherapy/with Rd) was safe and preferred over DARA IV. ClinicalTrials.gov, NCT02195479/NCT02252172.

Iron deficiency occurs frequently in pregnancy and can be diagnosed by serum ferritin-level measurement (threshold value < 30 μg/L). Screening for iron-deficiency anemia is recommended in every pregnant women, and should be done by serum ferritin-level screening in the first trimester and regular hemoglobin checks at least once per trimester. In the case of iron deficiency with or without anaemia in pregnancy, oral iron therapy should be given as first-line treatment. In the case of severe iron-deficiency anemia, intolerance of oral iron, lack of response to oral iron, or in the case of a clinical need for rapid and efficient treatment of anaemia (e.g., advanced pregnancy), intravenous iron therapy should be administered. In the postpartum period, oral iron therapy should be administered for mild iron-deficiency anemia (haemorrhagic anemia), and intravenous iron therapy for moderately severe-to-severe anemia (Hb < 95 g/L). If there is an indication for intravenous iron therapy in pregnancy or postpartum, ironcontaining drugs which have been studied in well-controlled clinical trials in pregnancy and postpartum such as ferric carboxymaltose must be preferred for safety reasons. While anaphylactic reactions are extremely rare with non-dextrane products, close surveillance during administration is recommended for all intravenous iron products., Дефіцит заліза часто виникає під час вагітності, і його можна діагностувати за допомогою дослідження рівня феритину в сироватці крові (порогове значення < 30 мкг/л). Скринінг на залізодефіцитну анемію рекомендується виконувати кожній вагітній, його слід проводити шляхом визначення рівня феритину в сироватці крові в І триместрі та шляхом регулярного дослідження концентрації гемоглобіну принаймні один раз на триместр. У разі дефіциту заліза з анемією або без неї під час вагітності повинна бути призначена пероральна терапія залізом як лікування першої лінії. У разі тяжкої залізодефіцитної анемії, непереносимості перорального заліза, відсутності відповіді на пероральне застосування заліза або за клінічної потреби швидкого та ефективного лікування анемії (наприклад, на пізніх термінах вагітності) слід використовувати внутрішньовенну терапію залізом. У післяпологовому періоді при легкій залізодефіцитній анемії (геморагічній анемії) необхідно призначати терапію пероральними феропрепаратами, а при анемії від середнього до тяжкого ступеня (Hb < 95 г/л) – внутрішньовенну терапію препаратами заліза. При показаннях до внутрішньовенної терапії препаратами заліза під час вагітності або після пологів з міркувань безпеки слід віддавати перевагу залізовмісним засобам, які вивчалися під час вагітності та після пологів у добре контрольованих клінічних дослідженнях, зокрема таким як карбоксимальтоза заліза. Досить рідко при використанні засобів, що не містять декстран, виникають анафілактичні реакції, тому рекомендується ретельнийнагляд за пацієнтами під час застосування всіх препаратів заліза для внутрішньовенного введення.

In the United States, HIV outbreaks are occurring in areas most affected by the opioid epidemic, including West Virginia (WV). Cultural Theory contends that multiple cultures co-exist within societies distinguished by their differing intensities of rules or norms of behavior (‘grid’) or degree of group allegiance/individual autonomy (‘group’). Accordingly, we would expect that perceptions about HIV, including stigma, correspond with individuals’ grid/group attributes. To explore this, we conducted qualitative interviews with people who inject drugs (PWID) recruited from a WV syringe service program. This paper focuses on our unexpected findings on stigma during a coinciding HIV outbreak. PWID living homeless identified as belonging to a ‘street family’. Its members were mutually distrustful and constrained by poverty and drug dependence but despite their conflicts, reported openness between each other about HIV + status. Interviewees living with HIV perceived little enacted stigma from peers since the local outbreak. Contrasting stigmatizing attitudes were attributed to the town’s mainstream society. The ‘High Five’ (Hi-V) Club, expressing defiance towards stigmatizing behavior outside the street family, epitomized the tensions between a desire for solidary and mutual support and a fatalistic tendency towards division and distrust. Fatalism may hinder cooperation, solidarity and HIV prevention but may explain perceived reductions in stigma.

General anesthetics and neuromuscular blockers are used together during surgery to stabilize patients in an unconscious state. Anesthetics act mainly by potentiating inhibitory ion channels and inhibiting excitatory ion channels, with the net effect of dampening nervous system excitability. Neuromuscular blockers act by antagonizing nicotinic acetylcholine receptors at the motor endplate; these excitatory ligand-gated ion channels are also inhibited by general anesthetics. The mechanisms by which anesthetics and neuromuscular blockers inhibit nicotinic receptors are poorly understood but underlie safe and effective surgeries. Here we took a direct structural approach to define how a commonly used anesthetic and two neuromuscular blockers act on a muscle-type nicotinic receptor. We discover that the intravenous anesthetic etomidate binds at an intrasubunit site in the transmembrane domain and stabilizes a non-conducting, desensitized-like state of the channel. The depolarizing neuromuscular blocker succinylcholine also stabilizes a desensitized channel but does so through binding to the classical neurotransmitter site. Rocuronium binds in this same neurotransmitter site but locks the receptor in a resting, non-conducting state. Together, this study reveals a structural mechanism for how general anesthetics work on excitatory nicotinic receptors and further rationalizes clinical observations in how general anesthetics and neuromuscular blockers interact.

Between 2015 and 2018, we provided training for 1806 municipal police officers in Tijuana, Mexico, in an effort to improve their knowledge and behaviors related to HIV and injection drug use. Correct knowledge of syringe possession laws improved from 56% before training to 94% after training and was sustained at 24 months (75%). Knowledge improvement was associated with decreases in arrests for syringe possession over time (adjusted odds ratio [AOR] = 0.87; 95% confidence interval [CI] = 0.85, 0.90). Officers with correct knowledge had significantly lower odds of reporting arrests (AOR = 0.63; 95% CI = 0.44, 0.89). Training was associated with sustained improvements in knowledge and practices that advance public health. (Am J Public Health. 2022;112(6):860–864. https://doi.org/10.2105/AJPH.2021.306702 )

The impact of preexposure prophylaxis uptake on sexual and injection-related behaviors among women who inject drugs is poorly understood. Over 24 weeks, preexposure prophylaxis uptake among women who inject drugs was associated with increased sharing of injection equipment but not syringes and no changes in condomless sex, providing limited evidence of risk compensation in this vulnerable population.

The neurosteroid allopregnanolone (ALLO) is under investigation as a treatment for benzodiazepine-refractory status epilepticus (SE). Here, we assess the cardiopulmonary safety of intravenous ALLO by itself and after a clinically recommended dose of midazolam (MDZ) in two healthy adult beagles. Each dog received ALLO (1 mg/kg, IV), and after a washout period of 2 weeks, each dog was dosed with MDZ (0.2 mg/kg, IV) followed 10 minutes later by ALLO. Behavioral state, vital signs, arterial blood gases, blood chemistries, and plasma ALLO concentrations were monitored for up to 6 hours after dosing. The dogs appeared sleepy but were fully responsive after both treatments. No depression of mean arterial pressure or respiratory rate was noted. Blood gas measurements failed to show evidence of drug-induced acute respiratory acidosis. Estimated maximum plasma ALLO concentrations were in the range of 1500 to 3000 ng/ml. The results indicate that intravenous ALLO can be used safely to treat benzodiazepine-refractory SE, even when administered shortly after a benzodiazepine.

