FDA Breakthrough Therapy Designation Reduced Late-Stage Drug Development Time.

The Food and Drug Administration's (FDA's) breakthrough therapy designation (BTD) program was created to increase patient access to safe and effective therapies by supporting the efficient clinical development of qualifying, clinically meaningful therapies. Using a new data set of key development milestones for drugs approved between 2006 and 2020, including both BTD drugs and a set of comparator drugs identified by FDA experts, we estimated the BTD program's impact on time spent in late-stage clinical development, measured as the elapsed time between a drug's end-of-Phase-II meeting with regulators and its approval for marketing. Our analysis suggests that the BTD program lowers late-stage clinical development time by 30 percent. Our findings provide insight into future regulatory and innovation policies aimed at driving efficiency in medical product development to ensure timely patient access to the most clinically meaningful therapies.

Tracing Digital Therapeutics Research Across Medical Specialties: Evidence from ClinicalTrials.gov.

Digital therapeutics (DTx), evidence-based software interventions for preventing, managing, or treating medical disorders, have rapidly evolved with healthcare's shift toward online, patient-centric solutions. This study scrutinizes DTx clinical trials from 2005 to 2022, analyzing their growth, funding, underlying medical specialties, and other R&D characteristics, using ClinicalTrials.gov data. Our analysis includes trials categorized via the ICD-11 system, covering active, recruiting, or completed studies and considering trials listing multiple conditions. In analyzing 5,889 registered DTx trials, we document a more than five-fold increase in such trials since 2011, and a compound annual growth rate of 22.82% since 2005. While most trials were single-center, the median number of study subjects increased in recent years, driven by larger interventional trials. The key disciplines driving this growth were psychiatry, neurology, oncology, and endocrinology. Mental health dominated DTx trials in recent years, led by neurocognitive disorders, substance abuse disorders, and mood disorders. Industry funding varied across disciplines and was particularly high in visual system diseases and dermatology. DTx trials have surged since 2005, accelerated by recent growth in mental health trials. These trends mirror developments toward remote healthcare delivery, amplified by digital health investments during the COVID-19 pandemic. Growing numbers of participants in DTx trials point to increased demand for more robust trials. However, because most trials are single-center and country-specific, more international cooperation and harmonized evaluation standards will be essential for DTx trials to become more efficient and provide validation across countries, health systems, and groups of individuals.

GoT-Splice protocol for multi-omics profiling of gene expression, cell-surface proteins, mutational status, and RNA splicing in human cells.

Studying RNA splicing factor mutations is challenging due to difficulties in distinguishing wild-type and mutant cells within complex human tissues and inaccuracies associated with reconstructing splicing signals from short-read sequencing data. Here, we present Genotyping of Transcriptomes (GoT)-Splice, a protocol that overcomes these limitations by combining GoT with enhanced long-read single-cell transcriptome and cell-surface proteomics profiling. We describe steps for long-read library preparation and analysis, followed by cDNA re-amplification, enrichment of mutation of interest, sample indexing, and GoT library preparation. For complete details on the use and execution of this protocol, please refer to Cortés-López et al.1.

Differences in Care Team Response to Patient Portal Messages by Patient Race and Ethnicity.

