Discovering Novel Hearing Loss Genes: Roles For Esrp1 And Gas2 In Inner Ear Development And Auditory Function

Hearing loss is the most common form of congenital birth defect, affecting an estimated 35 million children worldwide. To date, nearly 100 genes have been identified which contribute to a deafness phenotype in humans, however, many cases remain in which a causative mutation has yet to be found. In addition, the exact mechanism by which hearing loss occurs in the presence of many of these mutations is still not understood. This is due, in part, to the complex nature of the development and function of the cochlear duct, the organ of hearing. The cochlea undergoes an intricate morphogenetic development and requires the proper specification and maintenance of dozens of different cell types in order to function correctly. In the mature duct, an interplay between mechanotransducing sensory hair cells, supporting pillar and Dieters\u27 cells, and generation of electrochemical potential by the stria vascularis are necessary to respond to sound stimuli. We utilized exome and RNA-sequencing experiments combined with mouse genetics in order to discover novel genes that play roles in cochlear development and function. Exome sequencing of families with profound hearing loss uncovered mutations in Epithelial Splicing Regulatory Protein 1 (ESRP1), a critical regulator of alternative mRNA splicing. Analysis of Esrp1 mutant mice revealed a shortened cochlear duct, delay in hair cell differentiation and maturation, and loss of the stria vascularis due to inappropriate Fgf ligand usage, stemming from an alternatively spliced receptor, in these cells. To identify additional regulators of inner ear development we performed an RNA-seq experiment comparing the gene expression profiles of control and Smoecko otic vesicles, which lack a cochlear duct. This generated a dataset of hundreds of cochlear enriched transcripts including Growth Arrest Specific 2 (Gas2) a cytoskeletal binding protein with the potential to act as a regulator of cochlear development. We generated a Gas2 null mouse line and discovered that these animals have severe hearing impairment likely due to defects in microtubule organization in the pillar cells. Taken together, these studies implicate Esrp1 and Gas2 as novel hearing loss genes that regulate aspects of cochlear development and function

Ordering CT pulmonary angiography to exclude pulmonary embolism: defense versus evidence in the emergency room

Purpose: To identify reasons for ordering computed tomography pulmonary angiography (CTPA), to identify the frequency of reasons for CTPA reflecting defensive behavior and evidence-based behavior, and to identify the impact of defensive medicine and of training about diagnosing pulmonary embolism (PE) on positive results of CTPA. Methods: Physicians in the emergency department of a tertiary care hospital completed a questionnaire before CTPA after being trained about diagnosing PE and completing questionnaires. Results: Nine hundred patients received a CTPA during 3years. For 328 CTPAs performed during the 1-year study period, 140 (43%) questionnaires were completed. The most frequent reasons for ordering a CTPA were to confirm/rule out PE (93%), elevated D-dimers (66%), fear of missing PE (55%), and Wells/simplified revised Geneva score (53%). A positive answer for "fear of missing PE” was inversely associated with positive CTPA (OR 0.36, 95% CI 0.14-0.92, p=0.033), and "Wells/simplified revised Geneva score” was associated with positive CTPA (OR 3.28, 95% CI 1.24-8.68, p=0.017). The proportion of positive CTPA was higher if a questionnaire was completed, compared to the 2-year comparison period (26.4 vs. 14.5%, OR 2.12, 95% CI 1.36-3.29, p<0.001). The proportion of positive CTPA was non-significantly higher during the study period than during the comparison period (19.2 vs. 14.5%, OR 1.40, 95% CI 0.98-2.0, p=0.067). Conclusion: Reasons for CTPA reflecting defensive behavior—such as "fear of missing PE”—were frequent, and were associated with a decreased odds of positive CTPA. Defensive behavior might be modifiable by training in using guideline

Erratum to “The Challenge of Triaging Chest Pain Patients: The Bernese University Hospital Experience”

