Humoral and cellular immune responses after 6 months of a heterologous SARS-CoV-2 booster with the protein-based PHH-1V vaccine in a phase IIb trial (preprint)

The HIPRA-HH-2 was a multicentre, randomized, active-controlled, double-blind, non-inferiority phase IIb clinical trial to compare the immunogenicity and safety of a heterologous booster with PHH-1V adjuvanted recombinant vaccine versus a homologous booster with mRNA vaccine. Interim results showed a strong humoral and cellular immune response against the SARS-CoV-2 Wuhan-Hu-1 strain and the Beta, Delta, and Omicron BA.1 variants up to day 98 after dosing. Here we report that these humoral and cellular responses after PHH-1V dosing are sustained up to 6 months. These results are observed both when including or not participants who reported SARS-CoV-2 infection and in a high-risk population ([≥]65 years). Additional analysis revealed a non-inferiority of PHH-1V booster in eliciting neutralizing antibodies also for SARS-CoV-2 Omicron XBB.1.5 when compared to mRNA vaccine after 6 months. The PHH-1V vaccine provides long-lasting protection against a wide variety of SARS-CoV-2 emerging variants to prevent severe COVID-19. ClinicalTrials.gov Identifier: NCT05142553

Molecular and Clinical Epidemiology of SARS-CoV-2 Infection Among Vaccinated and Unvaccinated Individuals in a Large Healthcare Organization from New Jersey (preprint)

New Jersey was among the first states impacted by the COVID-19 pandemic, with one of the highest overall death rates in the nation. Nevertheless, relatively few reports have been published focusing specifically on New Jersey. Here we report on molecular, clinical, and epidemiologic observations from the largest healthcare network in the state, in a cohort of vaccinated and unvaccinated individuals with laboratory-confirmed SARS-CoV-2 infection. We conducted molecular surveillance of SARS-CoV-2-positive nasopharyngeal swabs collected in nine hospitals from December 2020 through June 2022, using both whole genome sequencing (WGS) and a real-time RT-PCR screening assay targeting spike protein mutations found in variants of concern (VOC) within our region. De-identified clinical data were obtained retrospectively, including demographics, COVID-19 vaccination status, ICU admission, ventilator support, mortality, and medical history. Statistical analyses were performed to identify associations between SARS-CoV-2 variants, vaccination status, clinical outcomes, and medical risk factors. A total of 5,007 SARS-CoV-2-positive nasopharyngeal swabs were successfully screened and/or sequenced. Variant screening identified three predominant VOC, including Alpha (n =714), Delta (n =1,877), and Omicron (n =1,802). Omicron isolates were further sub-typed as BA.1 (n =899), BA.2 (n =853), and BA.4/BA.5 (n =50); the remaining 614 isolates were classified as “Other”. Approximately 31.5% (1,577/5,007) of the samples were associated with vaccine breakthrough infections, which increased in frequency following the emergence of Delta and Omicron. Severe clinical outcomes included ICU admission (336/5007 = 6.7%), ventilator support (236/5007 = 4.7%), and mortality (430/5007 = 8.6%), with increasing age being the most significant contributor to each (p <0.001). Unvaccinated individuals accounted for 79.7% (268/336) of ICU admissions, 78.3% (185/236) of ventilator cases, and 74.4% (320/430) of deaths. Highly significant (p <0.001) increases in mortality were observed in individuals with cardiovascular disease, hypertension, cancer, diabetes, and hyperlipidemia, but not with obesity, thyroid disease, or respiratory disease. Significant differences (p <0.001) in clinical outcomes were also noted between SARS-CoV-2 variants, including Delta, Omicron BA.1, and Omicron BA.2. Vaccination was associated with significantly improved clinical outcomes in our study, despite an increase in breakthrough infections associated with waning immunity, greater antigenic variability, or both. Underlying comorbidities contributed significantly to mortality in both vaccinated and unvaccinated individuals, with increasing risk based on the total number of comorbidities. Real-time RT-PCR-based screening facilitated timely identification of predominant variants using a minimal number of spike protein mutations, with faster turnaround time and reduced cost compared to WGS. Continued evolution of SARS-CoV-2 variants will likely require ongoing surveillance for new VOCs, with real-time assessment of clinical impact.

