Functional and structural neuroretinal disorders in HIV Controllers. Prospective cohort study.

OBJECTIVE: To estimate the prevalence and cumulative incidence of neuro-retinal-disorders (NRD) in HIV-controllers. DESIGN: Prospective, single-centre, cohort study of people living with HIV (PLWH): elite-controllers, long-term-non-progressors and early diagnosed. METHODS: The study compared "HIV-controllers" (including elite-controllers and long-term-non-progressors), who were not on antiretroviral therapy (ART), and "HIV-treatment" (HIV-infected subjects with a recent diagnosis and on ART). A matched cohort of "non-HIV subjects" was created. NRD was defined as at least one altered (not normal) ophthalmological parameter (functional or structural). Functional (visual acuity, contrast sensitivity, chromatic vision, visual field) and structural parameters (ganglion cells, macular nerve fibre layer, peripapillary nerve fibre layers, vascular calibre) as well as quality of life (Medical Outcomes Study-HIV Short Form-30) were assessed. RESULTS: Between March 2012 and November 2015, the study included all HIV-controllers (16 elite-controllers, 1 long-term-non-progressor), 11 HIV-treatment and 16 non-HIV. Prevalence of NRD at baseline was 88.2% (15/17, 95% CI: 65.7%-96.7%), 90.9% (10/11, 95% CI: 62.3%-98.4%) and 56.3% (9/16, 95% CI: 33.2%-76.9%), respectively. Cumulative incidence at 3 years was 50% (1/2), 100% (1/1) and 33.3% (2/6), respectively. None of the participants manifested ocular clinical symptoms. Three years later, prevalence of NRD was 92.3% (12/13, 95% CI: 66.7%-98.6%), 75% (6/8, 95% CI: 40.9%-92.9%) and 50.0% (7/14, 95% CI: 26.8%-73.2%), respectively. Contrast sensitivity and structural parameters were globally the most affected among PLWH. Quality of life (total score) [median (interquartile range)] at baseline and 3 years was 82 (71-89) and 74 (63.5-79.25) in HIV-controllers and 80 (73-88) and 88 (83-92) in HIV-treatment. CONCLUSIONS: HIV-controllers and those individuals on ART presented a higher percentage of NRD than non-HIV. Our results suggest that NRD could be a biomarker of ocular aging among PLWH.

A novel germline variant in RET gene resulting in an additional cysteine in a family with familial medullary thyroid carcinoma.

Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant inherited disease, characterized by germ-line variants in RET proto-oncogene. Variants are frequently located in the RET extracellular cysteine-rich region domain, mainly affecting cysteines which are replaced by an alternative amino acid, resulting in a mispaired cysteine and the generation of RET dimers. We describe a novel c.1765A > T variant of RET proto-oncogene in a family with medullary thyroid carcinoma (MTC) that predicts the creation of an additional cysteine p.(Ser589Cys) in the cysteine-rich domain. In this site only three other punctual variants have been described, giving rise to extra cysteines. We have characterized the clinical phenotype of this family. The index case was a 79-year-old woman with MTC in both thyroid lobes. This variant co-segregates in this family in four affected members. One member was operated on at 31 years of age and already presented MTC, indicating that prophylactic thyroidectomy was appropriated. Variants predicting additional cysteines are not frequent in RET, and when present, they allow us to understand their implication in the disease. According to clinical data obtained in this family, this variant could be categorized as a moderate-risk of the disease.

A Cluster-Randomized Trial of Hydroxychloroquine as Prevention of Covid-19 Transmission and Disease

BackgroundCurrent strategies for preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections are limited to non-pharmacological interventions. Hydroxychloroquine (HCQ) has been proposed as a postexposure therapy to prevent Coronavirus disease 2019 (Covid-19) but definitive evidence is lacking. MethodsWe conducted an open-label, cluster-randomized trial including asymptomatic contacts exposed to a PCR-positive Covid-19 case in Catalonia, Spain. Clusters were randomized to receive no specific therapy (control arm) or HCQ 800mg once, followed by 400mg daily for 6 days (intervention arm). The primary outcome was PCR-confirmed symptomatic Covid-19 within 14 days. The secondary outcome was SARS-CoV-2 infection, either symptomatically compatible or a PCR-positive result regardless of symptoms. Adverse events (AEs) were assessed up to 28 days. ResultsThe analysis included 2,314 healthy contacts of 672 Covid-19 index cases identified between Mar 17 and Apr 28, 2020. A total of 1,198 were randomly allocated to usual care and 1,116 to HCQ therapy. There was no significant difference in the primary outcome of PCR-confirmed, symptomatic Covid-19 disease (6.2% usual care vs. 5.7% HCQ; risk ratio 0.89 [95% confidence interval 0.54-1.46]), nor evidence of beneficial effects on prevention of SARS-CoV-2 transmission (17.8% usual care vs. 18.7% HCQ). The incidence of AEs was higher in the intervention arm than in the control arm (5.9% usual care vs 51.6% HCQ), but no treatment-related serious AEs were reported. ConclusionsPostexposure therapy with HCQ did not prevent SARS-CoV-2 disease and infection in healthy individuals exposed to a PCR-positive case. Our findings do not support HCQ as postexposure prophylaxis for Covid-19. ClinicalTrials.gov registration numberNCT04304053

Safety and Tolerability of Alveolar Type II Cell Transplantation in Idiopathic Pulmonary Fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with limited response to currently available therapies. Alveolar type II (ATII) cells act as progenitor cells in the adult lung, contributing to alveolar repair during pulmonary injury. However, in IPF, ATII cells die and are replaced by fibroblasts and myofibroblasts. In previous preclinical studies, we demonstrated that ATII-cell intratracheal transplantation was able to reduce pulmonary fibrosis. The main objective of this study was to investigate the safety and tolerability of ATII-cell intratracheal transplantation in patients with IPF. METHODS: We enrolled 16 patients with moderate and progressive IPF who underwent ATII-cell intratracheal transplantation through fiberoptic bronchoscopy. We evaluated the safety and tolerability of ATII-cell transplantation by assessing the emergent adverse side effects that appeared within 12 months. Moreover, pulmonary function, respiratory symptoms, and disease extent during 12 months of follow-up were evaluated. RESULTS: No significant adverse events were associated with the ATII-cell intratracheal transplantation. After 12 months of follow-up, there was no deterioration in pulmonary function, respiratory symptoms, or disease extent. CONCLUSIONS: Our results support the hypothesis that ATII-cell intratracheal transplantation is safe and well tolerated in patients with IPF. This study opens the door to designing a clinical trial to elucidate the potential beneficial effects of ATII-cell therapy in IPF.

Causes of death in a contemporary cohort of patients with invasive aspergillosis.

Information regarding the processes leading to death in patients with invasive aspergillosis (IA) is lacking. We sought to determine the causes of death in these patients, the role that IA played in the cause, and the timing of death. The factors associated with IA-related mortality are also analyzed. We conducted a multicenter study (2008-2011) of cases of proven and probable IA. The causes of death and whether mortality was judged to be IA-related or IA-unrelated were determined by consensus using a six-member review panel. A multivariate analysis was performed to determine risk factors for IA-related death. Of 152 patients with IA, 92 (60.5%) died. Mortality was judged to be IA-related in 62 cases and IA-unrelated in 30. The most common cause of IA-related death was respiratory failure (50/62 patients), caused primarily by Aspergillus infection, although also by concomitant infections or severe comorbidities. Progression of underlying disease and bacteremic shock were the most frequent causes of IA-unrelated death. IA-related mortality accounted for 98% and 87% of deaths within the first 14 and 21 days, respectively. Liver disease (HR 4.54; 95% CI, 1.69-12.23) was independently associated with IA-related mortality, whereas voriconazole treatment was associated with reduced risk of death (HR 0.43; 95% CI, 0.20-0.93). In conclusion, better management of lung injury after IA diagnosis is the main challenge for physicians to improve IA outcomes. There are significant differences in causes and timing between IA-related and IA-unrelated mortality and these should be considered in future research to assess the quality of IA care.

Efficacy of linezolid compared to vancomycin in an experimental model of pneumonia induced by methicillin-resistant Staphylococcus aureus in ventilated pigs.

OBJECTIVE: To assess the efficacy of linezolid compared with vancomycin in an experimental model of pneumonia induced by methicillin-resistant Staphylococcus aureus (MRSA) in ventilated pigs. METHODS: Forty pigs (30 kg) were intubated and challenged via bronchoscopy with a suspension of 106 colony forming units of MRSA into every lobe. Afterwards, pigs were ventilated up to 96 hours. Twelve hours after bacterial inoculation, the animals were randomized into 4 groups of treatment: group 1, control; group 2, vancomycin twice daily; group 3, continuous infusion of vancomycin; and group 4, linezolid. Clinical and laboratory parameters were monitored throughout the study. Bacterial cultures of bronchoalveolar lavage fluid and lung tissue samples were performed at the end of the study. Measurements of histopathology derangements of lung samples and studies of intrapulmonary drug penetration were performed. RESULTS: A total of 34 animals completed the study. No differences in clinical and laboratory parameters were observed. The percentage of bronchoalveolar lavage fluid and lung tissue samples with positive cultures for MRSA in controls and groups 2, 3, and 4 was respectively 75%, 11%, 11%, and 0% (p < .01); 52%, 9%, 24%, and 2.5% (p < .01). Histopathology studies demonstrated signs of pneumonia in 95%, 69%, 58%, and 57% and signs of severe pneumonia in 48%, 29%, 22%, and 0% of controls and groups 2, 3, and 4, respectively (p < .01). In addition, pharmacokinetics/pharmacodynamics profile in serum and lung tissue showed better results for linezolid compared with both vancomycin treatments. CONCLUSIONS: In this animal model of MRSA pneumonia, linezolid showed a better efficacy than vancomycin showed because of a better pharmacokinetics/pharmacodynamics index.

Urgent pneumococcal urinary antigen, importance in the diagnosis of acquired pneumonia in HIV-1 patients.

The aim of our study was to determine the usefulness of pneumococcal urinary antigen (UA) collected in the emergency department (ED) for the microbiologic diagnosis of community-acquired pneumonia (CAP) in HIV patients and to compare it with other diagnostic tests. Prospective study from 1 January 2007 to 31 December 2008 included HIV-infected patients admitted at the ED with respiratory symptoms and who were diagnosed of CAP. UA, two blood cultures and sputum sample for culture determination were collected from every patient. Sixty-four patients were included. The mean age was 42 years. A total of 31 (48%) UA tests, 12 (19%) blood cultures and 21 (33%) sputum cultures tested positive. A microbiological diagnosis was obtained in 38 (59%) cases. Pneumococcal pneumonia was diagnosed in 32 cases. The statistical analysis showed that the test with best performance was the UA, both in relation to blood and sputum cultures (P<0.05). Two patients died during hospitalization (series mortality of 3%). In conclusion, given its good diagnostic performance, UA should be requested in the ED for the aetiological diagnosis of CAP.

A predictive index for the diagnosis of cirrhosis in hepatitis C based on clinical, laboratory, and ultrasound findings.

OBJECTIVE: To develop and validate a non-invasive index to predict the presence of cirrhosis in patients with chronic hepatitis C on the basis of clinical, laboratory, and ultrasound findings. MATERIALS AND METHODS: Data from the complete history and physical examination, serologic studies, liver ultrasound, and liver biopsy of patients with chronic hepatitis C were analyzed using multivariate regression to develop a cirrhosis predictive index. This index was then applied prospectively to another group of patients with chronic hepatitis C to determine its accuracy. RESULTS: Three hundred and thirty-two patients were included (mean age, 48.5+/-18.7 years; male-female ratio, 1.27). Sixty-seven patients (20%) had cirrhosis at histology. Logistic regression identified seven variables that predicted cirrhosis: age>or=60 years, platelet countor=1, prothrombin time (Ratio)>or=1.1, caudate hypertrophy, right lobe atrophy and splenomegaly. Patients scoring>or=22 in total had a statistically significant probability of cirrhosis (sensitivity, 80%; specificity, 96%; and diagnostic accuracy, 94%). CONCLUSION: Cirrhosis can be predicted in patients with chronic hepatitis C by the evaluation of seven clinical, laboratory, and sonographic variables. The index will be useful for the management and follow-up of hepatitis C patients drastically reducing the indications for biopsy in this context.

Causes and predictors of nonresponse to treatment of intensive care unit-acquired pneumonia.

OBJECTIVE: To prospectively evaluate the predictive factors for the nonresponse to empirical antibiotic treatment and mortality in patients with intensive care unit-acquired pneumonia. DESIGN: A 1-yr prospective cohort of patients with suspicion of intensive care unit-acquired pneumonia. SETTING: Five medical and surgical intensive care units of Hospital Clinic in Barcelona. PATIENTS: A total of 71 patients with intensive care unit-acquired pneumonia were studied. The definition of nonresponse included at least one of the following: failure to improve the Pao2/Fio2 ratio or need of intubation because of pneumonia, persistence of fever or hypothermia and purulent respiratory secretions, worsening of pulmonary infiltrates, or occurrence of septic shock or multiple organ dysfunction not present at onset of pneumonia. INTERVENTIONS: Clinical assessment, including severity scores, blood and quantitative cultures of respiratory secretions, and cytokine measurements in serum and bronchoalveolar lavage at onset of pneumonia and 72 hrs after antimicrobial treatment. MEASUREMENTS AND RESULTS: A total of 44 patients (62%) fulfilled criteria of nonresponse, and at least one cause of nonresponse could be determined in 28 cases (64%): inappropriate treatment in ten (23%), superinfection in six (14%), concomitant foci of infection in 12 (27%), and noninfectious causes in seven cases (16%). The remaining 16 patients with no definite cause of nonresponse presented with septic shock, multiple organ dysfunction, or acute respiratory distress syndrome. Increased levels of interleukin-6 at onset of pneumonia (odds ratio, 9.7; p =.014) was an independent predictor of nonresponse to treatment. Likewise, increased level of interleukin-6 at follow-up (odds ratio, 27; p =.001) was the only independent predictor for hospital mortality. CONCLUSION: Increased systemic inflammatory response was the main predictor of nonresponse to treatment and mortality.