A growing number of studies have reported the transduction of a myriad of parenchymal cell types following an intravenous recombinant adeno-associated virus (rAAV) injection. This finding has significant implications for potential routes of minimally invasive human gene therapy. However, to date, an empirically backed rationale for any mechanism underlying this extravascular transgene expression is lacking. What’s more, the literature is fragmented, with studies focusing on a single cell type or tissue that is often within the context of a disease, thereby confounding a broader interpretation of these results. We sought to build upon our previous study, which focused on the notion of endothelial cell contributions via transdifferentiation or extracellular vesicles to transgene expression by parenchymal cells. This previous work employed tamoxifen-induced cell lineage tracing in adult transgenic mice using the vascular endothelial cadherin (VEcad) promoter to drive reporter expression. Since VEcad has been shown to be expressed by very rare (0.3%) non-endothelial cell types, we initiated cell lineage tracing in this study specifically within the vascular compartment by intravenous delivery of rAAV serotype 9 (rAAV9), a variant shown to readily transduce endothelial cells among many other cell types. We also utilized multiple time points that matched our previous study for direct comparison in addition to examining 25 tissues and cell types in a context that did not involve pathogenic induction so that broad interpretations might be more readily possible. We found numerous cell types traced from intravenous rAAV9, all of which have been previously reported. However, importantly, we also observed that five cell types (including skeletal myocytes, pancreatic beta cells, pancreatic acinar cells, duodenal epithelial cells and ileal epithelial cells) traced from both intravenous rAAV9 and the VEcad promoter from our previous study. Thus, these five cell types warrant further investigation as potential downstream targets of endothelial cell transdifferentiation and/or extracellular vesicle recipients in vivo.

Identifying patients at risk of difficult intravenous access (DIVA) and increasing the success rates of peripheral intravenous catheterization (PIVC), preferably on the first catheterization attempt, is of clinical importance. The aim of this study was to compare the use of dynamic ultrasound guidance for PIVC with the traditional technique of visualization and palpation in patients with predicted DIVA. A systematic review and meta-analysis comparing ultrasound-guided PIVC with the traditional technique was performed. Data were systematically collected through MEDLINE and EMBASE databases from inception to March 2021. Eligibility criteria included randomized controlled trials performed on patients meeting criteria for difficult catheterization comprising either (a) no palpable or visible veins, (b) previous history of difficult venous catheterization, (c) patient age less than 4 years, (d) suspicion of difficult catheterization by operator, or (e) two or more unsuccessful attempts using the traditional technique before enrollment were included. For all outcomes, a random-effects meta-analysis using the DerSimonian and Laird method was performed. The primary outcome was the first-attempt success rate, and the secondary outcomes were the overall success rate and the number of attempts for successful intravenous catheterization. Bias was assessed using the Revised Cochrane Risk of Bias tool. Seven studies with a total of 994 patients were included. Patients comprised both children and adults and settings included operating rooms, emergency departments, and intensive care units. Ultrasound guidance was associated with a higher first-attempt success rate (OR, 3.07; 95% CI, 1.66-5.65; P < 0.001). For the secondary outcomes, ultrasound guidance was associated with a higher overall success rate (OR, 3.02; 95% CI, 1.04-8.79; P = 0.04); however, this finding did not meet statistical significance in a sensitivity analysis (OR, 2.90; 95% CI, 0.71-11.93; P = 0.14). Ultrasound was not associated with a significantly different number of attempts compared with the traditional technique (difference in means, 0.14; 95% CI, -0.32 to 0.05; P = 0.15). The use of ultrasound guidance resulted in an almost three-fold increase in odds for the first-attempt success rate in patients with predicted DIVA compared with the traditional technique of PIVC.

AimsIron deficiency is a common finding among patients with heart failure (HF) and is associated with adverse outcomes, including decreased quality of life, increased risk of hospitalization, and decreased survival. Intravenous ferric carboxymaltose (FCM) has been shown to improve outcomes among patients with HF and concomitant iron deficiency, but FCM is associated with an increased risk of hypophosphataemia. We aimed to better characterize this risk among HF populations.Methods and resultsThis pooled analysis examined data from 41 studies of adults with iron deficiency across disease states and therapeutic areas. Among the 7931 patients treated with FCM available for analysis, 14% made up the HF subgroup. Additional subgroups included women's health (36%), non-dialysis-dependent chronic kidney disease (NDD-CKD; 27%), haemodialysis-dependent chronic kidney disease (HD-CKD; 1%), gastrointestinal (10%), neurology (3%), and other (10%). The incidence of post-baseline moderate or severe hypophosphataemia (i.e. serum phosphate [PO4 3- ] level 60mL/min/1.73m2 vs.

First-pass metabolism alters arsenic biotransformation and its immunomodulatory activities. This study aims to determine the mRNA expression of intestinal-immunity- and permeability-associated genes, levels of cytokine/chemokines and levels of immunoglobulin isotypes when CD-1 mice were exposed to a single dose of intravenous (IV) sodium arsenite (50 µg/kg body weight (BW)) and to compare these responses to exposure via oral gavage (OG) (50 µg/kg BW). Samples were collected at 1, 4, 24 and 48 h post IV exposure and 24 and 48 h post OG. Sodium arsenite IV exposure led to a transient modulation of mRNA expression and protein levels of immunity-related genes involved in inflammation/apoptotic pathways and production of cytokines/chemokines, whereas it also led to downregulated expression of genes encoding tight junction, focal adhesion, and gap junction proteins, which are responsible for maintaining cell permeability. Oral exposure perturbed fewer cell-permeability-related genes at 24 and 48 h post exposure. At 24 h post exposure, OG decreased IgA and IgG2b levels; however, IV exposure significantly increased IgG2b, IgG3 and IgA in ileal tissue. Earlier, we showed significant downregulation of mRNA expression of genes involved in the immune-related pathways during OG in the intestinal mucosa of the same animals. Cumulatively, these results provide evidence that the exposure route of a xenobiotic can differentially impact the intestinal responses due to the impact of first-pass metabolism.

BACKGROUND: In the Netherlands therewereseveralreports on needlespiking: people have found themselvessubjectedtosurreptitiousinjections.CASE DESCRIPTION: A 23-year-old female was seenafterbeingsurroundedby a group of men andfeltwhatshethought was a jab. She was abletoevadethegroup. Several minutes later sheexperienceddizziness, nausea andvomiting. On physical examination, a bleedingpuncturewound was seen on her upper arm withaccompanying erythema. Toxicology on bloodand urine didnot show evidenceforintoxicationotherthan alcohol which was higherthanwouldbesuspectedbythenumber of drinks thevictimreported.CONCLUSION: There is evidencethatpeople are puncturedwithneedles in busy surroundings like thenightlife. Possiblealso drugs are injected. Experiencedsymptomsbyvictims (n=19) wereheterogeneousandnotlikelyattributedtooneandthesamecausal drug. Toxicologydidnotrevealanysubstanceuntilnow.

BACKGROUND: In the Netherlands therewereseveralreports on needlespiking: people have found themselvessubjectedtosurreptitiousinjections. CASE DESCRIPTION: A 23-year-old female was seenafterbeingsurroundedby a group of men andfeltwhatshethought was a jab. She was abletoevadethegroup. Several minutes later sheexperienceddizziness, nausea andvomiting. On physical examination, a bleedingpuncturewound was seen on her upper arm withaccompanying erythema. Toxicology on bloodand urine didnot show evidenceforintoxicationotherthan alcohol which was higherthanwouldbesuspectedbythenumber of drinks thevictimreported. CONCLUSION: There is evidencethatpeople are puncturedwithneedles in busy surroundings like thenightlife. Possiblealso drugs are injected. Experiencedsymptomsbyvictims (n=19) wereheterogeneousandnotlikelyattributedtooneandthesamecausal drug. Toxicologydidnotrevealanysubstanceuntilnow.