Importance: The COVID-19 pandemic was associated with substantial growth in patient portal messaging. Higher message volumes have largely persisted, reflecting a new normal. Prior work has documented lower message use by patients who belong to minoritized racial and ethnic groups, but research has not examined differences in care team response to messages. Both have substantial ramifications on resource allocation and care access under a new care paradigm with portal messaging as a central channel for patient-care team communication. Objective: To examine differences in how care teams respond to patient portal messages sent by patients from different racial and ethnic groups. Design, Setting, and Participants: In a cross-sectional design in a large safety-net health system, response outcomes from medical advice message threads sent from January 1, 2021, through November 24, 2021, from Asian, Black, Hispanic, and White patients were compared, controlling for patient and message thread characteristics. Asian, Black, Hispanic, and White patients with 1 or more adult primary care visits at Boston Medical Center in calendar year 2020 were included. Data analysis was conducted from June 23, 2022, through December 21, 2023. Exposure: Patient race and ethnicity. Main Outcomes and Measures: Rates at which medical advice request messages were responded to by care teams and the types of health care professionals that responded. Results: A total of 39 043 patients were included in the sample: 2006 were Asian, 21 600 were Black, 7185 were Hispanic, and 8252 were White. A total of 22 744 (58.3%) patients were women and mean (SD) age was 50.4 (16.7) years. In 2021, these patients initiated 57 704 medical advice request message threads. When patients who belong to minoritized racial and ethnic groups sent these messages, the likelihood of receiving any care team response was similar, but the types of health care professionals that responded differed. Black patients were 3.95 percentage points (pp) less likely (95% CI, -5.34 to -2.57 pp; P < .001) to receive a response from an attending physician, and 3.01 pp more likely (95% CI, 1.76-4.27 pp; P < .001) to receive a response from a registered nurse, corresponding to a 17.4% lower attending response rate. Similar, but smaller, differences were observed for Asian and Hispanic patients. Conclusions and Relevance: The findings of this study suggest lower prioritization of patients who belong to minoritized racial and ethnic groups during triaging. Understanding and addressing these disparities will be important for improving care equity and informing health care delivery support algorithms.

Tepid Uptake of Digital Health Technologies in Clinical Trials by Pharmaceutical and Medical Device Firms.

Digital health technologies (DHTs) can enable more patient-centric therapeutic development by generating evidence that captures how patients feel and function, enabling decentralized trial designs that increase participant inclusivity and convenience, and collecting and structuring patient-generated data for regulators to use in approval decisions alongside traditional clinical outcomes. Although a growing body of evidence has documented increasing use of DHTs in clinical trials overall, the use of DHTs in clinical trials supporting medical product development is unclear; here, we quantify the use of DHTs in clinical trials sponsored by pharmaceutical and medical device firms. Despite interest from pharmaceutical and medical device manufacturers in DHTs, we find tepid uptake of DHTs in trials by these sponsor types over time. Further, to date, these sponsors have most frequently used conventional, hardware-based technologies that have been available for many years (e.g., Holter monitors and glucose meters) rather than newer activity monitors, mobile apps, and other online-based tools that are frequently used by non-industry sponsors. Considering the recent and evolving nature of regulatory guidance around DHT use in clinical trials, our findings suggest that organizations pursuing product development still appear hesitant to incorporate DHTs in trials that provide the most critical evidence for regulatory review and impact how new products are used. This suggests there are likely additional opportunities for sponsors of regulated trials to incorporate (more) DHTs and patient-centric endpoints into product development clinical trials. However, additional regulatory clarity and efforts to reduce operational barriers may be needed in order to more fully capture these opportunities.

mTORC1 activity oscillates throughout the cell cycle promoting mitotic entry and differentially influencing autophagy induction.

Mechanistic Target of Rapamycin Complex 1 (mTORC1) is a master metabolic regulator that stimulates anabolic cell growth while suppressing catabolic processes such as autophagy. mTORC1 is active in most, if not all, proliferating eukaryotic cells. However, it remains unclear whether and how mTORC1 activity changes from one cell cycle phase to another. Here we tracked mTORC1 activity through the complete cell cycle and uncover oscillations in its activity. We find that mTORC1 activity peaks in S and G2, and is lowest in mitosis and G1. We further demonstrate that multiple mechanisms are involved in controlling this oscillation. The interphase oscillation is mediated through the TSC complex, an upstream negative regulator of mTORC1, but is independent of major known regulatory inputs to the TSC complex, including Akt, Mek/Erk, and CDK4/6 signaling. By contrast, suppression of mTORC1 activity in mitosis does not require the TSC complex, and instead involves CDK1-dependent control of the subcellular localization of mTORC1 itself. Functionally, we find that in addition to its well-established role in promoting progression through G1, mTORC1 also promotes progression through S and G2, and is important for satisfying the Wee1- and Chk1- dependent G2/M checkpoint to allow entry into mitosis. We also find that low mTORC1 activity in G1 sensitizes cells to autophagy induction in response to partial mTORC1 inhibition or reduced nutrient levels. Together these findings demonstrate that mTORC1 is differentially regulated throughout the cell cycle, with important phase-specific functional consequences in proliferating cells.

