A Phase 2b randomised, controlled, partially blinded trial of the HIV Nucleoside Reverse Transcriptase Inhibitor BMS-986001 (AI467003): Weeks 24 and 48 Efficacy, Safety, Bone and Metabolic Results

Background BMS-986001 is a thymidine analogue nucleoside reverse transcriptase inhibitor (NRTI) designed to maintain in-vitro antiviral activity while minimising off-target effects. We assessed the efficacy and safety of BMS-986001 versus tenofovir disoproxil fumarate in treatment-naive patients with HIV-1. Methods In this phase 2b, randomised, active-controlled trial (AI467003), we recruited treatment-naive (no current or previous exposure to an antiretroviral drug for >1 week) adults (aged at least 18 years) with HIV-1 from 47 sites across Asia, Australia, Europe, North America, South Africa, and South America. Patients with plasma HIV-1 RNA greater than 5000 copies per mL and CD4 counts greater than 200 cells per μL were randomly assigned (2:2:2:3) to receive BMS-986001 100 mg, 200 mg, or 400 mg once a day or to receive tenofovir disoproxil fumarate 300 mg once a day; each allocation was given with efavirenz 600 mg once a day and lamivudine 300 mg once a day. Both patients and investigators were masked to BMS-986001 dose (achieved with similar looking placebo tablets), but not allocation up to and including week 48. The primary endpoints were the proportion of patients with plasma HIV-1 RNA less than 50 copies per mL and safety events (serious adverse events and adverse events leading to discontinuation) through week 24; the main analysis was with a modified intention-to-treat population. Resistance analysis was a secondary endpoint, and additional safety parameters were exploratory endpoints. This trial is registered with ClinicalTrials.gov, number NCT01489046, and the European Clinical Trials Database, number EudraCT 2011-003329-89. Findings Patients were recruited between Jan 25, 2012, and Oct 3, 2012; 757 patients were assessed for eligibility and 301 were randomly assigned to receive either BMS-986001 once a day (67 patients to 100 mg, 67 to 200 mg, and 66 to 400 mg) or tenofovir disoproxil fumarate (n=101). 297 patients received at least one dose of study drug. At week 24, 57 (88%) of 65 patients for whom there were data in the 100 mg group, 54 (81%) of 67 in the 200 mg group, 62 (94%) of 66 in the 400 mg group achieved HIV-1 RNA less than 50 copies per mL, compared with 88 (89%) of 99 in the tenofovir disoproxil fumarate group (modified intention-to-treat population). BMS-986001 was generally well tolerated through week 48. Two patients had BMS-986001-related serious adverse events (atypical drug eruption and thrombocytopenia) and two in the tenofovir disoproxil fumarate group had study drug-related serious adverse events (potential drug-induced liver injury and depression or lipodystrophy) that led to discontinuation. NRTI resistance-associated mutations were reported in four (2%) of 198 patients, and non-NRTI mutations in 17 (9%) of 198 patients receiving BMS-986001 versus none of 99 and one (1%) of 99 patients receiving tenofovir disoproxil fumarate, respectively. Compared with tenofovir disoproxil fumarate, individuals in the BMS-986001 groups showed a smaller decrease in lumbar spine and hip bone mineral density but greater accumulation of limb and trunk fat, subcutaneous and visceral adipose tissue, and increased total cholesterol. Interpretation BMS-986001 had similar efficacy to that of tenofovir disoproxil fumarate and was associated with a smaller decrease in bone mineral density; however, greater resistance and gains in both peripheral and central fat accumulation were recorded for the investigational drug. Bristol-Myers Squibb has discontinued its involvement in the development of BMS-986001, and future decisions on development will be made by Oncolys BioPharma

Deep inspiration breath hold: dosimetric benefits to decrease cardiac dose during postoperative radiation therapy for breast cancer patients

