Do Ten Year Trends in Emergency Department Diagnoses of Rhabdomyolysis in Young Adult Males Parallel the Growth in Long Distance Ultra Running?

Ultra running, a sport that consists of races above the marathon marker of 26.2 miles, has rarely been studied in depth. Little peer-reviewed scientific information examines the morbidity or disease prevalence associated with long-distance ultrarunning. Furthermore, there is an increase in reports of rhabdomyolysis within the ultrarunning community, which may coincide with an increase in the demand for long-distance ultrarunning races. This study examined the rate of hospital or emergency room admissions with a diagnosis of rhabdomyolysis and assesses if the incidence of rhabdomyolysis events in young males parallels the growth of ultrarunning. We hypothesized that: • ED diagnoses of rhabdomyolysis in young adult males parallel the growth in ultrarunning. • There are geographic and seasonal variations in the population rate of ER, which correspond to locations and times where most training for ultrarunning events occurs. A regression test to trend the races & rhabdomyolysis frequencies/rates over time was conducted using patient data from NIS database and racing data from Ultrarunning.com. Our research has demonstrated a rise in the rates of rhabdomyolysis that mirror the rise of long-distance ultra running in young adult males

Clinical and epidemiological Studies in ANCA-associated vasculitis

Objectives:This thesis aims to provide an overview of the epidemiology of AAV in southern Sweden, to evaluate different classification criteria in AAV. In addition we study if infection is a risk factor for later development of AAV comparing patients with AAV with a matched population cohort and to examine the occurrence of severe infections as an outcome in AAV. Methods:All adult patients diagnosed with AAV between 1997 and 2019 in the study area of 14 municipalities in Southern Sweden were identified and classified according to EMA algorithm and to the recently published ACR/EULAR classification criteria. Changes in the incidence and prevalence of AAV were studied over 23 years. Using a non-AAV age, sex and place of residence matched population the association of prior infections and later development of AAV was analysed with a logistic regression model. Events of severe infections after AAV diagnosis were identified and studied, incidence rate of severe infections was calculated. Results:Stable incidence with 30 cases per million inhabitants and rising prevalence are observed under the study period. Incidences are rising with age. The prevalence of 469/million in 2015 is the highest ever reported. Classification with the new ACR/EULAR criteria shows good agreement with earlier criteria (96% EGPA, 85% GPA, 75% MPA) but even with a classification based on ANCA serology alone (PR3 99%, MPO 84%). Infection, especially in the respiratory tract, is associated with later development of AAV. A history of prior infections is more likely in MPO-positive cases. In patients with AAV, severe infection occurs in 40% of cases after the onset of AAV. The incidence rate of severe infection is 9.1 per 100 person-years of follow-up but significantly higher during the first year with 22.1 per 100 person-years. High age and high diesaese activity independently predict the occurrence of severe infection. Conclusion:The incidence of AAV is stable in our area. The prevalence has increased substantially during the last decades, which can be attributed to better treatment and management and therefore increased survival. An ANCA based classification of AAV produces similar results as the new ACR/EULAR classification criteria. MPO-positive AAV is associated with prior infection. Severe infections are common problem in AAV especially in the first year, they are among the leading causes of death in vasculitis patients

Morbilidade evitável relacionada com medicamentos: Desenvolvimento de novos indicadores e validação preliminar para cuidados primários em Portugal