Vitamin A deficiency impairs neutrophil-mediated control of Salmonella via SLC11A1 in mice.

In sub-Saharan Africa, multidrug-resistant non-typhoidal Salmonella serovars are a common cause of fatal bloodstream infection. Malnutrition is a predisposing factor, but the underlying mechanisms are unknown. Here we show that vitamin A deficiency, one of the most prevalent micronutrient deficits afflicting African children, increases susceptibility to disseminated non-typhoidal Salmonella disease in mice and impairs terminal neutrophil maturation. Immature neutrophils had reduced expression of Slc11a1, a gene that encodes a metal ion transporter generally thought to restrict pathogen growth in macrophages. Adoptive transfer of SLC11A1-proficient neutrophils, but not SLC11A1-deficient neutrophils, reduced systemic Salmonella burden in Slc11a1-/- mice or mice with vitamin A deficiency. Loss of terminal granulopoiesis regulator CCAAT/enhancer-binding protein ϵ (C/EBPϵ) also decreased neutrophil-mediated control of Salmonella, but not that mediated by peritoneal macrophages. Susceptibility to infection increased in Cebpe-/- Slc11a1+/+ mice compared with wild-type controls, in an Slc11a1-expression-dependent manner. These data suggest that SLC11A1 deficiency impairs Salmonella control in part by blunting neutrophil-mediated defence.

"If you're strung out and female, they will take advantage of you": A qualitative study exploring drug use and substance use service experiences among women in Boston and San Francisco.

BACKGROUND: Significant disparities in substance use severity and treatment persist among women who use drugs compared to men. Thus, we explored how identifying as a woman was related to drug use and treatment experiences. METHODS: The study recruited participants for a qualitative interview study in Boston and San Francisco from January-November 2020. Self-identified women, age ≥ 18 years, with nonprescribed opioid use in the past 14 days were eligible for inclusion. The study team developed deductive codes based on intersectionality theory and inductive codes generated from transcript review, and identified themes using grounded content analysis. RESULTS: The study enrolled thirty-six participants. The median age was 46; 58 % were White, 16 % were Black, 14 % were Hispanic, and 39 % were unstably housed. Other drug use was common with 81 % reporting benzodiazepine, 50 % cocaine, and 31 % meth/amphetamine use respectively. We found that gender (i.e., identifying as a woman) intersected with drug use and sex work practices and exacerbated experiences of marginalization. Violence was ubiquitous in drug use environments. Some women reported experiences of gender-based violence in substance use service settings that perpetuated cycles of trauma and reinforced barriers to care. Substance use services that were women-led, safe, and responsive to women's needs were valued and sought after. CONCLUSION: Women reported a cycle of trauma and drug use exacerbated by oppression in substance use services settings. In addition to increasing access to gender-responsive care, our study highlights the need for greater research and examination of practices within substance use service settings that may be contributing to gender-based violence.

RNA-mediated symmetry breaking enables singular olfactory receptor choice.

Olfactory receptor (OR) choice provides an extreme example of allelic competition for transcriptional dominance, where every olfactory neuron stably transcribes one of approximately 2,000 or more OR alleles1,2. OR gene choice is mediated by a multichromosomal enhancer hub that activates transcription at a single OR3,4, followed by OR-translation-dependent feedback that stabilizes this choice5,6. Here, using single-cell genomics, we show formation of many competing hubs with variable enhancer composition, only one of which retains euchromatic features and transcriptional competence. Furthermore, we provide evidence that OR transcription recruits enhancers and reinforces enhancer hub activity locally, whereas OR RNA inhibits transcription of competing ORs over distance, promoting transition to transcriptional singularity. Whereas OR transcription is sufficient to break the symmetry between equipotent enhancer hubs, OR translation stabilizes transcription at the prevailing hub, indicating that there may be sequential non-coding and coding mechanisms that are implemented by OR alleles for transcriptional prevalence. We propose that coding OR mRNAs possess non-coding functions that influence nuclear architecture, enhance their own transcription and inhibit transcription from their competitors, with generalizable implications for probabilistic cell fate decisions.