Background: Postoperative radiation therapy (RT) is the standard treatment for almost all patients diagnosed with breast cancer. Even with modern RT techniques, parts of the heart may still receive higher doses than those recommended by clinically validated dose limit restrictions, especially when the left breast is irradiated. Deep inspiration breath hold (DIBH) may reduce irradiated cardiac volume compared to free breathing (FB) treatment. This study aimed to evaluate the dosimetric impact on the heart and left anterior descending coronary artery (LAD) in FB and DIBH RT planning in patients with left breast cancer. Materials and methods: A retrospective cohort study of women diagnosed with left-sided breast cancer submitted to breast surgery followed by postoperative RT from 2015 to 2019. All patients were planned with FB and DIBH and  hypofractionated dose prescription (40.05 Gy in 15 fractions). Results: 68 patients were included in the study. For the coverage of the planned target volume evaluation [planning target volume (PTV) eval] there was no significant difference between the DIBH versus FB planning. For the heart and LAD parameters, all constraints evaluated favored DIBH planning, with statistical significance. Regarding the heart,  median V16.8 Gy was 2.56% in FB vs. 0% in DIBH (p < 0.001); median V8.8 Gy was 3.47% in FB vs. 0% in DIBH (p < 0.001) and the median of mean heart dose was 1.97 Gy in FB vs. 0.92 Gy in DIBH (p < 0.001). For the LAD constraints D2% < 42 Gy, the median dose was 34.87 Gy in FB versus 5.8  Gy in DIBH (p < 0.001); V16.8 Gy < 10%, the median was 15.87% in FB versus 0% in DIBH (p < 0.001) and the median of mean LAD dose was 8.13Gy in FB versus 2.92Gy in DIBH (p < 0.001). Conclusions: The DIBH technique has consistently demonstrated a significant dose reduction in the heart and LAD in all evaluated constraints, while keeping the same dose coverage in the PTV eval

Clinical Study Intraoperative Full-Dose of Partial Breast Irradiation with Electrons Delivered by Standard Linear Accelerators for Early Breast Cancer

is properly cited. Purpose. To assess feasibility, efficacy, toxicity, and cosmetic results of intraoperative radiotherapy (IORT) with electrons delivered by standard linear accelerators (Linacs) during breast conserving surgeries for early infiltrating breast cancer (BC) treatment. Materials and Methods. A total of 152 patients with invasive ductal carcinoma ( ≤ 3.0 cm) at low risk for local relapses were treated. All had unicentric lesions by imaging methods and negative sentinel node. After a wide local excision, 21 Gy were delivered on the parenchyma target volume with electron beams. Local recurrences (LR), survival, toxicity, and cosmetic outcomes were analyzed. Results. The median age was 58.3 years (range 40-85); median follow-up was 50.7 months (range 12-101.5). There were 5 cases with LR, 2 cases with distant metastases, and 2 cases with deaths related to BC. The cumulative incidence rates of LR, distant metastases, and BC death were 3.2%, 1.5%, and 1.5%, respectively. Complications were rare, and the cosmetic results were excellent or good in most of the patients. Conclusions. IORT with electrons delivered by standard Linacs is feasible, efficient, and well tolerated and seems to be beneficial for selected patients with early infiltrating BC

Phosphatidylserine-exposing extracellular vesicles in body fluids are an innate defence against apoptotic mimicry viral pathogens

Some viruses are rarely transmitted orally or sexually despite their presence in saliva, breast milk, or semen. We previously identified that extracellular vesicles (EVs) in semen and saliva inhibit Zika virus infection. However, the antiviral spectrum and underlying mechanism remained unclear. Here we applied lipidomics and flow cytometry to show that these EVs expose phosphatidylserine (PS). By blocking PS receptors, targeted by Zika virus in the process of apoptotic mimicry, they interfere with viral attachment and entry. Consequently, physiological concentrations of EVs applied in vitro efficiently inhibited infection by apoptotic mimicry dengue, West Nile, Chikungunya, Ebola and vesicular stomatitis viruses, but not severe acute respiratory syndrome coronavirus 2, human immunodeficiency virus 1, hepatitis C virus and herpesviruses that use other entry receptors. Our results identify the role of PS-rich EVs in body fluids in innate defence against infection via viral apoptotic mimicries, explaining why these viruses are primarily transmitted via PS-EV-deficient blood or blood-ingesting arthropods rather than direct human-to-human contact

Global burden of respiratory infections associated with seasonal influenza in children under 5 years in 2018: a systematic review and modelling study