Accurate diagnosis of the causes of chest pain and dyspnea remain challenging. In this preliminary observational study with a 5-year follow-up, we attempted to find a simplified approach to selecting patients with chest pain needing immediate care based on the initial evaluation in ED. During a 24-month period were randomly selected 301 patients and a conditional inference tree (CIT) was used as the basis of the prognostic rule. Common diagnoses were musculoskeletal chest pain (27%), ACS (19%) and panic attack (12%). Using variables of ACS symptoms we estimated the likelihood of ACS based on a CIT to be high at 91% (32), low at 4% (198) and intermediate at 20.5–40% in (71) patients. Coronary catheterization was performed within 24 hours in 91% of the patients with ACS. A culprit lesion was found in 79%. Follow-up (median 4.2 years) information was available for 70% of the patients. Of the 164 patients without ACS who were followed up, 5 were treated with revascularization for stable angina pectoris, 2 were treated with revascularization for myocardial infarction, and 25 died. Although a simple triage decision tree could theoretically help to efficient select patients needing immediate care we need also to be vigilant for those presenting with atypical symptoms

Extrapulmonary tuberculosis in HIV-infected patients in rural Tanzania: the prospective Kilombero and Ulanga antiretroviral cohort

In sub-Saharan Africa, diagnosis and management of extrapulmonary tuberculosis (EPTB) in people living with HIV (PLHIV) remains a major challenge. This study aimed to characterize the epidemiology and risk factors for poor outcome of extrapulmonary tuberculosis in people living with HIV (PLHIV) in a rural setting in Tanzania.; We included PLHIV >18 years of age enrolled into the Kilombero and Ulanga antiretroviral cohort (KIULARCO) from 2013 to 2017. We assessed the diagnosis of tuberculosis by integrating prospectively collected clinical and microbiological data. We calculated prevalence- and incidence rates and used Cox regression analysis to evaluate the association of risk factors in extrapulmonary tuberculosis (EPTB) with a combined endpoint of lost to follow-up (LTFU) and death.; We included 3,129 subjects (64.5% female) with a median age of 38 years (interquartile range [IQR] 31-46) and a median CD4+ cell count of 229/μl (IQR 94-421) at baseline. During the median follow-up of 1.25 years (IQR 0.46-2.85), 574 (18.4%) subjects were diagnosed with tuberculosis, whereof 175 (30.5%) had an extrapulmonary manifestation. Microbiological evidence by Acid-Fast-Bacillus stain (AFB-stain) or Xpert® MTB/RIF was present in 178/483 (36.9%) patients with pulmonary and in 28/175 (16.0%) of patients with extrapulmonary manifestations, respectively. Incidence density rates for pulmonary Tuberculosis (PTB and EPTB were 17.9/1000person-years (py) (95% CI 14.2-22.6) and 5.8/1000 py (95% CI 4.0-8.5), respectively. The combined endpoint of death and LTFU was observed in 1058 (33.8%) patients, most frequently in the subgroup of EPTB (47.2%). Patients with EPTB had a higher rate of the composite outcome of death/LTFU after TB diagnosis than with PTB [HR 1.63, (1.14-2.31); p = 0.006]. The adjusted hazard ratios [HR (95% CI)] for death/LTFU in EPTB patients were significantly increased for patients aged >45 years [HR 1.95, (1.15-3.3); p = 0.013], whereas ART use was protective [HR 0.15, (0.08-0.27); p <0.001].; Extrapulmonary tuberculosis was a frequent manifestation in this cohort of PLHIV. The diagnosis of EPTB in the absence of histopathology and mycobacterial culture remains challenging even with availability of Xpert® MTB/RIF. Patients with EPTB had increased rates of mortality and LTFU despite early recognition of the disease after enrollment

Inflammatory myopathy and severe rhabdomyolysis induced by leuprolide acetate therapy for prostate cancer: a case report