Breast Cancer Macrophage Heterogeneity and Self-renewal are Determined by Spatial Localization.

Tumor-infiltrating macrophages support critical steps in tumor progression, and their accumulation in the tumor microenvironment (TME) is associated with adverse outcomes and therapeutic resistance across human cancers. In the TME, macrophages adopt diverse phenotypic alterations, giving rise to heterogeneous immune activation states and induction of cell cycle. While the transcriptional profiles of these activation states are well-annotated across human cancers, the underlying signals that regulate macrophage heterogeneity and accumulation remain incompletely understood. Here, we leveraged a novel ex vivo organotypic TME (oTME) model of breast cancer, in vivo murine models, and human samples to map the determinants of functional heterogeneity of TME macrophages. We identified a subset of F4/80highSca-1+ self-renewing macrophages maintained by type-I interferon (IFN) signaling and requiring physical contact with cancer-associated fibroblasts. We discovered that the contact-dependent self-renewal of TME macrophages is mediated via Notch4, and its inhibition abrogated tumor growth of breast and ovarian carcinomas in vivo, as well as lung dissemination in a PDX model of triple-negative breast cancer (TNBC). Through spatial multi-omic profiling of protein markers and transcriptomes, we found that the localization of macrophages further dictates functionally distinct but reversible phenotypes, regardless of their ontogeny. Whereas immune-stimulatory macrophages (CD11C+CD86+) populated the tumor epithelial nests, the stroma-associated macrophages (SAMs) were proliferative, immunosuppressive (Sca-1+CD206+PD-L1+), resistant to CSF-1R depletion, and associated with worse patient outcomes. Notably, following cessation of CSF-1R depletion, macrophages rebounded primarily to the SAM phenotype, which was associated with accelerated growth of mammary tumors. Our work reveals the spatial determinants of macrophage heterogeneity in breast cancer and highlights the disruption of macrophage self-renewal as a potential new therapeutic strategy.

Dynamic HTA for digital health solutions: opportunities and challenges for patient-centered evaluation.

OBJECTIVES: Germany's 2019 Digital Healthcare Act (Digitale-Versorgung-Gesetz, or DVG) created a number of opportunities for the digital transformation of the healthcare delivery system. Key among these was the creation of a reimbursement pathway for patient-centered digital health applications (digitale Gesundheitsanwendungen, or DiGA). Worldwide, this is the first structured pathway for "prescribable" health applications at scale. As of October 10, 2023, 49 DiGA were listed in the official directory maintained by Germany's Federal Institute for Drugs and Medical Devices (BfArM); these are prescribable by physicians and psychotherapists and reimbursed by the German statutory health insurance system for all its 73 million beneficiaries. Looking ahead, a major challenge facing DiGA manufacturers will be the generation of the evidence required for ongoing price negotiations and reimbursement. Current health technology assessment (HTA) methods will need to be adapted for DiGA. METHODS: We describe the core issues that distinguish HTA in this setting: (i) explicit allowance for more flexible research designs, (ii) the nature of initial evidence generation, which can be delivered (in its final form) up to one year after becoming reimbursable, and (iii) the dynamic nature of both product development and product evaluation. We present the digital health applications in the German DiGA scheme as a case study and highlight the role of RWE in the successful evaluation of DiGA on an ongoing basis. RESULTS: When a DiGA is likely to be updated and assessed regularly, full-scale RCTs are infeasible; we therefore make the case for using real-world data and real-world evidence (RWE) for dynamic HTAs. CONCLUSIONS: Continous evaluation using RWD is a regulatory innovation that can help improve the quality of DiGAs on the market.

Effects of Remote Patient Monitoring Use on Care Outcomes Among Medicare Patients With Hypertension : An Observational Study.

