National Institutes Of Health Research Articles

Carlos A. Zarate, Jr.: Using clinical translational neuroscience to develop the next generation of antidepressant treatments that act more rapidly and effectively

Carlos A. Zarate, Jr., MD, spearheads transformative research in psychiatry and neuroscience. As a National Institutes of Health (NIH) Distinguished Investigator, he leads the Experimental Therapeutics and Pathophysiology Branch and the Section on the Neurobiology and Treatment of Mood Disorders at the National Institute of Mental Health (NIMH). His additional role as Clinical Professor of Psychiatry and Behavioral Sciences at George Washington University underscores his commitment to research and education. Dr. Zarate's pioneering work focuses on decoding the pathophysiology of treatment-resistant mood disorders and suicide while developing novel therapeutics that are reshaping approaches to patient care. His research integrates cutting-edge techniques from neuropsychopharmacology, electrophysiology, neuropsychology, neuroimaging, and genomics to forge new pathways in treating mood disorders. Perhaps most notably, Dr. Zarate's team has been instrumental in demonstrating that ketamine, an NMDA receptor antagonist, can produce rapid and long-lasting antidepressant and anti-suicidal effects. This discovery has catalyzed a paradigm shift in psychiatry, proving that antidepressant response within hours, not weeks, is achievable. Dr. Zarate's innovative approach extends beyond the lab. He employs a bi-directional translational strategy, seamlessly integrating clinical, behavioral, and imaging technologies with basic science collaborations. This holistic method has led to numerous breakthroughs in mood disorders research, addressing critical issues such as the speed and efficacy of current treatments. His exceptional contributions to the field have earned him numerous accolades, including election to the National Academy of Medicine in 2020. These honors recognize his research excellence, his innovative spirit, and his dedication to mentoring the next generation of scientists. We are privileged to feature Dr. Zarate in this Genomic Press interview. His insights promise to offer our readers a glimpse into the cutting edge of psychiatry and the tangible hope his work brings to millions suffering from mood disorders.

The Underuse of Clozapine and Long-Acting Injectable Antipsychotics.

Schizophrenia is among the most devastating and costly human diseases. The public face of the failure to appropriately treat schizophrenia includes approximately 100,000 homeless individuals with schizophrenia and related psychoses and 200,000 incarcerated individuals with similar diagnoses. Clozapine and long-acting injectable antipsychotics are among the most effective treatments, but both are markedly underused. The following organizations should take responsibility for fixing this problem: National Institute of Mental Health, Patient-Centered Outcomes Research Institute, Substance Abuse and Mental Health Services Administration, Centers for Medicare and Medicaid Services, U.S. Food and Drug Administration, American Psychiatric Association, and patient and family advocacy groups.

Prognostic significance of carotid artery stenosis in anterior circulation ischemic stroke patients

BackgroundThe carotid artery stenosis (CAS) is a notable risk element for ischemic stroke, accounting for 10 to 20% of such cases. There is a deficiency in research studies exploring the prognostic impact of CAS specifically in the anterior circulation acute ischemic stroke (AIS). Therefore, we conducted this study to evaluate the prognostic impact of CAS in individuals with anterior circulation AIS. Patients were categorized into two groups, patients with both anterior circulation AIS and CAS in comparison to patients with anterior circulation AIS without CAS (control group). We compared patient characteristics, neuroimaging, and outcome evaluations using a modified Rankin Scale (mRS) and the National Institute Health Stroke Scale (NIHSS) in both groups. P-value < 0.05 meaning statistical significance.ResultsFifty patients were involved in the current study; of them, 25 patients with both anterior circulation AIS and CAS and 25 patients with anterior circulation AIS without CAS. Both groups were comparable concerning age, gender, co-morbidities of diabetes, hypertension, smoking, and dyslipidemia with p-value > 0.05. The mean NIHSS was significantly elevated the CAS group compared to the control group (p = 0.037). Our results showed that patients with CAS ≥ 70% were associated with an mRS > 2 and a significantly higher NIHSS compared to control. The regression analysis showed that occlusion > 1/3, CAS ≥ 70%, and higher NIHSS score were considered independent predictors of mRS > 2. The mortality rate was significantly elevated in the CAS group versus the control group (p < 0.05). Both bilateral and unilateral CAS groups were comparable regarding NIHSS and mRS values.ConclusionPatients with anterior circulation AIS who had CAS of 70% or more, whether unilateral or bilateral, showed a higher likelihood of increased mortality and more severe strokes, as evidenced by elevated NIHSS and mRS scores.