<p>Abstract</p> <p>Introduction</p> <p>Leuprolide acetate is a synthetic analog of gonadotropin-releasing hormone used for the treatment of prostate cancer. Its side effects are hot flashes, nausea, and fatigue. We report a case of a patient with proximal inflammatory myopathy accompanied by severe rhabdomyolysis and renal failure following the second application of leuprolide acetate. Drug withdrawal and steroid therapy resulted in remission within six weeks of the diagnosis. To the best of our knowledge, our case report describes the second case of leuprolide acetate-induced inflammatory myopathy and the first case of severe leuprolide acetate-induced rhabdomyolysis and renal failure in the literature.</p> <p>Case presentation</p> <p>A 64-year-old Swiss Caucasian man was admitted to the hospital because of progressive proximal muscle weakness, dyspnea, and oliguria. He had been treated twice with leuprolide acetate in monthly doses. We performed a muscle biopsy, which excluded other causes of myopathy. The patient's renal failure and rhabdomyolysis were treated with rehydration and steroid therapy.</p> <p>Conclusion</p> <p>The aim of our case report is to highlight the rare but severe side effects associated with leuprolide acetate therapy used to treat patients with inflammatory myopathy: severe rhabdomyolysis and renal failure.</p

Ultrasound in managing extrapulmonary tuberculosis: a randomized controlled two-center study

Patients with clinically suspected tuberculosis are often treated empirically, as diagnosis - especially of extrapulmonary tuberculosis - remains challenging. This leads to an overtreatment of tuberculosis and to underdiagnosis of possible differential diagnoses.; This open-label, parallel-group, superiority randomized controlled trial is done in a rural and an urban center in Tanzania. HIV-positive and -negative adults (≥18 years) with clinically suspected extrapulmonary tuberculosis are randomized in a 1:1 ratio to an intervention- or control group, stratified by center and HIV status. The intervention consists of a management algorithm including extended focused assessment of sonography for HIV and tuberculosis (eFASH) in combination with chest X-ray and microbiological tests. Treatment with anti-tuberculosis drugs is started, if eFASH is positive, chest X-ray suggests tuberculosis, or a microbiological result is positive for tuberculosis. Patients in the control group are managed according national guidelines. Treatment is started if microbiology is positive or empirically according to the treating physician. The primary outcome is the proportion of correctly managed patients at 6 months (i.e patients who were treated with anti-tuberculosis treatment and had definite or probable tuberculosis, and patients who were not treated with anti-tuberculosis treatment and did not have tuberculosis). Secondary outcomes are the proportion of symptom-free patients at two and 6 months, and time to death. The sample size is 650 patients.; This study will determine, whether ultrasound in combination with other tests can increase the proportion of correctly managed patients with clinically suspected extrapulmonary tuberculosis, thus reducing overtreatment with anti-tuberculosis drugs.; PACTR, Registration number: PACTR201712002829221, registered December 1st 2017

Diagnoses made in an emergency department in rural sub-Saharan Africa

Information on diagnoses made in emergency departments situated in rural sub-Saharan Africa is scarce. The aim was: to evaluate the frequency of different diagnoses made in a new emergency department to define relevant healthcare requirements; and to find out if in-hospital mortality rates would decrease after the implementation of the emergency department.; In this observational study, we prospectively collated diagnoses of all patients presenting to the emergency department of the St Francis Referral Hospital in Ifakara, Tanzania during 1 year. In addition, we compared in-hospital mortality rates before and after the implementation of the emergency department.; From July 2016 through to June 2017, a total of 35,903 patients were included. The median age was 33.6 years (range 1 day to 100 years), 57% were female, 25% were children &lt;5 years, 4% were pregnant and 9% were hospitalised. The most common diagnoses were respiratory tract infection (12.6%), urinary tract infection (11.4%), trauma (9.8%), undifferentiated febrile illness (5.4%), and malaria (5.2%). The most common clinical diagnoses per age group were: lower respiratory tract infection (16.1%) in children &lt;5 years old; trauma (21.6%) in 5- to 17-year-olds; urinary tract infection (13.5%) in 18- to 50-year-olds; and hypertensive emergency (12.4%) in &gt;50-year-olds. Respiratory tract infections peaked in April during the rainy season, whereas malaria peaked 3 months after the rainy season. In-hospital mortality rates did not decrease during the study period (5.6% in 2015 vs 7.6% in 2017).; The majority of diagnosed disorders were of infectious or traumatic origin. The majority of febrile illnesses were poorly defined because of the lack of diagnostic methods. Trauma systems and inexpensive accurate diagnostic methods for febrile illnesses are needed in rural sub-Saharan Africa