BACKGROUND: Remote patient monitoring (RPM) is a promising tool for improving chronic disease management. Use of RPM for hypertension monitoring is growing rapidly, raising concerns about increased spending. However, the effects of RPM are still unclear. OBJECTIVE: To estimate RPM's effect on hypertension care and spending. DESIGN: Matched observational study emulating a longitudinal, cluster randomized trial. After matching, effect estimates were derived from a regression analysis comparing changes in outcomes from 2019 to 2021 for patients with hypertension at high-RPM practices versus those at matched control practices with little RPM use. SETTING: Traditional Medicare. PATIENTS: Patients with hypertension. INTERVENTION: Receipt of care at a high-RPM practice. MEASUREMENTS: Primary outcomes included hypertension medication use (medication fills, adherence, and unique medications received), outpatient visit use, testing and imaging use, hypertension-related acute care use, and total hypertension-related spending. RESULTS: 192 high-RPM practices (with 19 978 patients with hypertension) were matched to 942 low-RPM control practices (with 95 029 patients with hypertension). Compared with patients with hypertension at matched low-RPM practices, patients with hypertension at high-RPM practices had a 3.3% (95% CI, 1.9% to 4.8%) relative increase in hypertension medication fills, a 1.6% (CI, 0.7% to 2.5%) increase in days' supply, and a 1.3% (CI, 0.2% to 2.4%) increase in unique medications received. Patients at high-RPM practices also had fewer hypertension-related acute care encounters (-9.3% [CI, -20.6% to 2.1%]) and reduced testing use (-5.9% [CI, -11.9% to 0.0%]). However, these patients also saw increases in primary care physician outpatient visits (7.2% [CI, -0.1% to 14.6%]) and a $274 [CI, $165 to $384]) increase in total hypertension-related spending. LIMITATION: Lacked blood pressure data; residual confounding. CONCLUSION: Patients in high-RPM practices had improved hypertension care outcomes but increased spending. PRIMARY FUNDING SOURCE: National Institute of Neurological Disorders and Stroke.

A neural oscillatory signature of sustained anxiety.

BACKGROUND: Anxiety is a sustained response to uncertain threats; yet few studies have explored sustained neurobiological activities underlying anxious states, particularly spontaneous neural oscillations. To address this gap, we reanalysed magnetoencephalographic (MEG) data recorded during induced anxiety to identify differences in sustained oscillatory activity between high- and low-anxiety states. METHODS: We combined data from three previous MEG studies in which healthy adults (total N = 51) were exposed to alternating periods of threat of unpredictable shock and safety while performing a range of cognitive tasks (passive oddball, mixed-saccade or stop-signal tasks). Spontaneous, band-limited, oscillatory activity was extracted from middle and late intervals of the threat and safe periods, and regional power distributions were reconstructed with adaptive beamforming. Conjunction analyses were used to identify regions showing overlapping spectral power differences between threat and safe periods across the three task paradigms. RESULTS: MEG source analyses revealed a robust and widespread reduction in beta (14-30 Hz) power during threat periods in bilateral sensorimotor cortices extending into right prefrontal regions. Alpha (8-13 Hz) power reductions during threat were more circumscribed, with notable peaks in left intraparietal sulcus and thalamus. CONCLUSIONS: Threat-induced anxiety is underpinned by a sustained reduction in spontaneous beta- and alpha-band activity in sensorimotor and parietal cortical regions. This general oscillatory pattern likely reflects a state of heightened action readiness and vigilance to cope with uncertain threats. Our findings provide a critical reference for which to identify abnormalities in cortical oscillatory activities in clinically anxious patients as well as evaluating the efficacy of anxiolytic treatments.

A comparative case study of the accommodation of students with disabilities in online and in-person degree programs.

Fully online degree programs are an increasingly important part of the higher education ecosystem. Among the many challenges raised by the growth of fully online courses and degree programs is the question: Are institutions providing online students with disabilities accommodations that are comparable to those provided to students in traditional in-person degree programs? To explore this question, we compared students in a fully online biology degree program to students in the equivalent in-person degree program at a large research university. For each group, we assessed the frequency with which students register with the disability resource center, the range of specific accommodations provided, and course grades. Results show that students in the in-person program were nearly 30% more likely to be enrolled with the disability resource center, and that students in the online program were offered a narrower range of accommodations. However, in relative terms (i.e., compared to students without disabilities in their degree program), online students with disabilities perform better than in-person students with disabilities.