Introduction: Antimicrobial stewardship (AMS) strategies, such as intravenous-to-oral switch (IVOS), promote optimal antimicrobial use, contributing to safer and more effective patient care and tackling antimicrobial resistance (AMR). Aim: This study aimed to achieve nationwide multidisciplinary expert consensus on antimicrobial IVOS criteria for timely switch in hospitalised adult patients and to design an IVOS decision aid to operationalise agreed IVOS criteria in the hospital setting. Method: A four-step Delphi process was chosen to achieve expert consensus on IVOS criteria and decision aid; it included (Step One) Pilot/1st round questionnaire, (Step Two) Virtual meeting, (Step Three) 2nd round questionnaire and (Step 4) Workshop. This study follows the Appraisal of Guidelines for Research and Evaluation II instrument checklist. Results: The Step One questionnaire of 42 IVOS criteria had 24 respondents, 15 of whom participated in Step Two, in which 37 criteria were accepted for the next step. Step Three had 242 respondents (England n = 195, Northern Ireland n = 18, Scotland n = 18, Wales n = 11); 27 criteria were accepted. Step Four had 48 survey respondents and 33 workshop participants; consensus was achieved for 24 criteria and comments were received on a proposed IVOS decision aid. Research recommendations include the use of evidence-based standardised IVOS criteria. Discussion and Conclusion: This study achieved nationwide expert consensus on antimicrobial IVOS criteria for timely switch in the hospitalised adult population. For criteria operationalisation, an IVOS decision aid was developed. Further research is required to provide clinical validation of the consensus IVOS criteria and to expand this work into the paediatric and international settings.

Background HIV incidence has recently increased among people who inject drugs (PWID) across the United States, with outbreaks occurring in states with long-standing syringe service programs (SSPs) including Massachusetts (MA). Antiretroviral pre-exposure prophylaxis (PrEP) is an evidence-based HIV prevention strategy recommended for PWID, but uptake in this marginalized population is extraordinarily low. Methods We describe the design and procedures for a National Institute on Drug Abuse (NIDA)-funded (R01) randomized controlled trial (RCT) testing the efficacy of “PrEP for Health,” a multicomponent behavioral intervention to increase PrEP uptake, adherence, and persistence among HIV-negative PWID attending SSPs in two areas of the U.S. Northeast that are heavily affected by injection-related HIV transmission. Participants are equally randomized to receive the “PrEP for Health” intervention (involving individually tailored HIV and PrEP education, motivational interviewing, problem-solving skills and planning, and ongoing navigation support) or an enhanced standard of care (eSOC) control condition involving a brief educational video on the utility of PrEP for HIV prevention. Co-primary outcomes are PrEP uptake (using medical/pharmacy records) and adherence (using tenofovir quantification in hair samples); a secondary outcome is PrEP persistence (using medical/pharmacy records) over 12 months. Major assessments occur at baseline, 1-, 3-, 6-, and 12-month follow-up visits. Planned analyses will examine intervention efficacy, specific hypothesized conceptual mediators of the intervention effect (e.g., self-perceived HIV risk; PrEP knowledge, interest in use, motivation, and behavioral skills) and epidemiologically linked moderators (e.g., age; gender; condomless vaginal or anal sex). Discussion Findings from our extensive preliminary research with the study population revealed that a multicomponent, theory-based intervention targeting PrEP knowledge, motivation, self-efficacy, behavioral skills, and structural barriers to PrEP access is urgently needed for PWID who are at risk of HIV acquisition. We also learned that SSPs represent a highly acceptable service setting for delivering such interventions. In this study, we are evaluating the efficacy of the “PrEP for Health” intervention. If efficacious, findings from our implementation evaluation could help guide its dissemination to diverse SSPs and possibly other community-based settings accessed by this population. Trial registration ClinicalTrials.gov number NCT04430257, registered June 12, 2020.

Intravenous immunoglobulin (IVIG) is used as an immunomodulatory agent in many inflammatory conditions including Multisystem Inflammatory Syndrome-Children (MIS-C) and Kawasaki disease (KD). However, the exact mechanisms underlying its anti-inflammatory action are incompletely characterized. Here, we show that in KD, a pediatric acute vasculitis that affects the coronary arteries, IVIG induces a repertoire of natural Treg that recognize immunodominant peptides in the Fc heavy chain constant region. To address which antigen-presenting cell (APC) populations present Fc peptides to Treg, we studied the uptake of IgG by innate cells in subacute KD patients 2 weeks after IVIG and in children 1.6–14 years after KD. Healthy adults served as controls. IgG at high concentrations was internalized predominantly by two myeloid dendritic cell (DC) lineages, CD14+ cDC2 and ILT-4+ CD4+ tmDC mostly through Fcγ receptor (R) II and to a lesser extent FcγRIII. Following IgG internalization, these two DC lineages secreted IL-10 and presented processed Fc peptides to Treg. The validation of IVIG function in expanding Fc-specific Treg presented by CD14+ cDC2 and ILT-4+ CD4+ tmDC was addressed in a small cohort of patients with MIS-C. Taken together, these results suggest a novel immune regulatory function of IgG in activating tolerogenic innate cells and expanding Treg, which reveals an important anti-inflammatory mechanism of action of IVIG.

Objectives To evaluate the incidence of adverse drug reactions (ADRs), including hypersensitivity reactions (HSRs) and post-contrast acute kidney injury (PC-AKI), after intravenous (IV) administration of ioversol. Materials and methods A systematic literature search (1980–2021) of studies documenting IV use of ioversol and presence or absence of ADRs, HSRs, or PC-AKI was performed. Key information including patients’ characteristics, indication and dose of ioversol, safety outcome incidence, intensity and seriousness were extracted. Results Thirty-one studies (> 57,000 patients) were selected, including 4 pediatric studies. The incidence of ADRs in adults was reported in 12 studies from ioversol clinical development with a median (range) of 1.65% (0–33.3%), and 3 other studies with an incidence between 0.13 and 0.28%. The incidence of HSRs (reported in 2 studies) ranged from 0.20 to 0.66%, and acute events (4 studies) from 0.23 to 1.80%. Severe reactions were rare with a median (range) of 0 (0–4%), and none were reported among pediatric patients. The incidence of ADRs and HSRs with ioversol, especially those of severe intensity, was among the lowest in studies comparing different iodinated contrast media (ICM) of the same class. PC-AKI incidence was variable (1–42% in 5 studies); however, ioversol exposure per se did not increase the incidence. Conclusions When administered by the IV route, ioversol has a good safety profile comparable to that of other ICM within the same class, with a low incidence of severe/serious ADRs overall, and particularly HSRs. PC-AKI incidence does not seem to be increased compared to patients who did not receive ioversol. Further well-designed studies are warranted to confirm these results. Key Points • Ioversol has a good safety profile in adult and pediatric patients when IV administered. • ADR and HSR incidence with ioversol, especially those of severe intensity, was among the lowest compared to other ICM. • IV administration of ioversol per se did not increase PC-AKI incidence.