COVID-19 Vaccines for Children: An Update.

The coronavirus disease 2019 (COVID-19) pandemic has had a large effect on the pediatric population, with 16,000,000 cases and counting. Currently, there are two messenger RNA (mRNA)-based and a single adjuvanted, protein-based COVID-19 vaccine approved for use in children and adolescents in the United States. Multiple studies have highlighted that these vaccines are safe for use in children and adolescents and are effective at reducing COVID-19 infection and complications. Given the risk of the SARS-CoV-2 virus to the pediatric population and ongoing global viral transmission, it is advised that providers emphasize the value of COVID-19 vaccination for children and adolescents. [Pediatr Ann. 2023;52(3):e83-e88.].

Acute Kidney Injury in Critical Care COVID-19 Patients on Invasive Mechanical Ventilation: The Potential Preventive Role of Dexamethasone.

Background: A high incidence of acute kidney injury (AKI) has been reported in coronavirus disease 2019 (COVID-19) patients in critical care units and those undergoing invasive mechanical ventilation (IMV). The introduction of dexamethasone (DXM) as treatment for severe COVID-19 has improved mortality, but its effects in other organs remain under study. Objective: The objective of this study was to evaluate the association between DXM and AKI in COVID-19. Methods: In this prospective observational cohort study, we evaluated the incidence of AKI in critically ill COVID-19 patients undergoing mechanical ventilation, and the association of DXM treatment with the incidence, severity, and outcomes of AKI. The association between DXM treatment and AKI was evaluated by multivariable logistic regression. The association of the combination of DXM treatment and AKI on mortality was evaluated by Cox-regression analysis. Results: We included 552 patients. AKI was diagnosed in 311 (56%), of which 196 (63%) corresponded to severe (stage 2 or 3) AKI, and 46 (14.8%) received kidney replacement therapy. Two hundred and sixty-seven (48%) patients were treated with DXM. This treatment was associated to lower incidence of AKI (Odds Radio 0.34, 95% Confidence intervals [CI] 0.22-0.52, p < 0.001) after adjusting for age, body mass index, laboratory parameters, SOFA score, and vasopressor use. DXM treatment significantly reduced mortality in patients with severe AKI (HR 0.63, 95%CI 0.41-0.96, p = 0.032). Conclusions: The incidence of AKI is high in COVID-19 patients under IMV. DXM treatment is associated with a lower incidence of AKI and a lower mortality in the group with severe AKI.

Diversity of bat ectoparasites from the caves of selected Key Biodiversity Areas in Central Visayas, Philippines

Bats harbor numerous species of ectoparasites, such as ticks and mites. Many bat ectoparasites are implicated as vectors of pathogens ranging from bacteria to protozoa and viruses. Recent studies verified bats as a natural reservoir of multiple zoonotic viruses, including Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS) coronaviruses. This study assessed the composition, diversity, and prevalence of ectoparasites of cave-dwelling bats in the four Key Biodiversity Areas (KBAs) of Central Visayas. A total of 20 species of bats were recorded in the 30 surveyed caves. Of these, 30 species of ectoparasites belonging to eight families (dipteran flies Streblidae and Nycteribiidae, mites Spinturnicidae, Macronyssidae and Trombiculidae, ticks Argasidae and Ixodidae, and Ischnopsyllidae fleas) were collected and identified. Leptotrombidium sp. had the highest number of individuals (n=1,684) harbored in 12 bat host species. The highest prevalence (100%) was noted in four bat host species: Philippine pygmy fruit bat Haplonycteris fischeri Lawrence 1939, Philippine forest roundleaf bat Hipposideros obscurus Peters 1861, Philippine pygmy roundleaf bat Hipposideros pygmaeus Waterhouse 1843, and Common bent-winged bat Miniopterus schreibersii Kuhl 1817. The lowest prevalence was noted in the Round-eared tube-nosed bat Murina cyclotis Dobson 1872, where no ectoparasite was collected. The highest intensity (n=65) of ectoparasites was observed in the Common Asian ghost bat Megaderma spasma Linnaeus 1758. This study provides essential data for future reference in monitoring bat population status and conservation efforts in the region. Given the close relationship between the local human community and bats (e.g., hunting and consumption), more work is needed to address the potential pathogen risks from zoonotic transmission from bats and ectoparasites. © 2023, Society for Indonesian Biodiversity. All rights reserved.