Sumário: A morbilidade evitável relacionada com medicamentos (MERM) é um problema de saúde pública com considerável impacto negativo para os doentes e os sistemas de saúde. Os indicadores de MERM constituem medidas operacionais de gestão do risco terapêutico, uma vez que permitem identificar processos de cuidados de saúde que predizem um resultado clínico negativo potencialmente evitável. O uso destes indicadores pode contribuir para reduzir a morbilidade evitável relacionada com medicamentos, evitando danos desnecessários e desperdício de recursos. Objectivo: Desenvolver novos indicadores de MERM para cuidados primários em Portugal a partir da análise de resumos das características de medicamentos (RCM's) e determinar a validade preliminar de face e de conteúdo dos indicadores derivados para este setting. Métodos: A primeira fase deste estudo consistiu num ensaio piloto, com o intuito de testar uma metodologia de inclusão dos RCM's com base na frequência de dispensa da especialidade farmacêutica no ambulatório. Seguidamente procedeu-se ao desenvolvimento de mais indicadores de MERM utilizando a metodologia testada no ensaio piloto. Os indicadores obtidos foram alvo de uma primeira análise com base em aspectos como duplicações e relevância para cuidados primários, de modo a seleccionar os que poderiam passar à fase de validade preliminar de face e de conteúdo. Procedeu­ se então à pesquisa de evidência clínica em fontes de referência para estes indicadores. Na última fase do estudo estes indicadores, bem como a respectiva evidência clínica, foram analisados por um painel de peritos constituído por quatro académicos (dois médicos de família e dois farmacêuticos), sendo aprovados ou eliminados com base num critério de consenso. Resultados: Obteve-se um total de 64 indicadores de MERM, a partir da análise de 35 RCM's. Sujeitaram-se à determinação da validade preliminar de face e de conteúdo 44 indicadores. Foram aprovados por consenso 28 indicadores, tendo sido excluídos 17 (4 por consenso e 13 sem obtenção de consenso). Conclusão: É exequível derivar novos indicadores de MERM para cuidados primários a partir da análise de RCM's. A validade formal de face e de conteúdo destes indicadores obtidos será objecto de estudo de ulterior investigação. /ABSTRACT: Backgroud: Preventable drug-relate morbidity (PDRM) is a public health problem with significant negative impact at a patient and system level. PDRM indicators are operational measures of therapeutic risk management; they identifying processes of care leading to preventable adverse outcomes. The use of these indicators may contribute to tackle preventable drug related morbidity, avoiding unnecessary harm and waste of resources. Objective: To develop new PDRM indicators to Portuguese primary care based on the analysis of summaries of product characteristics (SPC’s) and to determine their preliminary face and content validity to this setting. Methods: Firstly a pilot study was conducted to test a methodology for including SPC's based on the most frequently sold medicines in the ambulatory. Then more indicators were developed using the previously tested methodology. The indicators obtained were analyzed in respect to aspects such as duplications and relevance for primary care to select those that could proceed to the next stage. Clinical evidence was searched for each of these indicators in gold-standard information sources. Finally, this set of indicators and the respective clinical evidence were analysised by a panel of four experts (two academic general practitioners and two academic pharmacists). Preliminary face and content validity was established by means of consensus. Results: A total of 64 indicators was obtained, based on the analysis of 35 SPCs. Forty­ four indicators were subjected to a preliminary assessment of face and content validity, resulting in 28 consensus-approved indicators. Seventeen indicators were excluded (4 rejected by consensus and 13 that did not reach consensus). Conclusion: lt is feasible to derive new PDRM indicators for primary care based on SPC's. The formal face and content validity of the indicators will be determined in a further study

Role of the Transient Receptor Potential Canonical 6 ion channel in genetic and acquired forms of proteinuric kidney disease