Rapid infusion (RI) of the rituximab biosimilar CT-P10 is currently only an approved treatment regimen for the treatment of rheumatoid arthritis. Although both CT-P10 and reference rituximab are known to be frequently administered using a RI regimen (≤90 min) in clinical practice, published data on the safety of RI of CT-P10 in patients with NHL and CLL are limited. Hence, this study collected real-world safety and effectiveness data on RI-CT-P10 from the medical records of 196 patients with NHL or CLL in 10 European centers, 6 months after the date of the first RI (index date); the infusion-related reaction (IRR) rate was compared to previously published data. Ten percent (95% confidence interval 6%-15%; n = 20/196) of patients experienced an infusion-related reaction (IRR) on day 1-2 post-index, which was not significantly different (p = 0.45) to the IRR rate for rituximab described in a previous meta-analysis (8.8%). During the observation period, 2% of patients experienced grade 3-5 IRRs and 85% (n = 166) experienced an adverse event (non-IRR). The most common reason for discontinuation of first-line CT-P10 was planned treatment completion (81%; n = 158). Complete response and partial response to CT-P10 was observed in 74% (n = 142/192) and 22% (n = 42/192) of patients, respectively. The results of this real-world study demonstrate that the safety and effectiveness profile of RI-CT-P10 is similar to RI of reference rituximab and therefore support the current use of RI-CT-P10 in patients with NHL and CLL.

Objective The aim of the study was to investigate the effectiveness of user testing for improving healthcare professionals' retrieval and comprehension of information in medicines guidelines. Methods The United Kingdom's Injectable Medicines Guide was selected as a case study. This gives guidance to nurses on preparing and administering intravenous medicines on hospital wards, in line with standard UK practice. Three rounds of user testing were completed with 10 hospital nurses per round, using the Injectable Medicines Guide for voriconazole and aminophylline. Participants used the guidelines to answer 17 questions related to the administration of these medicines. Answers were scored for "finding" and "understanding" the required information. Semistructured interviews explored participants' opinions of guideline content, design, and wording, with responses analyzed thematically. The guidelines were revised between rounds. Results In round 1, 8 of 17 questions were answered correctly by all participants. Participants had difficulty with dose, dilution, administration rate, and adverse effects questions. Revisions included new subsections and increased calculation support. In round 2, 14 of 17 questions were answered correctly by all participants. Difficulty persisted with dose and administration rate questions and further revisions made. In round 3, 15 of 17 questions were answered correctly by all participants. Across all rounds, participants considered appropriate subheadings and information order as important for fast location of information. Specific, detailed, and practical instructions were perceived as important to improve understandability and usefulness. Conclusions Key information in medicines guidelines may not be found and/or understood by healthcare professionals. User testing increased information retrieval and comprehension and could have an important role in improving the safety of medicines use.

Background In the context of increasing injection-related HIV outbreaks across the United States, particularly among people who inject drugs (PWID) experiencing homelessness, there is an urgent need to expand access to pre-exposure prophylaxis (PrEP) for HIV prevention. Peer-based interventions for PrEP could be helpful for promoting PrEP uptake, yet the social experiences of using PrEP among PWID experiencing homelessness have not been thoroughly explored. Methods To better understand social experiences surrounding PrEP use among PWID experiencing homelessness, we conducted qualitative interviews from March-December 2020 with current and former PrEP patients of an innovative, low-threshold program implemented by Boston Health Care for the Homeless Program (BHCHP) in Boston, MA. Thematic analysis of coded interview data explored participants’ perspectives and experiences with PrEP disclosure and discussions within their social networks. Results Among interviews with 21 participants, we identified the following four interrelated aspects of their social experiences using PrEP: (1) participants’ were aware of increasing HIV transmission within their social networks, which motivated their PrEP use and disclosure; (2) participants generally avoided disclosing their PrEP use within public spaces or casual conversations; (3) participants expressed greater willingness to discuss PrEP with their close social contacts; and (4) some participants self-identified as leaders or expressed interest in leading the dissemination of PrEP information within their social networks. Conclusions Findings highlight the significance of PrEP disclosure and discussions within the social networks of PWID experiencing homelessness, suggesting a need for continued social network and intervention research—particularly to establish the feasibility and acceptability of peer-based interventions for promoting PrEP—with this marginalized population.

ObjectiveThis study was undertaken to describe the safety, tolerability, pharmacokinetics, and immunogenicity of elezanumab (ABT-555), a fully human monoclonal antibody (mAb) directed against repulsive guidance molecule A (RGMa), in healthy and multiple sclerosis (MS) study participants.MethodsThe single-center, first-in-human, single ascending dose (SAD) study evaluated elezanumab (50-1,600mg intravenous [IV] and 150mg subcutaneous) in 47 healthy men and women. The multicenter multiple ascending dose (MAD; NCT02601885) study evaluated elezanumab (150mg, 600mg, and 1,800mg) in 20 adult men and women with MS, receiving either maintenance or no immunomodulatory treatment.ResultsNo pattern of study drug-related adverse events was identified for either the SAD or MAD elezanumab regimens. Across both studies, the Tmax occurred within 4 hours of elezanumab IV infusion, and the harmonic mean of t1/2 ranged between 18.6 and 67.7 days. Following multiple dosing, elezanumab Cmax , area under the curve, and Ctrough increased dose-proportionally and resulted in dose-dependent increases in elezanumab cerebrospinal fluid (CSF) concentrations. Elezanumab CSF penetration was 0.1% to 0.4% across both studies, with CSF levels of free RGMa decreased by >40%. Changes in CSF interleukin-10 (IL-10) and free RGMa demonstrated dose/exposure-dependence.InterpretationThe elezanumab pharmacokinetic profile supports monthly, or bimonthly, administration of up to 1,800mg with the option of a loading dose of 3,600mg. Elezanumab partitioning into CSF is within the range expected for mAbs. Reduced CSF levels of free RGMa demonstrate central nervous system target binding of elezanumab with an apparent maximal effect at 1,800mg IV. Exposure-associated increases in CSF IL-10, an anti-inflammatory cytokine with neuroprotective/neurorestorative properties, support potential pathway modulation in MS participants. ANN NEUROL 2023;93:285-296.

Recovery after anesthesia has a significant impact on a patient’s return to daily life. This study was performed to compare the postoperative quality of recovery according to the method of anesthesia administered among patients undergoing OPCAB using the Korean version of the Quality of Recovery-40 (QoR-40K) questionnaire. This single-blind, prospective study (trial number: KCT0004726) was performed using a population of 102 patients undergoing OPCAB under general anesthesia. The patients were randomly assigned to one of two groups using a computer-generated list: a total intravenous anesthesia group (Group T) and a balanced anesthesia group (Group B). The QoR-40K score was measured preoperatively and at 24 and 48 h after extubation. There was no significant difference in the QoR-40K scores between the groups at 24 and 48 h after extubation. In addition, there were no significant differences between groups with respect to any of the five dimensions of QoR-40K at 24 and 48 h after extubation. Finally, there were no differences in the postoperative opioid consumption, time to extubation, or length of hospital stay. In this study, there was no difference in the QoR-40K score at 24 h after extubation between Groups T and B. Therefore, both methods of anesthesia are suitable for use when performing OPCAB.

A selective, sensitive, and rapid liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantitation of ICG in rat plasma. The chromatographic separation was achieved using an ACE excel C18 (3 µm, 50 × 3.0 mm) column, with a mobile phase composition of 0.1% formic acid and 0.1% formic acid in acetonitrile, using a gradient flow at a rate of 0.3 mL/min. The MS was operated at a unit resolution in the multiple reaction monitoring mode, using the precursor ion → product ion combinations of 753.3 → 330.2 m/z (ICG) and 747.45 → 717.50 (Cy7.5 amine) with a run time of 5 min. The assay was linear over a concentration range of 1–1000 ng/mL with a regression coefficient (r2) of 0.998 or better. The inter and intra-batch precision (% relative standard deviation, %RSD) was lower than 13.5%, with accuracy (%Bias) between −10.03% and 11.56%. The ICG was stable under laboratory storage and handling conditions. The validated method was successfully applied to preclinical pharmacokinetic (PK) studies of ICG at a dose of 0.39 mg/kg in rats. PK parameters suggested the highest plasma concentration within 2 min of intravenous dosing with restricted systemic distribution and rapid clearance.