Impacto de la pandemia por COVID-19 sobre un programa de consulta electrónica universal (e-consulta) entre médicos de atención primaria y cardiólogos Impact of the COVID-19 pandemic above a universal electronic consultation program (e-consultation) between general practitioners and cardiologists

Introducción y objetivos: Los programas de telemedicina entre clínico y paciente se han desarrollado con fuerza durante la pandemia de enfermedad por COVID-19, pero no hay datos de experiencias entre clínicos. Nuestro objetivo es analizar el impacto de la pandemia por COVID-19 en la actividad y resultados en salud de un programa de consulta electrónica universal (e-consulta) para todas las derivaciones de pacientes entre médicos de atención primaria y el Servicio de Cardiología de nuestra área. Métodos: Analizamos mediante regresión logística 25121 pacientes con al menos una e-consulta entre 2018 y 2021 realizada con el Servicio de Cardiología de nuestra área sanitaria. También se realizó el análisis de regresión logística del impacto de la pandemia por COVID-19 sobre la resolución de la e-consulta y tiempo de espera de la atención, hospitalizaciones y mortalidad, tomando como referencia las consultas realizadas durante 2018. Resultados: Observamos que una menor demora en la atención y resolución de la e-consulta (sin necesidad de atención presencial) se asociaba a un mejor pronóstico. Los períodos de pandemia COVID-19 presentaron similares resultados a los del 2018. Conclusiones: Los resultados de nuestro estudio muestran una significativa reducción de las derivaciones a través de e-consulta durante el primer año de la pandemia por COVID-19 con recuperación posterior de la demanda asistencial sin que los períodos de pandemia se asociasen con peores resultados en salud. La reducción del tiempo de demora de resolución de la e-consulta y el grupo sin necesidad de consulta presencial se asociaron a un mejor pronóstico.

Effectiveness of an inactivated SARS-CoV-2 vaccine in children and adolescents: a large-scale observational study.

Background: Policymakers urgently need evidence to adequately balance the costs and benefits of mass vaccination against COVID-19 across all age groups, including children and adolescents. In this study, we aim to assess the effectiveness of CoronaVac's primary series among children and adolescents in Chile. Methods: We used a large prospective national cohort of about two million children and adolescents 6-16 years to estimate the effectiveness of an inactivated SARS-CoV-2 vaccine (CoronaVac) in preventing laboratory-confirmed symptomatic SARS-CoV-2 infection (COVID-19), hospitalisation, and admission to an intensive care unit (ICU) associated with COVID-19. We compared the risk of individuals treated with a complete primary immunization schedule (two doses, 28 days apart) with the risk of unvaccinated individuals during the follow-up period. The study was conducted in Chile from June 27, 2021, to January 12, 2022, when the SARS-CoV-2 Delta variant was predominant but other variants of concern were co-circulating, including Omicron. We used inverse probability-weighted survival regression models to estimate hazard ratios of complete immunization over the unvaccinated status, accounting for time-varying vaccination exposure and adjusting for relevant demographic, socioeconomic, and clinical confounders. Findings: The estimated adjusted vaccine effectiveness for the inactivated SARS-CoV-2 vaccine in children aged 6-16 years was 74.5% (95% CI, 73.8-75.2), 91.0% (95% CI, 87.8-93.4), 93.8% (95% CI, 87.8-93.4) for the prevention of COVID-19, hospitalisation, and ICU admission, respectively. For the subgroup of children 6-11 years, the vaccine effectiveness was 75.8% (95% CI, 74.7-76.8) for the prevention of COVID-19 and 77.9% (95% CI, 61.5-87.3) for the prevention of hospitalisation. Interpretation: Our results suggest that a complete primary immunization schedule with the inactivated SARS-CoV-2 vaccine provides effective protection against severe COVID-19 disease for children 6-16 years. Funding: Agencia Nacional de Investigación y Desarrollo (ANID) Millennium Science Initiative Program and Fondo de Financiamiento de Centros de Investigación en Áreas Prioritarias (FONDAP).