Podocyte foot processes and the interposed glomerular slit diaphragm are critical components of the permeability barrier in the kidney. Mutations in several podocyte genes have been identified as the cause for progressive kidney failure and focal segmental glomerulosclerosis (FSGS). Podocyte injury is a hallmark of glomerular disease and usually involves the rearrangement of the podocyte actin cytoskeleton. Cell-specific therapies targeting podocyte injury are currently not available. In 2004, a mutation in the TRPC6 ion channel was found to cosegregate with hereditary FSGS. Based on this finding it was hypothesized that TRPC6 is expressed in podocytes, and that TRPC6-mediated Ca2+ signaling contributes to the regulation of the podocyte actin cytoskeleton. According to this model, dysfunction of TRPC6 leads to a disruption of normal cytoskeletal organization, podocyte injury, and proteinuric disease. To test this hypothesis, four specific aims were outlined. First, to explore TRPC6 mutations in genetic FSGS. Second, to investigate its association with the glomerular filtration barrier. Third, to study TRPC6 expression in acquired forms of proteinuric kidney disease. Fourth, to investigate the molecular basis of TRPC6 contribution to the pathophysiology of proteinuric kidney disease In genetic forms of FSGS, additional TRPC6 mutations were identified in five families with a history of FSGS. TRPC6-related FSGS presented as a late-onset disorder in individuals aged 17-57, and was not restricted to certain ethnic groups. All mutations occured in evolutionary conserved sites, and encoded amino acid substitutions at the amino- and carboxy-terminal ends of TRPC6. Two mutants, R895C and E897K, displayed increased current amplitudes, suggesting a pathogenic role of increased channel activity in TRPC6-related FSGS. In an effort to understand the molecular basis for TRPC6 in the kidney, the association of TRPC6 with the glomerular filter was studied. TRPC6 was found to be expressed in podocytes near the glomerular slit diaphragm. TRPC6 colocalized and associated with the slit diaphragm proteins nephrin and podocin. The presence of TRPC6 in podocyte foot processes and its association with slit diaphragm proteins supports a role of TRPC6 in the regulation of glomerular filtration. Since most proteinuric kidney diseases appear not as genetic but acquired disorders, TRPC6 was studied in humans with acquired glomerular diseases and in experimental models thereof. TRPC6 expression was induced in patients with minimal change disease and membranous glomerulopathy, as well as in passive Heymann nephritis (PHN) rats and puromycin aminonucleoside (PAN) rats. PAN-mediated podocyte injury correlated with increased receptor-operated calcium entry in vitro. TRPC6 gene delivery in mice was sufficient to induce proteinuria, and studies in cultured podocytes suggest that TRPC6 overexpression disrupts the actin cytoskeleton. The present data suggest that in both genetic and acquired forms of proteinuric kidney disease, misregulation of TRPC6 – either by presence of mutated hyperactive channels, or by precence of too many wildtype channels – plays a pathogenic role. Together, the results of this work may have broad implications for the pathophysiology of TRPC6-related human kidney diseases, and promote the development of anti-proteinuric drugs interfering with TRPC6 channel function

Improved treatment options for the control of soil-transmitted helminthiasis: From repurposed drugs to reinfection patterns