Vascular access for the provision of medication and fluids through peripheral intravenous catheters (PIVCs) and intraosseous (IO) devices is common in modern health care. In the prehospital setting obtaining this access can be vital, with delays or failures negatively impacting patient outcomes. However, both PIVCs and IO devices have a risk of failure, can injure patients, or be portals of infection with subsequent negative patient outcomes. Research exploring the use and risks of these devices in the prehospital setting is limited compared to hospital settings. The changing nature of prehospital care, and the guidelines that impact when these devices are used, mean it is important to examine current PIVC and IO device practices, identify areas of concern, and explore ways to maintain safe practice. Data from the United States of America (USA) National Emergency Medical Service Information System (NEMSIS) and the Queensland Ambulance Service (QAS) were analysed to describe the incidence of insertion and usage of PIVC and IO devices, and explore factors associated with their insertion.

PurposeIntravenous paclitaxel (IVpac) is complicated by neuropathy and requires premedication to prevent hypersensitivity-type reactions. Paclitaxel is poorly absorbed orally; encequidar (E), a novel P-glycoprotein pump inhibitor, allows oral absorption.MethodsA phase III open-label study comparing oral paclitaxel plus E (oPac + E) 205 mg/m2 paclitaxel plus 15 mg E methanesulfonate monohydrate 3 consecutive days per week versus IVpac 175 mg/m2 once every 3 weeks was performed. Women with metastatic breast cancer and adequate organ function, at least 1 year from last taxane, were randomly assigned 2:1 to oPac + E versus IVpac. The primary end point was confirmed radiographic response using RECIST 1.1, assessed by blinded independent central review. Secondary end points included progression-free survival (PFS) and overall survival (OS).ResultsFour hundred two patients from Latin America were enrolled (265 oPac + E, 137 IVpac); demographics and prior therapies were balanced. The confirmed response (intent-to-treat) was 36% for oPac + E versus 23% for IVpac (P = .01). The PFS was 8.4 versus 7.4 months, respectively (hazard ratio, 0.768; 95.5% CI, 0.584 to 1.01; P = .046), and the OS was 22.7 versus 16.5 months, respectively (hazard ratio, 0.794; 95.5% CI, 0.607 to 1.037; P = .08). Grade 3-4 adverse reactions were 55% with oPac + E and 53% with IVpac. oPac + E had lower incidence and severity of neuropathy (2% v 15% > grade 2) and alopecia (49% v 62% all grades) than IVpac but more nausea, vomiting, diarrhea, and neutropenic complications, particularly in patients with elevated liver enzymes. On-study deaths (8% oPac + E v 9% IVpac) were treatment-related in 3% and 0%, respectively.ConclusionoPac + E increased the confirmed tumor response versus IVpac, with trends in PFS and OS. Neuropathy was less frequent and severe with oPac + E; neutropenic serious infections were increased. Elevated liver enzymes at baseline predispose oPac + E patients to early neutropenia and serious infections (funded by Athenex, Inc; ClinicalTrials.gov identifier: NCT02594371).

PURPOSE: Fluid overload is common in critical illness and is associated with mortality. This study investigated the feasibility of a randomised trial comparing conservative fluid administration and deresuscitation (active removal of accumulated fluid using diuretics or ultrafiltration) with usual care in critical illness.METHODS: Open-label, parallel-group, allocation-concealed randomised clinical feasibility trial. Mechanically ventilated adult patients expected to require critical care beyond the next calendar day were enrolled between 24 and 48 h following admission to the intensive care unit (ICU). Patients were randomised to either a 2-stage fluid strategy comprising conservative fluid administration and, if fluid overload was present, active deresuscitation, or usual care. The primary endpoint was fluid balance in the 24 h up to the start of study day 3. Secondary endpoints included cumulative fluid balance, mortality, and duration of mechanical ventilation.RESULTS: One hundred and eighty patients were randomised. After withdrawal of 1 patient, 89 patients assigned to the intervention were compared with 90 patients assigned to the usual care group. The mean plus standard deviation (SD) 24-h fluid balance up to study day 3 was lower in the intervention group (- 840 ± 1746 mL) than the usual care group (+ 130 ± 1401 mL; P CONCLUSIONS: A strategy of conservative fluid administration and active deresuscitation is feasible, reduces fluid balance compared with usual care, and may cause benefit or harm. In view of wide variations in contemporary clinical practice, large, adequately powered trials investigating the clinical effectiveness of conservative fluid strategies in critically ill patients are warranted.

Introduction: The acute seizure in childhood is a medical emergency which is usually managed by benzodiazepines used as a first line of therapy. There are no strict guidelines of using intranasal lorazepam in India. Many paediatricians use it in an emergency situation as it is inexpensive, easy to administer and even treatment can be started at home. Very few studies are available to compare efficacy and safety of intravenous lorazepam with intranasal lorazepam in childhood seizure, though both routes have comparable pharmacokinetic profile. Intravenous lorazepam (0.1 mg/kg) is already recommended as a first-line treatment of acute childhood seizures in India. There are very few studies regarding the usefulness of intranasal lorazepam. With this background, we compared intranasal lorazepam with the more widely accepted intravenous lorazepam for control of acute seizure. Aim: To compare effectiveness and safety of intranasal and intravenous lorazepam in acute seizure in children aged 5-12 years. Materials and methods: This is an analytical observational cross-sectional study involving patients with acute seizure who received lorazepam via either the intravenous or intranasal route. Formulation and dosage of lorazepam were the same in both routes. Results: Distributions of patient groups according to sex, age, and weight were statistically not significant (p=0.42, p=0.391, and p=0.605, respectively). Time to control seizure within 10 min and persistent cessation of seizure activity were similar in both groups. Safety parameters showed no differences statistically. Conclusions: Though intravenous lorazepam is recommended as first-line treatment, intranasal lorazepam may be a good alternative choice in a convulsing child.

N,N-dimethyltryptamine (DMT) is a psychedelic compound that is believed to have potential as a therapeutic option in several psychiatric disorders. The number of clinical investigations with DMT is increasing. However, very little is known about the pharmacokinetic properties of DMT as well as any relationship between its exposure and effects. This study aimed to characterize population pharmacokinetics of DMT as well as the relationship between DMT plasma concentrations and its psychedelic effects as measured through subjective intensity ratings. Data were obtained from 13 healthy subjects after intravenous administration of DMT. The data were analyzed using nonlinear mixed-effects modeling in NONMEM. DMT plasma concentrations were described by a two-compartment model with first-order elimination leading to formation of the major metabolite indole 3-acetic acid. The relationship between plasma concentrations and psychedelic intensity was described by an effect site compartment model with a sigmoid maximum effect (Emax ) response. DMT clearance was estimated at 26 L/min, a high value indicating elimination of DMT to be independent of blood flow. Higher concentrations of DMT were associated with a more intense experience with the concentration of DMT at the effect site required to produce half of the maximum response estimated at 95 nM. The maximum achievable intensity rating was 10 and the simulated median maximum rating was zero, 2, 4, 8, and 9 after doses of 1, 4, 7, 14, and 20 mg, respectively. The model can be useful in predicting suitable doses for clinical investigations of DMT based on the desired intensity of the subjective experience.