Background: Seasonal influenza virus is a common cause of acute lower respiratory infection (ALRI) in young children. In 2008, we estimated that 20 million influenza-virus-associated ALRI and 1 million influenza-virus-associated severe ALRI occurred in children under 5 years globally. Despite this substantial burden, only a few low-income and middle-income countries have adopted routine influenza vaccination policies for children and, where present, these have achieved only low or unknown levels of vaccine uptake. Moreover, the influenza burden might have changed due to the emergence and circulation of influenza A/H1N1pdm09. We aimed to incorporate new data to update estimates of the global number of cases, hospital admissions, and mortality from influenza-virus-associated respiratory infections in children under 5 years in 2018. Methods: We estimated the regional and global burden of influenza-associated respiratory infections in children under 5 years from a systematic review of 100 studies published between Jan 1, 1995, and Dec 31, 2018, and a further 57 high-quality unpublished studies. We adapted the Newcastle-Ottawa Scale to assess the risk of bias. We estimated incidence and hospitalisation rates of influenza-virus-associated respiratory infections by severity, case ascertainment, region, and age. We estimated in-hospital deaths from influenza virus ALRI by combining hospital admissions and in-hospital case-fatality ratios of influenza virus ALRI. We estimated the upper bound of influenza virus-associated ALRI deaths based on the number of in-hospital deaths, US paediatric influenza-associated death data, and population-based childhood all-cause pneumonia mortality data in six sites in low-income and lower-middle-income countries. Findings: In 2018, among children under 5 years globally, there were an estimated 109·5 million influenza virus episodes (uncertainty range [UR] 63·1–190·6), 10·1 million influenza-virus-associated ALRI cases (6·8–15·1); 870 000 influenza-virus-associated ALRI hospital admissions (543 000–1 415 000), 15 300 in-hospital deaths (5800–43 800), and up to 34 800 (13 200–97 200) overall influenza-virus-associated ALRI deaths. Influenza virus accounted for 7% of ALRI cases, 5% of ALRI hospital admissions, and 4% of ALRI deaths in children under 5 years. About 23% of the hospital admissions and 36% of the in-hospital deaths were in infants under 6 months. About 82% of the in-hospital deaths occurred in low-income and lower-middle-income countries. Interpretation: A large proportion of the influenza-associated burden occurs among young infants and in low-income and lower middle-income countries. Our findings provide new and important evidence for maternal and paediatric influenza immunisation, and should inform future immunisation policy particularly in low-income and middle-income countries. Funding: WHO; Bill & Melinda Gates Foundation.Fil: Wang, Xin. University of Edinburgh; Reino UnidoFil: Li, You. University of Edinburgh; Reino UnidoFil: O'Brien, Katherine L.. University Johns Hopkins; Estados UnidosFil: Madhi, Shabir A.. University of the Witwatersrand; SudáfricaFil: Widdowson, Marc Alain. Centers for Disease Control and Prevention; Estados UnidosFil: Byass, Peter. Umea University; SueciaFil: Omer, Saad B.. Yale School Of Public Health; Estados UnidosFil: Abbas, Qalab. Aga Khan University; PakistánFil: Ali, Asad. Aga Khan University; PakistánFil: Amu, Alberta. Dodowa Health Research Centre; GhanaFil: Azziz-Baumgartner, Eduardo. Centers for Disease Control and Prevention; Estados UnidosFil: Bassat, Quique. University Of Barcelona; EspañaFil: Abdullah Brooks, W.. University Johns Hopkins; Estados UnidosFil: Chaves, Sandra S.. Centers for Disease Control and Prevention; Estados UnidosFil: Chung, Alexandria. University of Edinburgh; Reino UnidoFil: Cohen, Cheryl. National Institute For Communicable Diseases; SudáfricaFil: Echavarría, Marcela Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; ArgentinaFil: Fasce, Rodrigo A.. Public Health Institute; ChileFil: Gentile, Angela. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Gordon, Aubree. University of Michigan; Estados UnidosFil: Groome, Michelle. University of the Witwatersrand; SudáfricaFil: Heikkinen, Terho. University Of Turku; FinlandiaFil: Hirve, Siddhivinayak. Kem Hospital Research Centre; IndiaFil: Jara, Jorge H.. Universidad del Valle de Guatemala; GuatemalaFil: Katz, Mark A.. Clalit Research Institute; IsraelFil: Khuri Bulos, Najwa. University Of Jordan School Of Medicine; JordaniaFil: Krishnan, Anand. All India Institute Of Medical Sciences; IndiaFil: de Leon, Oscar. Universidad del Valle de Guatemala; GuatemalaFil: Lucero, Marilla G.. Research Institute For Tropical Medicine; FilipinasFil: McCracken, John P.. Universidad del Valle de Guatemala; GuatemalaFil: Mira-Iglesias, Ainara. Fundación Para El Fomento de la Investigación Sanitaria; EspañaFil: Moïsi, Jennifer C.. Agence de Médecine Préventive; FranciaFil: Munywoki, Patrick K.. No especifíca;Fil: Ourohiré, Millogo. No especifíca;Fil: Polack, Fernando Pedro. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Rahi, Manveer. University of Edinburgh; Reino UnidoFil: Rasmussen, Zeba A.. National Institutes Of Health; Estados UnidosFil: Rath, Barbara A.. Vienna Vaccine Safety Initiative; AlemaniaFil: Saha, Samir K.. Child Health Research Foundation; BangladeshFil: Simões, Eric A.F.. University of Colorado; Estados UnidosFil: Sotomayor, Viviana. Ministerio de Salud de Santiago de Chile; ChileFil: Thamthitiwat, Somsak. Thailand Ministry Of Public Health; TailandiaFil: Treurnicht, Florette K.. University of the Witwatersrand; SudáfricaFil: Wamukoya, Marylene. African Population & Health Research Center; KeniaFil: Lay-Myint, Yoshida. Nagasaki University; JapónFil: Zar, Heather J.. University of Cape Town; SudáfricaFil: Campbell, Harry. University of Edinburgh; Reino UnidoFil: Nair, Harish. University of Edinburgh; Reino Unid