National survey study of nirmatrelvir-ritonavir prescribing processes and access barriers during the severe acute respiratory coronavirus virus 2 (SARS-CoV-2) omicron surge of the coronavirus disease 2019 (COVID-19) pandemic.

In this national survey, we found that individual patient assessments by pharmacists were more common at facilities using centralized prescribing for nirmetralvir-ritonavir (Paxlovid) than decentralized prescribing. Provider discomfort was initially less with centralized prescribing, but later, there was no difference in provider discomfort based on prescribing mechanism.

Policy evaluation using model over-fitting: the Nordic case.

The interest of this article is to better understand the effects of different public policy alternatives to handle the COVID-19 pandemic. In this work we use the susceptible, infected, recovered (SIR) model to find which of these policies have an actual impact on the dynamic of the spread. Starting with raw data on the number of deceased people in a country, we over-fit our SIR model to find the times ti at which the main parameters, the number of daily contacts and the probability of contagion, require adjustments. For each ti, we go to historic records to find policies and social events that could explain these changes. This approach helps to evaluate events through the eyes of the popular epidemiological SIR model, and to find insights that are hard to recognize in a standard econometric model.

A Nonrandomized Trial of the Effects of Passive Simulated Jogging on Short-Term Heart Rate Variability in Type 2 Diabetic Subjects.

Background: Diabetes mellitus has reached global epidemic proportions, with type 2 diabetes (T2DM) comprising more than 90% of all subjects with diabetes. Cardiovascular autonomic neuropathy (CAN) frequently occurs in T2DM. Heart rate variability (HRV) reflects a neural balance between the sympathetic and parasympathetic autonomic nervous systems (ANS) and a marker of CAN. Reduced HRV has been shown in T2DM and improved by physical activity and exercise. External addition of pulses to the circulation, as accomplished by a passive simulated jogging device (JD), restores HRV in nondiseased sedentary subjects after a single session. We hypothesized that application of JD for a longer period (7 days) might improve HRV in T2DM participants. Methods: We performed a nonrandomized study on ten T2DM subjects (age range 44-73 yrs) who were recruited and asked to use a physical activity intervention, a passive simulated jogging device (JD) for 7 days. JD moves the feet in a repetitive and alternating manner; the upward movement of the pedal is followed by a downward movement of the forefoot tapping against a semirigid bumper to simulate the tapping of feet against the ground during jogging. Heart rate variability (HRV) analysis was performed using an electrocardiogram in each subject in seated posture on day 1 (baseline, BL), after seven days of JD (JD7), and seven days after discontinuation of JD (Post-JD). Time domain variables were computed, viz., standard deviation of all normal RR intervals (SDNN), standard deviation of the delta of all RR intervals (SDΔNN), and the square root of the mean of the sum of the squares of differences between adjacent RR intervals (RMSSD). Frequency domain measures were determined using a standard Fast Fourier spectral analysis, as well as the parameters of the Poincaré plots (SD1 and SD2). Results: Seven days of JD significantly increased SDNN, SDΔNN, RMSSD, and both SD1 and SD2 from baseline values. The latter parameters remained increased Post-JD. JD did not modify the frequency domain measures of HRV. Conclusion: A passive simulated jogging device increased the time domain and Poincaré variables of HRV in T2DM. This intervention provided effortless physical activity as a novel method to harness the beneficial effects of passive physical activity for improving HRV in T2DM subjects.