Sonography to rule out tuberculosis in sub-Saharan Africa: a prospective observational study

Patients with suspected tuberculosis are often overtreated with antituberculosis drugs. We evaluated the diagnostic value of the focused assessment with sonography for HIV-associated tuberculosis (FASH) in rural Tanzania.; In a prospective cohort study, the frequency of FASH signs was compared between patients with confirmed tuberculosis and those without tuberculosis. Clinical and laboratory examination, chest x-ray, Xpert MTB/RIF assay, and culture from sputum, sterile body fluids, lymph node aspirates, and Xpert MTB/RIF urine assay was done.; Of 191 analyzed patients with a 6-month follow-up, 52.4% tested positive for human immunodeficiency virus, 21.5% had clinically suspected pulmonary tuberculosis, 3.7% had extrapulmonary tuberculosis, and 74.9% had extrapulmonary and pulmonary tuberculosis. Tuberculosis was microbiologically confirmed in 57.6%, probable in 13.1%, and excluded in 29.3%. Ten of eleven patients with splenic or hepatic hypoechogenic lesions had confirmed tuberculosis. In a univariate model, abdominal lymphadenopathy was significantly associated with confirmed tuberculosis. Pleural- and pericardial effusion, ascites, and thickened ileum wall lacked significant association. In a multiple regression model, abnormal chest x-ray (odds ratio [OR] = 6.19; 95% confidence interval [CI], 1.96-19.6;; P; &lt; .002), ≥1 FASH-sign (OR = 3.33; 95% CI, 1.21-9.12;; P; = .019), and body temperature (OR = 2.48; 95% CI, 1.52-5.03;; P; = .001 per °C increase) remained associated with tuberculosis. A combination of ≥1 FASH sign, abnormal chest x-ray, and temperature ≥37.5°C had 99.1% sensitivity (95% CI, 94.9-99.9), 35.2% specificity (95% CI, 22.7-49.4), and a positive and negative predictive value of 75.2% (95% CI, 71.3-78.7) and 95.0% (95% CI, 72.3-99.3).; The absence of FASH signs combined with a normal chest x-ray and body temperature <37.5°C might exclude tuberculosis

Point-of-care ultrasound: a useful diagnostic tool in Africa

In resource limited settings with limited tests and diagnostic tools, most of diagnoses are based on clinical findings, and patients are managed empirically, e.g. with anti-tuberculosis drugs. This article aims at describing the use of point-of-care ultrasound in diagnosing the most important conditions in Africa, in addition to clinical work-up. Different protocols exist for the diagnosis of trauma-related disorders, tuberculosis, schistosomiasis, thromboembolism, causes of dyspnea, and non- traumatic shock. Point-of-care ultrasound might be a beneficial tool in Africa, aiding diagnostics and management of patients with these conditions. However, studies must be done to assess the impact of point-of-care ultrasound on mortality

Herzinsuffizienz in Afrika?

Heart Failure in Africa; Abstract.; In Africa, mortality due to heart failure is twice as high as in other low- to middle-income countries and five times as high as in high-income countries. Arterial hypertension is by far the most common cause of heart failure, followed by cardiomyopathies and rheumatic heart diseases. At diagnosis, most patients suffer already from an advanced disease stage. Only a few patients are aware of arterial hypertension, and few are treated and have their hypertension well controlled. Only a minority of patients have a well-controlled hypertension. The neglect of chronic non-communicable diseases on the health agenda leads to poor awareness, poor diagnostic resources, preventions strategies and treatment options. International guidelines cannot be properly followed in these circumstances. Information at community level and in healthcare facilities is urgently needed as well as training of healthcare staff, implementation of improved diagnostics and treatment of arterial hypertension and heart failure