This study evaluated the association between impulsivity and linkage to HIV care among Russians living with HIV recruited from an inpatient narcology hospital. Linking Infectious and Narcology Care (LINC) study participants who completed the Barratt Impulsiveness Scale (BIS) were included in these analyses. The primary independent variable was impulsivity score which was categorized as high impulsivity (BIS score > 71) vs. low impulsivity (BIS score

Vincent Tran,1 Sharon E Reid,2,3 Amanda Roxburgh,1,4– 6 Carolyn A Day1,2 1Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Camperdown, New South Wales, Australia; 2Edith Collins Centre (Translational Research in Alcohol, Drugs and Toxicology), Sydney Local Health District, Sydney, New South Wales, Australia; 3Sydney School of Public Health, Faculty of Medicine and Health, The University of Sydney, Camperdown, New South Wales, Australia; 4Health Risks Program, Burnet Institute, Melbourne, Victoria, Australia; 5National Drug and Alcohol Research Centre, UNSW, Randwick, New South Wales, Australia; 6Monash Addiction Research Centre, Monash University, Clayton, Victoria, AustraliaCorrespondence: Carolyn A Day Tel +61 2 95191446Email carolyn.day@sydney.edu.auBackground: Drug consumption rooms (DCRs) and supervised injecting facilities (SIFs) provide a safe environment in which people who inject drugs (PWIDs) can inject under hygienic and supervised conditions. Numerous reviews have documented the benefits of these facilities; however, there is a lack of clarity surrounding their long-term effects.Purpose: To conduct, with a systematic approach, a literature review, of published peer-reviewed literature assessing the long-term impacts of DCRs/SIFs.Methods: A systematic search of the PubMed and Embase database was performed using the keywords: (“SUPERVISED” OR “SAFE&ast;”) AND (“CONSUMPTION” OR “INJECT&ast;” OR “SHOOTING”) AND (“FACILITY&ast;” OR “ROOM&ast;” OR “GALLERY&ast;” OR “CENTRE&ast;” OR “CENTER&ast;” OR “SITE&ast;”). Included studies were original articles reporting outcomes for five or more years and addressed at least one of the following client or community outcomes; (i) drug-related harms; (ii) access to substance use treatment and other health services; (iii) impact on local PWID population; (iv) impact on public drug use, drug-related crime and violence; and (v) local community attitudes to DCRs.Results: Four publications met our inclusion criteria, addressing four of the five outcomes. Long-term data suggested that while the health of PWID naturally declined over time, DCRs/SIFs helped reduce injecting-related harms. The studies showed that DCRs/SIFs facilitate drug treatment, access to health services and cessation of drug injecting. Local residents and business owners reported less public drug use and public syringe disposal following the opening of a DCR/SIF.Conclusion: Long-term evidence on DCRs/SIFs is consistent with established short-term research demonstrating the benefits of these facilities. A relative paucity of studies was identified, with most evidence originating from Sydney and Vancouver. The overall body of evidence would be improved by future studies following outcomes over longer periods and being undertaken in a variety of jurisdictions and models of DCRs/SIFs.Keywords: safe injecting facilities, intravenous, Injecting, harm reduction

Our aim was to evaluate lung injury due to oxidative stress and antioxidant activity levels in an infrarenal ischemia–reperfusion model and to compare prevention effects of single and combined use of propofol and remifentanil. In this study, a total of 40 adult Wistar Albino rats were randomly divided into five groups of eight rats as SHAM, physiological saline, intraperitoneal propofol, remifentanil, and propofol and remifentanil groups. Blood and tissue samples were obtained after 80 min of reperfusion. The malondialdehyde (MDA) level, a measure of lipid peroxidation, was measured in lung tissue samples and red blood cells; additionally, total oxidant status and total antioxidant capacity of lung tissues were measured and histopathological examination was performed. Distant organ (lung) injury developed due to lower extremity ischemia–reperfusion was created by infrarenal aortic clamping. The lipid peroxidation product MDA and total oxidant levels were increased, but there was insufficient antioxidant protection both in the lung tissues and red blood cells. While propofol prevented this injury consistent with its proposed antioxidant properties; no protective effect of remifentanil was observed. On the contrary, it showed oxidative stress increasing effect. This study concluded that the antioxidant effect of propofol was suppressed by remifentanil in the case of combined use.

Background Drug consumption rooms (DCRs) and supervised injecting facilities (SIFs) provide a safe environment in which people who inject drugs (PWIDs) can inject under hygienic and supervised conditions. Numerous reviews have documented the benefits of these facilities; however, there is a lack of clarity surrounding their long-term effects. Purpose To conduct, with a systematic approach, a literature review, of published peer-reviewed literature assessing the long-term impacts of DCRs/SIFs. Methods A systematic search of the PubMed and Embase database was performed using the keywords: ("SUPERVISED" OR "SAFE*") AND ("CONSUMPTION" OR "INJECT*" OR "SHOOTING") AND ("FACILITY*" OR "ROOM*" OR "GALLERY*" OR "CENTRE*" OR "CENTER*" OR "SITE*"). Included studies were original articles reporting outcomes for five or more years and addressed at least one of the following client or community outcomes; (i) drug-related harms; (ii) access to substance use treatment and other health services; (iii) impact on local PWID population; (iv) impact on public drug use, drug-related crime and violence; and (v) local community attitudes to DCRs. Results Four publications met our inclusion criteria, addressing four of the five outcomes. Long-term data suggested that while the health of PWID naturally declined over time, DCRs/SIFs helped reduce injecting-related harms. The studies showed that DCRs/SIFs facilitate drug treatment, access to health services and cessation of drug injecting. Local residents and business owners reported less public drug use and public syringe disposal following the opening of a DCR/SIF. Conclusion Long-term evidence on DCRs/SIFs is consistent with established short-term research demonstrating the benefits of these facilities. A relative paucity of studies was identified, with most evidence originating from Sydney and Vancouver. The overall body of evidence would be improved by future studies following outcomes over longer periods and being undertaken in a variety of jurisdictions and models of DCRs/SIFs.

Summary Background Spinal muscular atrophy is a rare, autosomal recessive, neuromuscular disease caused by biallelic loss of the survival motor neuron 1 (SMN1) gene, resulting in motor neuron dysfunction. In this STR1VE-EU study, we aimed to evaluate the safety and efficacy of onasemnogene abeparvovec gene replacement therapy in infants with spinal muscular atrophy type 1, using broader eligibility criteria than those used in STR1VE-US. Methods STR1VE-EU was a multicentre, single-arm, single-dose, open-label phase 3 trial done at nine sites (hospitals and universities) in Italy (n=4), the UK (n=2), Belgium (n=2), and France (n=1). We enrolled patients younger than 6 months (180 days) with spinal muscular atrophy type 1 and the common biallelic pathogenic SMN1 exon 7–8 deletion or point mutations, and one or two copies of SMN2. Patients received a one-time intravenous infusion of onasemnogene abeparvovec (1·1 × 1014 vector genomes [vg]/kg). The outpatient follow-up consisted of assessments once per week starting at day 7 post-infusion for 4 weeks and then once per month until the end of the study (at age 18 months or early termination). The primary outcome was independent sitting for at least 10 s, as defined by the WHO Multicentre Growth Reference Study, at any visit up to the 18 months of age study visit, measured in the intention-to-treat population. Efficacy was compared with the Pediatric Neuromuscular Clinical Research (PNCR) natural history cohort. This trial is registered with ClinicalTrials.gov , NCT03461289 (completed). Findings From Aug 16, 2018, to Sept 11, 2020, 41 patients with spinal muscular atrophy were assessed for eligibility. The median age at onasemnogene abeparvovec dosing was 4·1 months (IQR 3·0–5·2). 32 (97%) of 33 patients completed the study and were included in the ITT population (one patient was excluded despite completing the study because of dosing at 181 days). 14 (44%, 97·5% CI 26–100) of 32 patients achieved the primary endpoint of functional independent sitting for at least 10 s at any visit up to the 18 months of age study visit (vs 0 of 23 untreated patients in the PNCR cohort; p Interpretation STR1VE-EU showed efficacy of onasemnogene abeparvovec in infants with symptomatic spinal muscular atrophy type 1. No new safety signals were identified, but further studies are needed to show long-term safety. The benefit–risk profile of onasemnogene abeparvovec seems favourable for this patient population, including those with severe disease at baseline. Funding Novartis Gene Therapies.

Background Occlusions of intravenous (IV) tubing can prevent vital and time-critical medication or solutions from being delivered into the bloodstream of patients receiving IV therapy. At low flow rates (≤ 1 ml/h) the alarm delay (time to an alert to the user) can be up to 2 h using conventional pressure threshold algorithms. In order to reduce alarm delays we developed and evaluated the performance of two new real-time occlusion detection algorithms and one co-occlusion detector that determines the correlation in trends in pressure changes for multiple pumps. Methods Bench-tested experimental runs were recorded in triplicate at rates of 1, 2, 4, 8, 16, and 32 ml/h. Each run consisted of 10 min of non-occluded infusion followed by a period of occluded infusion of 10 min or until a conventional occlusion alarm at 400 mmHg occurred. The first algorithm based on binary logistic regression attempts to detect occlusions based on the pump’s administration rate Q(t) and pressure sensor readings P(t). The second algorithm continuously monitored whether the actual variation in the pressure exceeded a threshold of 2 standard deviations (SD) above the baseline pressure. When a pump detected an occlusion using the SD algorithm, a third algorithm correlated the pressures of multiple pumps to detect the presence of a shared occlusion. The algorithms were evaluated using 6 bench-tested baseline single-pump occlusion scenarios, 9 single-pump validation scenarios and 7 multi-pump co-occlusion scenarios (i.e. with flow rates of 1 + 1, 1 + 2, 1 + 4, 1 + 8, 1 + 16, and 1 + 32 ml/h respectively). Alarm delay was the primary performance measure. Results In the baseline single-pump occlusion scenarios, the overall mean ± SD alarm delay of the regression and SD algorithms were 1.8 ± 0.8 min and 0.4 ± 0.2 min, respectively. Compared to the delay of the conventional alarm this corresponds to a mean time reduction of 76% (P = 0.003) and 95% (P = 0.001), respectively. In the validation scenarios the overall mean ± SD alarm delay of the regression and SD algorithms were respectively 1.8 ± 1.6 min and 0.3 ± 0.2 min, corresponding to a mean time reduction of 77% and 95%. In the multi-pump scenarios a correlation > 0.8 between multiple pump pressures after initial occlusion detection by the SD algorithm had a mean ± SD alarm delay of 0.4 ± 0.2 min. In 2 out of the 9 validation scenarios an occlusion was not detected by the regression algorithm before a conventional occlusion alarm occurred. Otherwise no occlusions were missed. Conclusions In single pumps, both the regression and SD algorithm considerably reduced alarm delay compared to conventional pressure limit-based detection. The SD algorithm appeared to be more robust than the regression algorithm. For multiple pumps the correlation algorithm reliably detected co-occlusions. The latter may be used to localize the segment of tubing in which the occlusion occurs. Trial registration Not applicable.

Resumen: Objetivo: Determinar la equivalencia de la administración de ácido tranexámico (TXA) tópico, intravenoso o combinado en la reducción de la pérdida sanguínea tras la artroplastia de cadera primaria. Material y métodos: Estudio prospectivo de 285 artroplastias primarias de cadera divididas en 4 grupos. El grupo A recibió 2,5 g de TXA tópico, el grupo B no recibió TXA, el grupo C 1 g de TXA intravenoso y el grupo D la administración combinada. La variable principal fue la pérdida sanguínea aplicando la fórmula de Nadler y de hemoglobina total. Resultados: La pérdida sanguínea fue significativamente mayor en el grupo B (grupo A: 797,13 ml; grupo B: 1.308,24; grupo C: 986,30 y grupo D: 859,09 ml; p

Most oncolytic virotherapy has thus far employed viruses deficient in genes essential for replication in normal cells but not in cancer cells. Intra-tumoral injection of such viruses has resulted in clinically significant anti-tumor effects on the lesions in the vicinity of the injection sites but not on distant visceral metastases. To overcome this limitation, we have developed a receptor-retargeted oncolytic herpes simplex virus employing a single-chain antibody for targeting tumor-associated antigens (RR-oHSV) and its modified version with additional mutations conferring syncytium formation (RRsyn-oHSV). We previously showed that RRsyn-oHSV exhibits preserved antigen specificity and an ∼20-fold higher tumoricidal potency in vitro relative to RR-oHSV. Here, we investigated the in vivo anti-tumor effects of RRsyn-oHSV using human cancer xenografts in immunodeficient mice. With only a single intra-tumoral injection of RRsyn-oHSV at very low doses, all treated tumors regressed completely. Furthermore, intra-venous administration of RRsyn-oHSV resulted in robust anti-tumor effects even against large tumors. We found that these potent anti-tumor effects of RRsyn-oHSV may be associated with the formation of long-lasting tumor cell syncytia not containing non-cancerous cells that appear to trigger death of the syncytia. These results strongly suggest that cancer patients with distant metastases could be effectively treated with our RRsyn-oHSV., Graphical abstract, Exceptionally strong anti-tumor potency was achieved by intra-tumoral or intra-venous administration of receptor-retargeted syncytial oncolytic herpes simplex virus (RRsyn-oHSV). The robustness of RRsyn-oHSV was associated with the formation of long-lasting tumor cell syncytia not containing non-cancerous cells that otherwise trigger death of the syncytia before their sufficient expansion.

Background: The risk of anesthesia increases with age, so it is necessary to choose a safe and effective method. In this study, we compared the effectiveness of intranasal fentanyl with intravenous fentanyl in patients undergoing cataract surgery. Methods: This study was a triple-blind prospective randomized clinical trial (The patient, physician, and data analyzer were unaware of the patient grouping). The study was performed from April 2017 to March 2019 in Feyz Hospital, Isfahan, Iran. 90 patients over 18 years of age who were candidates for cataract surgery were included in the study and were divided in two groups receiving intravenous fentanyl (IVF) or intranasal fentanyl (INF). The dose of fentanyl in both groups was 1.5 μg/kg with a maximum of 100 μg. In the IVF group, 1 ml of normal saline was dripped into each nasal passage 10 minutes before surgery and intravenously fentanyl was injected 2 minutes before surgery. In the INF group, 1 ml of fentanyl was administered into each nostril 10 minutes before surgery and 2 ml of saline was administered intravenously two minutes before surgery. Results: In this study, there was no significant difference between the two groups in terms of mean heart rate (P=0.762), mean arterial blood oxygen saturation (P=0.262), mean systolic blood pressure (P=0.264), mean arterial blood pressure (0.462), satisfaction rate Patient (P=0.231), duration of surgery (P=0.612) and pain intensity (P=0.87). But in the intravenous fentanyl group (IVF), the level of sedation (P=0.002) and the level of surgeon satisfaction (P

General anesthesia increases the production of reactive oxygen species (ROS), which can exacerbate or increase oxidative stress and thus affect the prognosis of surgical procedures. Oxidative stress has been implicated in the development of cardiovascular, dermatologic, oncologic, and other diseases in dogs, as well as ischemia and reperfusion injury. Some anesthetics, such as halogenated anesthetics, have been shown to stimulate the production of ROS, while others, such as propofol, have antioxidant properties. However, the antioxidant effects of these anesthetics may not be sufficient to counteract oxidative damage at the doses used clinically. Nevertheless, the effects of anesthetics should be considered to minimize oxidative damage during anesthesia in dogs to improve the outcome of procedures requiring general anesthesia. This mini-review addresses the current knowledge on oxidative stress during inhalational and intravenous anesthesia in dogs. There is still a lack of information on the management of anesthesia in dogs with respect to oxidative stress. Further research, including comprehensive clinical studies is needed to better understand oxidative injury mechanisms and improve perioperative protocols during anesthesia in dogs.