Safety and immunogenicity of the protein-based PHH-1V compared to BNT162b2 as a heterologous SARS-CoV-2 booster vaccine in adults vaccinated against COVID-19: a multicentre, randomised, double-blind, non-inferiority phase IIb trial.

Background: A SARS-CoV-2 protein-based heterodimer vaccine, PHH-1V, has been shown to be safe and well-tolerated in healthy young adults in a first-in-human, Phase I/IIa study dose-escalation trial. Here, we report the interim results of the Phase IIb HH-2, where the immunogenicity and safety of a heterologous booster with PHH-1V is assessed versus a homologous booster with BNT162b2 at 14, 28 and 98 days after vaccine administration. Methods: The HH-2 study is an ongoing multicentre, randomised, active-controlled, double-blind, non-inferiority Phase IIb trial, where participants 18 years or older who had received two doses of BNT162b2 were randomly assigned in a 2:1 ratio to receive a booster dose of vaccine-either heterologous (PHH-1V group) or homologous (BNT162b2 group)-in 10 centres in Spain. Eligible subjects were allocated to treatment stratified by age group (18-64 versus ≥65 years) with approximately 10% of the sample enrolled in the older age group. The primary endpoints were humoral immunogenicity measured by changes in levels of neutralizing antibodies (PBNA) against the ancestral Wuhan-Hu-1 strain after the PHH-1V or the BNT162b2 boost, and the safety and tolerability of PHH-1V as a boost. The secondary endpoints were to compare changes in levels of neutralizing antibodies against different variants of SARS-CoV-2 and the T-cell responses towards the SARS-CoV-2 spike glycoprotein peptides. The exploratory endpoint was to assess the number of subjects with SARS-CoV-2 infections ≥14 days after PHH-1V booster. This study is ongoing and is registered with ClinicalTrials.gov, NCT05142553. Findings: From 15 November 2021, 782 adults were randomly assigned to PHH-1V (n = 522) or BNT162b2 (n = 260) boost vaccine groups. The geometric mean titre (GMT) ratio of neutralizing antibodies on days 14, 28 and 98, shown as BNT162b2 active control versus PHH-1V, was, respectively, 1.68 (p < 0.0001), 1.31 (p = 0.0007) and 0.86 (p = 0.40) for the ancestral Wuhan-Hu-1 strain; 0.62 (p < 0.0001), 0.65 (p < 0.0001) and 0.56 (p = 0.003) for the Beta variant; 1.01 (p = 0.92), 0.88 (p = 0.11) and 0.52 (p = 0.0003) for the Delta variant; and 0.59 (p ≤ 0.0001), 0.66 (p < 0.0001) and 0.57 (p = 0.0028) for the Omicron BA.1 variant. Additionally, PHH-1V as a booster dose induced a significant increase of CD4+ and CD8+ T-cells expressing IFN-γ on day 14. There were 458 participants who experienced at least one adverse event (89.3%) in the PHH-1V and 238 (94.4%) in the BNT162b2 group. The most frequent adverse events were injection site pain (79.7% and 89.3%), fatigue (27.5% and 42.1%) and headache (31.2 and 40.1%) for the PHH-1V and the BNT162b2 groups, respectively. A total of 52 COVID-19 cases occurred from day 14 post-vaccination (10.14%) for the PHH-1V group and 30 (11.90%) for the BNT162b2 group (p = 0.45), and none of the subjects developed severe COVID-19. Interpretation: Our interim results from the Phase IIb HH-2 trial show that PHH-1V as a heterologous booster vaccine, when compared to BNT162b2, although it does not reach a non-inferior neutralizing antibody response against the Wuhan-Hu-1 strain at days 14 and 28 after vaccination, it does so at day 98. PHH-1V as a heterologous booster elicits a superior neutralizing antibody response against the previous circulating Beta and the currently circulating Omicron BA.1 SARS-CoV-2 variants in all time points assessed, and for the Delta variant on day 98 as well. Moreover, the PHH-1V boost also induces a strong and balanced T-cell response. Concerning the safety profile, subjects in the PHH-1V group report significantly fewer adverse events than those in the BNT162b2 group, most of mild intensity, and both vaccine groups present comparable COVID-19 breakthrough cases, none of them severe. Funding: HIPRA SCIENTIFIC, S.L.U.

Bleeding and Thrombotic Complications in COVID-19-Associated ARDS Requiring ECMO.

BACKGROUND: We analyzed bleeding and thrombotic complications in COVID-19-associated ARDS requiring extracorporeal membrane oxygenation (ECMO). METHODS: This was a single-center observational study of adult subjects undergoing ECMO for COVID-19 (n = 67) or all other cause of ARDS (n = 60), excluding trauma patients. RESULTS: In the COVID-19 group, duration of invasive mechanical ventilation prior to ECMO was lower (2 [0-4] d vs 3 [1-6] d) and ECMO retrieval less frequent (71% vs 87%). No significant differences were found in Simplified Acute Physiology Score II, Acute Physiology and Chronic Health Evaluation II (APACHE II), or in the in-hospital survival predicted by the Respiratory ECMO Survival Prediction score. During the first 7 d of ECMO support, the COVID-19 group presented higher platelets and fibrinogen, lower activated partial thromboplastin time, but no differences in D-dimer. Thrombotic complications were similar between groups. Higher rates of severe bleeding, namely airway bleeding (37.3% vs 15.0%) and hemothorax (13.4% vs 3.3%), were found in COVID-19, with lower hemoglobin and higher red blood cell transfusions. COVID-19 ARDS was associated with longer ECMO duration (47 [17-80] d vs 19 [12-30] d) and absence of a statistically significant difference concerning in-hospital mortality. CONCLUSIONS: COVID-19-associated ARDS requiring ECMO presented high rates of severe bleeding complications and a protracted course. Further studies are needed to clarify the risks and benefits of ECMO in severe COVID-19-associated ARDS.

Long Short Term Memory based Covid-19 Mutation Detection for RNA Sequence dataset

Mutation detection for the various strains of Covid 19 evolves the constraints of time, accuracy and precision. RNA sequencing with deep learning enables the detection of the mutation variant from the sequence dataset and helps for the development of tests that are used for the diagnosis and future predictions. Analyzing and researching on Covid- 19 structure and the epidemiological study aid to the accurate methodology selection and process implementation. Efficient data preprocessing of the RNA sequence adds to the accuracy of the model which was built using LSTM. This paper proposes a Long Short Term Memory (LSTM) based deep learning modeling helps the RNA sequence dataset model to predict the RNA mutant variant. The model acquired an accuracy of 91.7 % and a loss function of 3.08%. © 2022 IEEE.

International Travel Vaccine Recommendations for Children.

Children are at risk of contracting diseases while traveling internationally. Beyond the importance of receiving routine vaccinations, physicians should also discuss with parents the effectiveness of vaccination as a strategy to protect their child against disease before travel. This article (1) explores the universally recommended routine vaccines that are particularly important for children to be up to date before travel (ie, measles, mumps, rubella; hepatitis A and B; polio; meningococcal; coronavirus disease 2019 [COVID-19]; and influenza) and (2) explains the travel-specific vaccination recommendations (ie, dengue, cholera, typhoid, tick-borne encephalitis, yellow fever, Japanese encephalitis, and rabies). Physicians can encourage parents to consult the Centers for Disease Control and Prevention website for travel vaccine recommendations (https://wwwnc.cdc.gov/travel). Children must remain up to date on universally recommended vaccines and receive the appropriate vaccines before international travel to prevent serious illness and limit the spread of diseases in the United States. [Pediatr Ann. 2023;52(3):e106-e113.].

Effectiveness of Localized Lockdowns in the COVID-19 Pandemic.

