Tenofovir Disoproxil Fumarate/Emtricitabine and Baricitinib for Patients at High Risk of Severe Coronavirus Disease 2019: The PANCOVID Randomized Clinical Trial.

BACKGROUND: This study was designed to evaluate if patients with high risk for severe coronavirus disease 2019 (COVID-19) would benefit from treatment with tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) followed by baricitinib in case of hypoxemia and systemic inflammation. METHODS: PANCOVID is an open-label, double-randomized, phase 3 pragmatic clinical trial including adults with symptomatic COVID-19 with ≥2 comorbidities or aged ≥60 years and was conducted between 10 October 2020 and 23 September 2021. In the first randomization, patients received TDF/FTC or no TDF/FTC. In the second randomization, patients with room air oxygen saturation <95% and at least 1 increased inflammatory biomarker received baricitinib plus dexamethasone or dexamethasone alone. The primary endpoint was 28-day mortality. Main secondary endpoint was 28-day disease progression or critical care unit admission or mortality. The trial was stopped before reaching planned sample size due to the decrease in the number of cases and a mortality rate substantially lower than expected. RESULTS: Of the 355 included participants, 97% were hospitalized at baseline. Overall, 28-day mortality was 3.1%. The 28-day mortality relative risk (RR) for participants treated with TDF/FTC was 1.76 (95% confidence interval [CI], .52-5.91; P = .379); it was 0.42 (95% CI, .11-1.59; P = .201) for those treated with baricitinib. The 28-day RR for the main secondary combined endpoint for participants treated with TDF/FTC was 0.95 (95% CI, .66-1.40; P = .774); it was 0.90 (95% CI, .61-1.33; P = .687) for those treated with baricitinib. CONCLUSIONS: Our results do not suggest a beneficial effect of TDF/FTC; nevertheless, they are compatible with the beneficial effect of baricitinib already established by other clinical trials. CLINICAL TRIALS REGISTRATION: EudraCT: 2020-001156-18.

A Tale of Two Hospitals: Comparing CAPA Infections in Two ICUs During the Spanish Fourth Pandemic Wave.

PURPOSE: COVID-19 associated pulmonary aspergillosis (CAPA) is a new clinical entity linked to SARS-CoV-2 infection that is causing a rise on the risk of complications and mortality, particularly in critical patients. METHODS: We compared diagnostic and clinical features in two cohorts of patients with severe COVID-19 admitted in the intensive care units (ICU) of two different hospitals in Madrid, Spain, between February and June 2021. Clinical and microbiological relevant aspects for CAPA diagnosis were collected for further classification. CAPA was classified as colonization, possible, probable, proven, and tracheobronchial aspergillosis according to the ECMM/ISHAM consensus, with some modifications to consider tracheobronchial aspirate as sample comparable to non-bronchoscopic lavages (NBL). RESULTS: 56 patients admitted in HULP (Hospital Universitario La Paz) ICU and 61 patients admitted in HEEIZ (Hospital de Emergencias Isabel Zendal) ICU had clinical suspicion of invasive fungal disease in the context of COVID-19 infection. Cultures were positive for Aspergillus spp. in 32 patients. According to 2020 European Confederation of Medical Mycology and the International Society for Human and Animal Mycology (ECMM/ISHAM) consensus, 11 patients were diagnosed with possible CAPA and 10 patients with probable CAPA. Global incidence for CAPA was 6.3%. Global median days between ICU admission and diagnosis was 14 day. Aspergillus fumigatus complex was the main isolated species. Antifungal therapy was used in 75% of patients with CAPA suspicion, with inter-hospital differences in the administered antifungals. Global overall mortality rate for CAPA patients was 66.6% (14/21). All-cause mortality in non-CAPA cohorts were of 26.3% in HULP group (34/129) and 56.8% (104/183) in HEEIZ group. CONCLUSIONS: There were no significant differences in incidence between the two hospitals, and differences in antifungal therapy did not correlate with differences in mortality, reflecting that both first-line azoles and Amphotericin B could be effective in treating CAPA infections, according to the current guideline indications.

Duplex Ultrasound Screening for Deep and Superficial Vein Thrombosis in COVID-19 Patients.