Federated electronic health records for the European Health Data Space.

The European Commission's draft for the European Health Data Space (EHDS) aims to empower citizens to access their personal health data and share it with physicians and other health-care providers. It further defines procedures for the secondary use of electronic health data for research and development. Although this planned legislation is undoubtedly a step in the right direction, implementation approaches could potentially result in centralised data silos that pose data privacy and security risks for individuals. To address this concern, we propose federated personal health data spaces, a novel architecture for storing, managing, and sharing personal electronic health records that puts citizens at the centre-both conceptually and technologically. The proposed architecture puts citizens in control by storing personal health data on a combination of personal devices rather than in centralised data silos. We describe how this federated architecture fits within the EHDS and can enable the same features as centralised systems while protecting the privacy of citizens. We further argue that increased privacy and control do not contradict the use of electronic health data for research and development. Instead, data sovereignty and transparency encourage active participation in studies and data sharing. This combination of privacy-by-design and transparent, privacy-preserving data sharing can enable health-care leaders to break the privacy-exploitation barrier, which currently limits the secondary use of health data in many cases.

Single-cell multi-omics defines the cell-type-specific impact of splicing aberrations in human hematopoietic clonal outgrowths.

RNA splicing factors are recurrently mutated in clonal blood disorders, but the impact of dysregulated splicing in hematopoiesis remains unclear. To overcome technical limitations, we integrated genotyping of transcriptomes (GoT) with long-read single-cell transcriptomics and proteogenomics for single-cell profiling of transcriptomes, surface proteins, somatic mutations, and RNA splicing (GoT-Splice). We applied GoT-Splice to hematopoietic progenitors from myelodysplastic syndrome (MDS) patients with mutations in the core splicing factor SF3B1. SF3B1mut cells were enriched in the megakaryocytic-erythroid lineage, with expansion of SF3B1mut erythroid progenitor cells. We uncovered distinct cryptic 3' splice site usage in different progenitor populations and stage-specific aberrant splicing during erythroid differentiation. Profiling SF3B1-mutated clonal hematopoiesis samples revealed that erythroid bias and cell-type-specific cryptic 3' splice site usage in SF3B1mut cells precede overt MDS. Collectively, GoT-Splice defines the cell-type-specific impact of somatic mutations on RNA splicing, from early clonal outgrowths to overt neoplasia, directly in human samples.

Recurrent photic zone euxinia limited ocean oxygenation and animal evolution during the Ediacaran.

The Ediacaran Period (~635-539 Ma) is marked by the emergence and diversification of complex metazoans linked to ocean redox changes, but the processes and mechanism of the redox evolution in the Ediacaran ocean are intensely debated. Here we use mercury isotope compositions from multiple black shale sections of the Doushantuo Formation in South China to reconstruct Ediacaran oceanic redox conditions. Mercury isotopes show compelling evidence for recurrent and spatially dynamic photic zone euxinia (PZE) on the continental margin of South China during time intervals coincident with previously identified ocean oxygenation events. We suggest that PZE was driven by increased availability of sulfate and nutrients from a transiently oxygenated ocean, but PZE may have also initiated negative feedbacks that inhibited oxygen production by promoting anoxygenic photosynthesis and limiting the habitable space for eukaryotes, hence abating the long-term rise of oxygen and restricting the Ediacaran expansion of macroscopic oxygen-demanding animals.

Technical comment on "Reexamination of 2.5-Ga 'whiff' of oxygen interval points to anoxic ocean before GOE".

Many lines of inorganic geochemical evidence suggest transient "whiffs" of environmental oxygenation before the Great Oxidation Event (GOE). Slotznick et al. assert that analyses of paleoredox proxies in the Mount McRae Shale, Western Australia, were misinterpreted and hence that environmental O2 levels were persistently negligible before the GOE. We find these arguments logically flawed and factually incomplete.