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p<0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p<0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised

Remdesivir and three other drugs for hospitalised patients with COVID-19: final results of the WHO Solidarity randomised trial and updated meta-analyses.

BACKGROUND World Health Organization expert groups recommended mortality trials of four repurposed antiviral drugs - remdesivir, hydroxychloroquine, lopinavir, and interferon beta-1a - in patients hospitalized with coronavirus disease 2019 (Covid-19). METHODS We randomly assigned inpatients with Covid-19 equally between one of the trial drug regimens that was locally available and open control (up to five options, four active and the local standard of care). The intention-to-treat primary analyses examined in-hospital mortality in the four pairwise comparisons of each trial drug and its control (drug available but patient assigned to the same care without that drug). Rate ratios for death were calculated with stratification according to age and status regarding mechanical ventilation at trial entry. RESULTS At 405 hospitals in 30 countries, 11,330 adults underwent randomization; 2750 were assigned to receive remdesivir, 954 to hydroxychloroquine, 1411 to lopinavir (without interferon), 2063 to interferon (including 651 to interferon plus lopinavir), and 4088 to no trial drug. Adherence was 94 to 96% midway through treatment, with 2 to 6% crossover. In total, 1253 deaths were reported (median day of death, day 8; interquartile range, 4 to 14). The Kaplan-Meier 28-day mortality was 11.8% (39.0% if the patient was already receiving ventilation at randomization and 9.5% otherwise). Death occurred in 301 of 2743 patients receiving remdesivir and in 303 of 2708 receiving its control (rate ratio, 0.95; 95% confidence interval [CI], 0.81 to 1.11; P = 0.50), in 104 of 947 patients receiving hydroxychloroquine and in 84 of 906 receiving its control (rate ratio, 1.19; 95% CI, 0.89 to 1.59; P = 0.23), in 148 of 1399 patients receiving lopinavir and in 146 of 1372 receiving its control (rate ratio, 1.00; 95% CI, 0.79 to 1.25; P = 0.97), and in 243 of 2050 patients receiving interferon and in 216 of 2050 receiving its control (rate ratio, 1.16; 95% CI, 0.96 to 1.39; P = 0.11). No drug definitely reduced mortality, overall or in any subgroup, or reduced initiation of ventilation or hospitalization duration. CONCLUSIONS These remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had little or no effect on hospitalized patients with Covid-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay. (Funded by the World Health Organization; ISRCTN Registry number, ISRCTN83971151; ClinicalTrials.gov number, NCT04315948.)

Elective Cancer Surgery in COVID-19-Free Surgical Pathways During the SARS-CoV-2 Pandemic: An International, Multicenter, Comparative Cohort Study.

PURPOSE: As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19-free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS: This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19-free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS: Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19-free surgical pathways. Patients who underwent surgery within COVID-19-free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19-free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score-matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19-free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION: Within available resources, dedicated COVID-19-free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks