Digital health technologies (DHTs) are revolutionizing medical research, offering unprecedented insights into health monitoring and disease detection through continuous, real-world data collection. Here we characterize t...Digital health technologies (DHTs) are revolutionizing medical research, offering unprecedented insights into health monitoring and disease detection through continuous, real-world data collection. Here we characterize the data in one of the largest and most demographically rich DHT datasets as part of the All of Us Research Program. Through a historic device distribution effort, the program reached a broad range of participants nationwide, yielding a DHT dataset with an expanded a large demographic scope. This dataset contains Fitbit data from more than 59,000 participants spanning 14 years with more than 39 million step observations and 31 million sleep observations. Nearly half (46%) of participants with Fitbit data also contributed electronic health records, physical measurements, genomics and survey data. This resource enables researchers to study relationships between digital health metrics and clinical outcomes, advancing DHT methodologies through its large size, broad representation and multi-modal data linkage.
Hansford HJ, McAuley JH, Swanson SA
… +17 more, Islam N, Dahabreh IJ, Dickerman BA, Egger M, Garcia-Albeniz X, Golub RM, Lodi S, Moreno-Betancur M, Pearson SA, Schneeweiss S, Sterne JAC, Sharp MK, Jones MD, Stuart EA, Lee H, Hernán MA, Cashin AG
Thadhani R, Hiemstra TF, Vatish M
… +30 more, Stepan H, Cerdeira AS, Brockelsby J, James T, Lia M, Cornelis A, Krause E, Spath MR, Grüttner B, Todorova P, Hagmann H, Yeung KR, Xu B, Heffernan S, Pears S, Waugh R, Thompson J, Iliopoulos J, Sunderland N, Killingsworth M, Makris A, Hennessy A, Lo A, Tan AY, Kussie P, Chang Y, Hanssens L, Miltenyi S, Benzing T, Karumanchi SA
Soluble Fms-like tyrosine kinase 1 (sFlt-1), a protein secreted by the placenta, plays a central role in the pathogenesis of preeclampsia-a life-threatening pregnancy complication for which no disease-specific treatment...Soluble Fms-like tyrosine kinase 1 (sFlt-1), a protein secreted by the placenta, plays a central role in the pathogenesis of preeclampsia-a life-threatening pregnancy complication for which no disease-specific treatment currently exists. We developed a strategy to selectively deplete circulating sFlt-1 and then conducted a single-arm, open-label trial to reduce circulating sFlt-1 in women with very preterm preeclampsia. The primary endpoints were safety and tolerability. Extracorporeal apheresis with an adsorber containing high-affinity IgG1 antibodies against sFlt-1 resulted in an approximately 50% reduction of circulating sFlt-1 levels in pregnant baboons. In women with preterm preeclampsia treated with single ascending doses (phase A, n = 7, preapheresis, mean ± s.d., sFlt-1: 15,120 ± 4,484 pg ml), maternal and fetal vital signs and umbilical artery pulsatility indices remained stable when comparing measures before, during and after apheresis. In women with very preterm preeclampsia treated with multiple doses (phase B, n = 9, median gestational age 30.3 (interquartile range, 29.3-30.9) weeks, systolic and diastolic blood pressures 146 ± 10 and 92 ± 5 mmHg, respectively, and preapheresis circulating sFlt-1 levels 11,960 ± 3,056 pg ml), each apheresis reduced sFlt-1 levels by 16.7 ± 7.6% and mean arterial pressures by 4.1 ± 7.8 mmHg. Reductions in mean arterial pressures after apheresis strongly correlated with reductions in circulating sFlt-1 (R = 0.63, Spearman's correlation). Pregnancy continued from admission for a median of 10 (range, 3-19) days. Compared to antenatal estimated birth weights, neonatal birth weights generally remained stable or increased among those with the longest extensions. Treatment-related adverse events included mild hypocalcemia (n = 3), skin hemorrhage at the puncture site (n = 1) and false labor (n = 1). Selective removal of sFlt-1 by apheresis appeared to be safe and well tolerated in women with very preterm preeclampsia. Controlled trials are needed to confirm the additional safety and efficacy of this approach. ClinicalTrials.gov registration: NCT02923206 .
Diffuse intrinsic pontine glioma (DIPG) is the pediatric tumor with the worst prognosis. BIOMEDE was a randomized phase 2 trial comparing the efficacy in terms of overall survival (OS) (primary endpoint) of epidermal gro...Diffuse intrinsic pontine glioma (DIPG) is the pediatric tumor with the worst prognosis. BIOMEDE was a randomized phase 2 trial comparing the efficacy in terms of overall survival (OS) (primary endpoint) of epidermal growth factor receptor (EGFR) inhibitor erlotinib, mTOR inhibitor everolimus and multitargeted tyrosine kinase inhibitor dasatinib in combination with radiotherapy in patients with a biopsy-proven DIPG. Tumors were assessed centrally for immunohistochemical biomarkers (EGFR overexpression or PTEN loss) together with whole-exome and RNA sequencing. A cohort of 66 children with the same inclusion criteria and treated previously with temozolomide-based regimen was used to compare outcome. Treatment allocation was performed by randomization in 233 patients, designed so that a drug could not be allocated if the corresponding biomarker was absent: 36 received erlotinib, 102 received dasatinib and 95 received everolimus. The trial was ended for futility of the primary endpoint following the recommendations of the independent data monitoring committee: OS from biopsy was not different from the control cohort (median OS = 10.8 months (95% confidence interval (CI): 9.5-13.0)) in any of the three arms (median OS = 9.7 months (95% CI: 7.8-14.6) for erlotinib; 9.9 months (95% CI: 8.8-11.2) for dasatinib; and 11.9 months (95% CI: 10.7-14.2) for everolimus). Everolimus showed significantly less ocular, renal, skin and gastrointestinal side effects and treatment discontinuation for toxicity (secondary endpoint). TP53 mutations, frequently linked to multiple structural chromosomal aberrations, were the strongest predictor for poor survival in multivariate analysis (hazard ratio = 2.8 (95% CI: 1.9-4.2), P < 0.0001). Both mutations in and activation of the mTOR pathway were associated with a better response to everolimus. Four long-term survivors treated with an mTOR inhibitor were alive free of treatment over 6 years from diagnosis. With comprehensive tumor profiling, BIOMEDE validated prognostic biomarkers as well as informative theranostic biomarkers for future trials. ClinicalTrials.gov: NCT02233049 .