Background Post-vaccination myopericarditis is reported after immunization with coronavirus disease 2019 (COVID-19) messenger RNA (mRNA) vaccines. The effect of inadvertent intravenous injection of this vaccine on the heart is unknown. Methods We compared the clinical manifestations, histopathological changes, tissue mRNA expression, and serum levels of cytokine/chemokine and troponin in Balb/c mice at different time points after intravenous (IV) or intramuscular (IM) vaccine injection with normal saline (NS) control. Results Although significant weight loss and higher serum cytokine/chemokine levels were found in IM group at 1–2 days post-injection (dpi), only IV group developed histopathological changes of myopericarditis as evidenced by cardiomyocyte degeneration, apoptosis, and necrosis with adjacent inflammatory cell infiltration and calcific deposits on visceral pericardium, although evidence of coronary artery or other cardiac pathologies was absent. Serum troponin level was significantly higher in IV group. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike antigen expression by immunostaining was occasionally found in infiltrating immune cells of the heart or injection site, in cardiomyocytes and intracardiac vascular endothelial cells, but not skeletal myocytes. The histological changes of myopericarditis after the first IV-priming dose persisted for 2 weeks and were markedly aggravated by a second IM- or IV-booster dose. Cardiac tissue mRNA expression of interleukin (IL)-1β, interferon (IFN)-β, IL-6, and tumor necrosis factor (TNF)-α increased significantly from 1 dpi to 2 dpi in the IV group but not the IM group, compatible with presence of myopericarditis in the IV group. Ballooning degeneration of hepatocytes was consistently found in the IV group. All other organs appeared normal. Conclusions This study provided in vivo evidence that inadvertent intravenous injection of COVID-19 mRNA vaccines may induce myopericarditis. Brief withdrawal of syringe plunger to exclude blood aspiration may be one possible way to reduce such risk.

The study evaluated the safety, tolerability, pharmacokinetics (PK) and anti‐drug antibody (ADA) of the recombinant human thymosin β4 (NL005) for single and multiple intravenous injections in healthy subjects. Seven cohorts, with 54 healthy subjects, were given a single intravenous dose of NL005 or placebo and were observed for 28 days. The cohorts received ascending doses of either 0.05, 0.25, 0.5, 2.0, 5.0, 12.5 or 25.0 μg/kg in the single‐dose trial. A total of 30 healthy subjects were randomly enrolled in the multiple‐dose trial, and 3 cohorts (0.5, 2.0 and 5.0 μg/kg) were administered once human thymosin β4 daily for 10 days and observed for 28 days. The adverse events were mild to moderate in intensity. There were no dose‐limiting toxicities or serious adverse events. The plasma concentration, maximum peak concentration (C max) and AUC of each dose group increased with the increase in the dose. The tendency of terminal clearance in each dose group was consistent, and there was no obvious accumulation after continuous administration. Thus, the drug can be concluded to be well tolerated and safe in healthy people and suitable for use in a clinical study for the treatment of acute myocardial infarction.

OBJECTIVE To evaluate changes in health-related quality of life (HRQoL) and disability in children with systemic juvenile idiopathic arthritis (JIA) or polyarticular JIA treated with tocilizumab. METHODS Secondary analyses of two double-blind, placebo-controlled trials of intravenous tocilizumab in children with active systemic JIA or polyarticular JIA were conducted. Patient-reported outcomes of disability (Childhood Health Assessment Questionnaire [C-HAQ]), HRQoL (Child Health Questionnaire Parent Form 50 [CHQ-P50], health concepts, physical summary score [CHQ-P50-PhS], psychosocial summary score [CHQ-P50-PsS]), pain, and well-being (100-mm visual analog scale [VAS]) were measured at weeks 0 and 12 for systemic JIA, weeks 16 and 40 for polyarticular JIA, and week 104 for both JIA subgroups. RESULTS The trial included 112 patients with systemic JIA and 188 patients with polyarticular JIA. In patients with polyarticular JIA, the mean ± SD C-HAQ score decreased from 1.39 ± 0.74 at baseline to 0.67 ± 0.65 at week 16 (P < 0.001). In patients with systemic JIA, the mean ± SD CHQ-P50-PhS improved more with tocilizumab therapy than with placebo at week 12 (7.3 ± 10.2 versus 2.4 ± 10.6) (P < 0.05). Almost all mean CHQ-P50 health concept scores, CHQ-P50-PsS, and CHQ-P50-PhS improved (P ≤ 0.002) by week 104 for patients with systemic JIA. Patients with polyarticular JIA and patients with systemic JIA showed significant reductions in disability (mean ± SD C-HAQ scores of -1.09 ± 0.71 and -1.17 ± 0.80, respectively), improvements in well-being (mean ± SD well-being VAS scores of -43.76 ± 26.61 and -51.53 ± 23.57, respectively), and decreases in pain (mean ± SD pain VAS scores of -41.56 ± 31.06 and -51.26 ± 26.79, respectively) (P < 0.001); in patients with polyarticular JIA and patients with systemic JIA who were treated with tocilizumab, 92.9% of polyarticular JIA patients and 96.8% of systemic JIA patients reported no more than minimal pain (a score of ≤35 mm on the VAS) at week 104. CONCLUSION Tocilizumab treatment was associated with significantly reduced disability and pain and improved HRQoL in patients with systemic JIA and polyarticular JIA.

Background Intravenous misplacement of a nephrostomy tube is a rare complication of percutaneous nephrolithotomy (PCNL) or percutaneous nephrostomy. The mechanism of misplacement of a nephrostomy tube into the vascular system is seldom investigated. One type of the possible mechanism is that the puncture needle penetrates a major intrarenal tributary of the renal vein and enters the collecting system. However, the guidewire is located outside the collecting system near the large branches of renal vein or perforates into the renal vein. The dilation is performed and causes a large torn injury. Subsequently, the nephrostomy tube is placed inside the vessel when radiological monitoring is not used. However, there is no imaging evidence and the scene of procedure is not demonstrated. This paper reports two cases of visualization of the renal vein filled with contrast agent during PCNL. The findings may be good evidence to support the step of renal vein injury in patients with intravenous nephrostomy tube misplacement. Case presentation We presented two cases with visualization of the renal vein filled with contrast agent during PCNL. In the process of injecting the contrast agent through the puncture needle, we could see the renal vein. Moreover, it was identified that the puncture needle tip was not on the optimal position. The position of puncture needle tip lay outside the collecting system, which was close to the calyceal infundibulum and branches of renal vein. Conclusions Visualization of the renal vein filled with contrast agent may be good evidence to verify the renal vein injury in patients with intravenous nephrostomy tube misplacement during PCNL or percutaneous nephrostomy. The suboptimal location of the puncture needle tip and visualization of the renal vein filled with contrast agent indicate the renal vein injury. One type of mechanism of intravenous nephrostomy tube misplacement is as following. Firstly, the guidewire stays outside the collecting system. Subsequently, dilatation directed by the guidewire results in the injury of the vein. Then, the nephrostomy tube migrates into the venous system due to prompt tube inserting and the direction of the sheath and/or the guidewire to the injured vein.