Nonpharmaceutical interventions, such as social distancing and lockdowns, have been essential to control of the coronavirus disease 2019 (COVID-19) pandemic. In particular, localized lockdowns in small geographic areas have become an important policy intervention for preventing viral spread in cases of resurgence. These localized lockdowns can result in lower social and economic costs compared with larger-scale suppression strategies. Using an integrated data set from Chile (March 3-June 15, 2020) and a novel synthetic control approach, we estimated the effect of localized lockdowns, disentangling its direct and indirect causal effects on transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Our results showed that the effects of localized lockdowns are strongly modulated by their duration and are influenced by indirect effects from neighboring geographic areas. Our estimates suggest that extending localized lockdowns can slow down SARS-CoV-2 transmission; however, localized lockdowns on their own are insufficient to control pandemic growth in the presence of indirect effects from contiguous neighboring areas that do not have lockdowns. These results provide critical empirical evidence about the effectiveness of localized lockdowns in interconnected geographic areas.

Genomic surveillance reveals dynamic shifts in the connectivity of COVID-19 epidemics (preprint)

The maturation of genomic surveillance in the past decade has enabled tracking of the emergence and spread of epidemics at an unprecedented level. During the COVID-19 pandemic, for example, genomic data revealed that local epidemics varied considerably in the frequency of SARS-CoV-2 lineage importation and persistence, likely due to a combination of COVID-19 restrictions and changing connectivity. Here, we show that local COVID-19 epidemics are driven by regional transmission, including across international boundaries, but can become increasingly connected to distant locations following the relaxation of public health interventions. By integrating genomic, mobility, and epidemiological data, we find abundant transmission occurring between both adjacent and distant locations, supported by dynamic mobility patterns. We find that changing connectivity significantly influences local COVID-19 incidence. Our findings demonstrate a complex meaning of 'local' when investigating connected epidemics and emphasize the importance of collaborative interventions for pandemic prevention and mitigation.

COVID-19 in transplant recipients: The Spanish experience

We report the nationwide experience with solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients diagnosed with coronavirus disease 2019 (COVID-19) in Spain until 13 July 2020. We compiled information for 778 (423 kidney, 113 HSCT, 110 liver, 69 heart, 54 lung, 8 pancreas, 1 multivisceral) recipients. Median age at diagnosis was 61 years (interquartile range [IQR]: 52-70), and 66% were male. The incidence of COVID-19 in SOT recipients was two-fold higher compared to the Spanish general population. The median interval from transplantation was 59 months (IQR: 18-131). Infection was hospital-acquired in 13% of cases. No donor-derived COVID-19 was suspected. Most patients (89%) were admitted to the hospital. Therapies included hydroxychloroquine (84%), azithromycin (53%), protease inhibitors (37%), and interferon-β (5%), whereas immunomodulation was based on corticosteroids (41%) and tocilizumab (21%). Adjustment of immunosuppression was performed in 85% of patients. At the time of analysis, complete follow-up was available from 652 patients. Acute respiratory distress syndrome occurred in 35% of patients. Ultimately, 174 (27%) patients died. In univariate analysis, risk factors for death were lung transplantation (odds ratio [OR]: 2.5;95% CI: 1.4-4.6), age >60 years (OR: 3.7;95% CI: 2.5-5.5), and hospital-acquired COVID-19 (OR: 3.0;95% CI: 1.9-4.9).

Tenofovir Disoproxil Fumarate/Emtricitabine and Baricitinib for Patients at High Risk of Severe COVID-19: The PANCOVID Randomized Clinical Trial.

BACKGROUND: This study was designed to evaluate if patients with high risk for severe COVID-19 would benefit from treatment with 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 older than 60 years conducted between 10 October 2020 and 23 September 2021. In the first randomization patients received TDF/FTC or not TDF/FTC. In the second randomization patients with room-air O2 saturation <95% and at least one 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 EudraCT registration number: 2020-001156-18. 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% CI 0.52-5.91; p= 0.379); it was 0.42 (95% CI 0.11-1.59; p= 0.201) 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 0.66-1.40; p = 0.774); it was 0.90 (95%CI 0.61-1.33; p = 0.687) 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.