Phage therapy is an exciting strategy against antimicrobial-resistant bacterial infections, but critical knowledge gaps regarding its clinical application persist. Here we present a case study of a 22-year-old male patie...Phage therapy is an exciting strategy against antimicrobial-resistant bacterial infections, but critical knowledge gaps regarding its clinical application persist. Here we present a case study of a 22-year-old male patient with cystic fibrosis, presenting with a recurrent, invasive and ultimately lethal Bordetella bronchialis infection, who failed compassionate-use phage therapy. Using longitudinal clinical samples, we found that our patient harbored pre-existing antibodies against active prophages induced from the genome of the infecting pathogen. Notably, these antibodies may have contributed to clinical failure by cross-reacting with and effectively neutralizing therapeutic phage. We also uncovered bacterial heteroresistance, characterized by bacterial subpopulations from the initial infection with reduced phage susceptibility, as a possible further contributor to treatment failure. These findings highlight the intricate interplay between host immunology, bacterial genetic diversity and phage biology, bearing broad importance for clinical phage therapy. Future phage therapy patients, especially those with chronic infections, should be screened for antiphage immunity and bacterial heteroresistance before phage treatment.
Finkel RS, Crawford TO, Mercuri E
… +16 more, Sumner CJ, Garcia Romero MDM, Day JW, Montes J, Sun P, Tichler B, Paradis AD, Boesch E, Inra J, Littauer R, Sohn J, Monine M, Gambino G, Foster R, Farewell R, Fradette S
Kebede Y, Ndlovu N, Nabadda S
… +96 more, Sawadogo C, Fuller D, Pai M, Ashenafi A, Vojnov L, Kadam R, Kallarakal A, Jani I, Mushavi A, Jallow F, Coulibaly SO, Baptiste S, Ehrenkrantz P, Mertz C, Kang G, De Lussigny S, Ghadrshenas A, Fleming K, Kao K, Williams J, Van Germet W, Kaiser B, Gadde R, Rodriguez W, Fongwen N, Mataka A, Mashate S, Bryant J, Ondoa P, Otieno O, Kachuwaire O, Maryogo-Robinson L, Staley S, Agarwal N, Brodsky S, Patil A, Mesfin M, Anupindi R, Rupani S, Mbulawa M, Albert H, Kohli M, Pai N, Loembe M, Nyaruhirira A, Titanji B, Bhadelia N, Desalegn D, Mimbe D, Ochieng E, Mataranyika M, Biscornet L, Mulenga N, Tsai Y, Islam R, Williams F, Ndasi J, Ntoumi F, Lamorde M, Vubil A, Sultane T, Pal A, Magnet S, Maggiore P, Luo R, Sayed S, Shakoor S, Umutesi G, Domingo G, Bitilinyu-Bangoh J, Dieye A, Otieno C, Tamadea L, Murenzi G, Carter J, Ocen F, Capri A, Schroeder L, Wilson M, Gerth-Guyette E, Nsamba D, Awinibuno I, Odiabara K, Kujinga T, Rahman F, Ndlovu Z, Dumas D, Sambe N, Bansal Y, Qin ZZ, Donoso-Bach L, Estelle R, Dlamini S, Obiekea C, Bradley K, Peter T
Persistent gaps in access to quality diagnostic tests undermine progress toward improved health outcomes and resilience to disease outbreaks in Africa. Furthermore, resources for strengthening laboratory systems have fac...Persistent gaps in access to quality diagnostic tests undermine progress toward improved health outcomes and resilience to disease outbreaks in Africa. Furthermore, resources for strengthening laboratory systems have faced growing constraints owing to recent reductions in official direct financial assistance, highlighting an urgent need to identify investments that are high impact and minimally donor reliant. In this Perspective, we present a set of priority systems strengthening interventions based on expected impact and feasibility. These include the need for efficient and integrated testing networks, the establishment and implementation of national essential diagnostic lists, modernized procurement and supply chain practices, improved digital health standards and targeted strengthening of testing infrastructure for epidemic-prone diseases. These initiatives should be customized to local contexts and supported by reliable financing, enhanced national leadership and management capacity and updated policies. We propose that collective action focused on these priorities will improve health outcomes and be cost-saving-and will be superior to existing, more fragmented efforts to close gaps in testing. This also provides a pathway to self-reliance in health security and universal healthcare in the Africa region.