BACKGROUND: There is growing evidence regarding the venous thromboembolic (VTE) pathophysiology of coronavirus disease 2019 (COVID-19). Several studies have reported varying incidences of this disease. OBJECTIVES: The main purpose of this study was to determine the real incidence of deep or superficial vein thrombosis in COVID-19. The study also aimed to identify risk and protective factors for VTE. METHODS: Patients were consecutively enrolled and assessed with a bilateral Duplex ultrasonography of lower limbs during hospitalization. The exam was repeated weekly until discharge, and then follow-up for 1 month. RESULTS: Two-hundred and thirty-three patients were enrolled. Mean age was 54.4 years (SD 12.7) and 47.8% were female. About 127 patients (54.5%) had comorbidities. At enrollment, patients were normotensive and had normal saturation (95.6%-SD 1.6, with a respiratory rate of 19.1 rpm-SD 4.0), with 130 needing at least supplementary oxygen therapy (55.8%). About 147 patients (63.1%) had at least 1 Duplex ultrasonography study performed and 1.7% had 5 or more studies. One patient had a distal posterior tibial vein thrombosis, which showed signs of chronicity and was congruent with the patient history. Therefore, the incidence of thrombotic events was nearly zero. DISCUSSION: Our study results suggest that performing a Duplex Ultrasonography screening protocol in stable COVID-19 patient populations, who may need hospitalization but are without symptoms of vein thrombosis, is not founded. We presumably emphasize the advantage of using intermediate LMWH doses as well as early walking in COVID-19 patients.

A Comparison of the Efficacy of Treatment With Fidaxomicin Versus Vancomycin in Clostridioides difficile Infection.

Background Clostridioides difficile infection (CDI) is a major cause of diarrhea in hospitalized adult patients. This study aims to evaluate the clinical characteristics, clinical cure, recurrence and mortality in patients with CDI treated with either fidaxomicin or vancomycin. Methods A retrospective case-control study was conducted on patients with CDI treated with either fidaxomicin or vancomycin at a hospital from January 2019 to March 2022. Results We assessed 140 patients with CDI episodes, 70 patients treated with fidaxomicin and 70 with vancomycin. Seventy (50%) were male. Median age was 70 years old (IQR: 56-81). Fidaxomicin group had more recurrent CDI episodes within six months (59% vs 11%, p ≤ 0.001), more severity (43% vs 16%, p ≤ 0.001) and less treatment response (84% vs 100%, p ≤ 0.002) compared with vancomycin group. Recurrence and mortality rates in the follow-up period did not differ in both groups. Conclusions Our study found fidaxomicin treatment had worse outcomes due to restricted usage, potentially impacting its effectiveness in CDI. This finding is especially significant for patients with severe or recurrent CDI, as prescribing of the drug was limited until May 2022 in Spain with the lifting of this restriction, further research is necessary to better understand the potential benefits of fidaxomicin in treating CDI.

Effect of HIV infection and antiretroviral therapy initiation on genome-wide DNA methylation patterns.

BACKGROUND: Previous epigenome-wide association studies have shown that HIV infection can disrupt the host DNA methylation landscape. However, it remains unclear how antiretroviral therapy (ART) affects the HIV-induced epigenetic modifications. METHODS: 184 individuals with HIV from the NEAT001/ANRS143 clinical trial (with pre-ART and post-ART samples [96 weeks of follow-up]) and 44 age-and-sex matched individuals without HIV were included. We compared genome-wide DNA methylation profiles in whole blood between groups adjusting for age, sex, batch effects, and DNA methylation-based estimates of leucocyte composition. FINDINGS: We identified 430 differentially methylated positions (DMPs) between HIV+ pre-ART individuals and HIV-uninfected controls. In participants with HIV, ART initiation modified the DNA methylation levels at 845 CpG positions and restored 49.3% of the changes found between HIV+ pre-ART and HIV-uninfected individuals. We only found 15 DMPs when comparing DNA methylation profiles between HIV+ post-ART individuals and participants without HIV. The Gene Ontology enrichment analysis of DMPs associated with untreated HIV infection revealed an enrichment in biological processes regulating the immune system and antiviral responses. In participants with untreated HIV infection, DNA methylation levels at top HIV-related DMPs were associated with CD4/CD8 ratios and viral loads. Changes in DNA methylation levels after ART initiation were weakly correlated with changes in CD4+ cell counts and the CD4/CD8 ratio. INTERPRETATION: Control of HIV viraemia after 96 weeks of ART initiation partly restores the host DNA methylation changes that occurred before antiretroviral treatment of HIV infection. FUNDING: NEAT-ID Foundation and Instituto de Salud Carlos III, co-funded by European Union.

Clinical Cure of a Difficult-to-Treat Resistant Pseudomonas aeruginosa Ventriculitis Using Cefiderocol: A Case Report and Literature Review.

Ventriculitis is a complication of meningitis (community-acquired or nosocomial) or other central nervous system (CNS) infections such as brain abscess. They are associated with a different spectrum of microorganisms, from resistant gram-negative bacilli to staphylococci, that can lead serious illness with high mortality. Difficult-to-treat resistance (DTR) gram-negative bacilli may increase to 20% of deaths respective to susceptible isolates of the same bacteria. We present the first report of a clinical cured case of DTR Pseudomonas aeruginosa ventriculitis in which cefiderocol penetration into the CNS has been confirmed in blood and cerebrospinal fluid. Cefiderocol might be considered for difficult-to-treat CNS infections in view of the recent new cases published as well as our case.

Risks and benefits of reducing the number of drugs to treat HIV-1 infection.

Introduction: Despite the efficacy and safety of antiretroviral therapy, new treatment options are needed to address the concerns of patients and physicians regarding long-term toxicities, costs, and convenience of lifelong antiretroviral therapy. To achieve this goal, one strategy is to reduce the number of drugs in the antiretroviral regimen.Areas covered: We review the recent evidence on the efficacy and safety of reduced drug regimens and their potential risks and benefits. There is currently strong evidence showing that some two-drug regimens have a comparable efficacy and short-term safety compared to standard three-drug regimens. The fixed-dose combination of dolutegravir/lamivudine is already an alternative for many treatment-naïve and virologically suppressed HIV-1 infected adults supported by large randomized clinical trials. The co-formulation dolutegravir plus rilpivirine is also a switch strategy for maintenance therapy. Long-acting injectable cabotegravir plus rilpivirine has already regulatory approval, and islatravir plus doravirine is an expected option in the near future. Some two-drug regimens have not been as successful.Expert opinion: Long-term safety issues of these two-drug regimens remain to be determined, but with the overwhelming evidence available in virological control and short-term safety, the potential benefits of some of these two-drug regimens appear to outweigh the risks.

[Hemogram reference values for Lisbon metropolitan area population]. / Valores de referência para hemograma na população da zona metropolitana de Lisboa.

The haemogram is, probably, one of the most requested analysis for laboratorial evaluation not only for ill patients but also in periodic evaluation of healthy subjects, allowing us to foil the presence of eventual illness, since there is an enormous variety of pathologies that can induce haemogram changes. The haematological parameters of healthy subjects are influenced by numerous factors. The ideal would be each laboratory should determine and establish his own reference values for each parameter, having in account all the variables. Since the available data for haematological parameters in the Portuguese population is very insufficient, it becomes necessary to report to exterior data based in populations with different characteristics from ours, which makes reference values' reliability questionable. To overcome this problem, we felt the necessity to evaluate our own population (healthy adults from metropolitan Lisbon area) concerning haemogram reference values, comparing the obtained results with those from the bibliography. We analyzed 363 blood samples from blood-donors that fulfilled the previously established protocol. The samples were collected before blood donation and the haemograms were done on the same day. We proceeded to the informatic registration of haemogram results, to the gathering of important data, to the characterization of the target population and to the statistical analysis of the obtained results. The sample population was globally analyzed and several groups were compared, according to sex, age group and possible history of smoking habits. Although we did not find in the bibliography data concerning the quantitative analysis of similar groups compared to ours, globally we concluded that the obtained results are similar to those described by other authors, both in qualitative and quantitative terms. The obtained results can only be of reference for this population and created subgroups. The definition of reference values for the Portuguese population requires the study of a much larger sample, due to the populational diversity that characterizes our country.