Background: Soil-transmitted helminths (STHs) are a group of intestinal dwelling parasitic nematode worms that disproportionally affect socio-economically deprived populations in warm and tropical environments living with inadequate sanitation, poor hygiene and unsatisfactory educational coverage. Intestinal helminths are transmitted through contamination of soil with human feces and by subsequent accidental ingestion of soil with parasite eggs (Ascaris lumbricoides, Trichuris trichiura and occasionally Ancylostoma duodenale) or by penetration of the worm larvae (hookworm) into the skin and body of the human host. Soil-transmitted helminths are responsible for the largest burden of neglected tropical diseases, with about 1.5 billion infected people worldwide. Although most infections are asymptomatic and of light intensity, heavier intensity infections can cause severe morbidity. Chronic high-intensity manifestations caused by STH infections can lead to physical and intellectual growth retardation, perpetuating a vicious cycle of poor health and poverty. The World Health Organization (WHO) has advocated targeted preventive chemotherapy (PC), the periodic mass drug administration (MDA) of single dose benzimidazoles (i.e., albendazole and mebendazole) to at-risk population groups, without prior diagnosis. The main goal of this strategy is to reduce morbidity by decreasing infection intensities and to ultimately eliminate STH infections as a public health problem. This is defined as the decrease of prevalence of moderate and heavy infection intensities to below 2% as assessed in preschool- and school-aged children by 2030. However, several factors might jeopardize the success of PC, including the low efficacy of the currently used benzimidazoles, its inability to prevent reinfections and the potential emergence of anthelmintic resistance due to mounting drug pressure. On Pemba Island, Tanzania, STH infections were recognized as a major public health problem in the early 1990s. Since then, PC has been widely implemented (coverage rate >80%), but STH prevalence remains high to date. Hence, development of new and safe broad-spectrum drugs, repurposing of available drugs or the use of drug combinations to expand the armamentarium of treatment options is of paramount importance to help control and eliminate STH infections. Goal and specific objectives: The first objective of my PhD was to test the efficacy and safety of ascending doses of moxidectin alone or combined with albendazole (400 mg) against trichuriasis. The second objective was to evaluate the short-term and long-term outcomes 14-21 days, six and 12 months post-treatment of ivermectin-albendazole and albendazole alone in an expanded study population (6-60 years) aiming to inform and update STH control guidelines and programs. The third objective was to compare the performance of the microscopic Kato-Katz method to the molecular polymerase chain reaction (qPCR) and its impact on drug efficacy and day-to-day variation. The fourth objective was to test fecal calprotectin (FC) and fecal occult blood (FOB) as potential surrogate markers for STH attributable morbidity. Insights gained from the ivermectin-albendazole trial on trial methodology, trial procedures and mitigation strategies to overcome challenges faced during clinical research taking place in resource-limited environments is presented as fifth objective. Methods: This PhD work consisted of two clinical trials. The first was a phase II, randomized, placebo-controlled, dose-finding study on moxidectin in adolescents aged between 16 and 18 years on Pemba Island in 2018. Screened individuals were asked to provide two stool samples at baseline to assess STH ova by the Kato-Katz method. Eligible adolescents were physically examined and questioned for clinical symptoms by a trial physician prior to treatment administration. Trichuris trichiura-infected adolescents were randomly assigned to seven treatment arms: 8, 16, or 24 mg of moxidectin monotherapy; 8, 16, or 24 mg of moxidectin plus 400 mg of albendazole combination therapy; or placebo. The primary outcome was cure rate (CR) against T. trichiura, analyzed 13 to 20 days post-treatment. Adverse events were assessed 3h, 24h, 48h, 72h and 13-20 days after treatment, graded on severity, relatedness and expectedness as specified in the trial protocol. The second study was a Phase III, multi-country, randomized, standard of care-controlled, blinded, parallel group, single dose, superiority trial on ivermectin-albendazole in Côte d’Ivoire, Lao People’s Democratic Republic (Lao PDR) and on Pemba Island, Tanzania between 2018 and 2020. The study was conducted in communities aged 6-60 years. Screened individuals provided two stool samples at baseline, 14-21 days, six and 12 months post-treatment. Similar to the first study, the Kato-Katz method was employed for STH diagnosis and, in addition, an aliquot of stool (~1 g) was mixed with 80% ethanol and preserved at 4°C and later shipped at room temperature to Swiss Tropical and Public Health Institute in Basel, Switzerland for subsequent qPCR analyses. Furthermore, fecal rapid tests (FC and FOB), were used as potential proxy markers for STH attributable morbidity. Hence, a semi-quantitative chromatographic immunoassay (Actim® Fecal Calprotectin test/Actim® Fecal Blood test, Medix Biochemica, Finland) was applied for FC and FOB detection from participants diagnosed positive for T. trichiura and concomitant STH infections and identified STH negative participants as controls. Before treatment administration, all participants underwent a physical examination and a rapid diagnostic test for hemoglobin levels, pregnancy in all female participants (≥12 years), malaria (Côte d’Ivoire and Lao PDR) and lymphatic filariasis (Côte d’Ivoire and on Pemba Island, Tanzania) was applied. Drug efficacies (in terms of egg reduction rates (ERRs) and CRs), reinfections and new infections were assessed 14-21 days, six and 12 months post-treatment. Adverse events were captured 3h, 24h and 14-21 days after treatment, graded on severity, relatedness and expectedness as specified in the trial protocol. Results: We found that 8 mg of moxidectin (the lowest tested dose) performed as well as 16 mg and 24 mg, and that the combination of moxidectin and albendazole was significantly more efficacious against T. trichiura than albendazole alone. Likewise, we revealed superiority of the ivermectin-albendazole combination therapy compared to albendazole alone against T. trichiura infections in Lao PDR and on Pemba Island. Similarly, the ivermectin-albendazole combination therapy led to a larger reduction of moderate and heavy T. trichiura infections and successfully reduced the prevalence of these infections to below 1.5% within 12 months. However, ivermectin-albendazole was not found to be superior to albendazole alone in Côte d’Ivoire. Moreover, we observed a higher sensitivity of qPCR compared to quadruple Kato-Katz, revealing significantly lower CRs for ivermectin-albendazole, when two qPCR samples were assessed pre- and post-treatment. In addition, we did not find an association between the presence of intestinal inflammation or mucosal bleeding, assessed with FC and FOB as respective proxy markers, and STH infection status or infection intensity. Conclusion: Promising efficacies and safety for moxidectin-albendazole and ivermectin-albendazole against T. trichiura were found. Hence, both drug combinations might be valuable alternatives in PC programs. The combination of 8 mg moxidectin and 400 mg albendazole should be further investigated in younger age groups, with longer follow-up periods and in different settings to help guiding recommendations for future STH control. Prior to MDA implementation with ivermectin-albendazole, careful decisions on the frequency of deworming adapted to the epidemiological parasite profile in each setting have to be made, while variations in treatment responses should be considered. In addition to that, standardized and accurate molecular diagnostic tools, which are applicable in peripheral field settings for the assessment of drug efficacy and for future monitoring within STH control and/or elimination programs, should be developed. Further studies are needed to identify suitable, standardized, low-cost proxy markers of STH attributable morbidity to monitor the clinical impact of STH control interventions. A strategic plan adapted to each setting with a distinct focus on community engagement and workforce is crucial for successful preparation, screening and implementation of randomized controlled trials. Gained knowledge on improvements of trial methodology, trial procedures and mitigation strategies to overcome challenges faced during clinical research in resource-constrained healthcare environments are valuable information that should be made available to the related research network. Moreover, potential drug donors and preferably local anthelmintic drug production facilities will need to be identified to meet the demand for STH control programs

HUMAN VISCERAL AFFERENT RECORDINGS: A PRE-CLINICAL HUMAN MODEL OF VISCERAL PAIN.

PhDAim: We have recently developed electrophysiological recordings of human visceral afferent (HVA) activity in isolated gastrointestinal tissues. The aim of the this study was 1) test the mechano- and chemosensitivity of HVAs, 2) characterise subpopulations of HVAs based on their response to mechanical stimuli, 3) test the effect of drugs that have/are in clinical trials on the mechanosensitivity (von Frey hair (VFH) probing and appendix distension) of HVAs. Methods: All experiments were performed in accordance with UK human ethics regulations [NREC09/H0704/2]. Surgically resected human ileum, colon, and appendix were obtained from consenting patients undergoing bowel resection. Tissues were pinned in a tissue bath, or cannulated (appendix), and superfused with carbongenated Krebs buffer, at 6ml/min, 32-34°C. Mesenteric nerve bundles were carefully dissected and afferent activity was recorded using suction electrodes. Tissues were tested for mechanosensitivity (VFHs, stretching, mucosal stroking, distension) and chemosensitivity (bradykinin (BK), ATP (adenosine trisphosphate), PGE2 (prostaglandin E2), serotonin (aka 5-hydroxytryptamine (5-HT)), histamine, adenosine). The receptors involved in the activation of HVAs by BK, or ATP were also investigated. The response of HVAs to VFH probing or distension was tested before and after the application of tegaserod, STa endotoxin, or a transient receptor potential vanilloid 4 (TRPV4) agonist (GSK1016790A) or antagonist (HC067047). Results and Conclusion: HVAs were characterised as mesenteric, serosal, muscular, or muscular-mucosal. HVAs were chemosensitive to all mediators. Bradykinin B2 receptors are the most important receptors involved in the activation of HVAs by BK. P2Y receptors may play an important role in the activation of HVAs by ATP. Application of tegaserod, HC067047 or STa endotoxin reduced the HVA response to mechanical stimuli. HVA recordings are feasible and practical and are suitable for both basic scientific mechanistic studies, and could potentially be used as a pre-clinical model, in conjunction with animal experiments, to help predict the efficacy of novel compounds before clinical trials