Success and opportunities of the American Academy of Pediatrics Marshall Klaus research grant program in neonatal-perinatal medicine.

Physician-scientists are a crucial link between clinical practice and research. The American Academy of Pediatrics (AAP) initiated the Marshall Klaus Perinatal Research Award to enhance the development of research skills among physicians training in Neonatal-Perinatal Medicine. In this study, we sought to identify trends in funding along with geographical and demographic variables of the applicants and mentees and assess the applicants' scholarly productivity and funding from the National Institutes of Health (NIH). We reviewed the data of applicants and awardees from 2015-2024. We found that basic science applications had a higher funding likelihood than clinical/translational applications. The geographical distribution of awardees is skewed. There was a significant association between awardee status and K08 or K23 funding attainment. Future efforts should support more equitable award distribution and a diverse research landscape in neonatal-perinatal medicine.

7056 Can ChatGPT Educate Multicultural Patients About Metabolic Syndrome?

Abstract Disclosure: G. Wu: None. E. Cheng: None. V.V. Toram: None. K. Rosen: None. A. Wong: None. W. Zhao: None. M. Del Buono: None. Background: Metabolic Syndrome, which affects Asians, is a major risk factor for diabetes. According to the National Institute of Health (NIH), 1 in 3 Americans have Metabolic Syndrome. Diabetes affects 30 million Americans, and 8 million more are undiagnosed. ChatGPT and Bard are Artificial Intelligence (AI) mediated LLMs launched on 11/30/2022 and 3/21/2023, respectively, that generate real-time conversational responses. Purpose: Can ChatGPT educate our multicultural patients about metabolic syndrome? Methods: 1. User prompt into ChatGPT and Bard: What is metabolic syndrome? I am a South Asian male, 40 years old, with a cholesterol level of 250 and a fasting blood sugar level of 120. The exact prompt was used with an Asian male as a substitute. 2. The prompt was translated into Telugu, Hindi, Simplified Chinese, and Traditional Chinese via Google Translate. 3. Flesch-Kincade (FK) method of ascertaining reading level was used. FK is used by the US Department of Education. Results: Flesch-Kincaid reading ease: ChatGPT: English=29.2, Telugu=60.1, Hindi=33.4, Chinese (Trad.)=14.5, Chinese (Simp.)=22.6 Bard: English=35.3, Telugu=52, Hindi=51.7, Chinese (Trad.)=52, Chinese (Simp.)=36.8 Language Group Comparison to English: ChatGPT: Indian Languages p=0.004; Chinese Languages p=0.081. Bard: Indian Languages p=0.007; Chinese Languages p=0.136. Of note, the Telegu response has one incorrect response. Conclusions: In conclusion, ChatGPT and Bard can provide factual responses based on English prompts. Foreign prompts can yield inaccurate information. Physicians and their teams still need to supervise patient usage. Presentation: 6/2/2024

Xpert Breast Cancer STRAT4 Assay using fine-needle aspiration biopsy samples in a resource-constrained setting: a prospective diagnostic accuracy study

Use of fine-needle aspiration biopsy (FNAB) specimens on Xpert Breast Cancer STRAT4 Assay (STRAT4; Cepheid, Sunnyvale, CA, USA), a CE-marked in-vitro diagnostic medical device, could potentially increase access to breast cancer biomarker testing in resource-constrained settings. We aimed to assess the performance of a research use-only version of STRAT4 using FNAB specimens in Tanzania. In this prospective diagnostic accuracy study, patients aged 18 years or older with palpable breast masses presenting to the FNAB Clinic at Muhimbili National Hospital (Dar es Salaam, Tanzania) were recruited consecutively. Patients who were pregnant, lactating, or had a previous diagnosis of breast cancer were excluded. STRAT4 testing was performed on off-label FNAB samples using four protocols: the 1 × protocol (using the standard lysate method) on FNAB smears (1 × FNAB), quick lysis and Maui protocols (both on FNAB smears), and the 1 × protocol on formalin-fixed paraffin-embedded (FFPE) cell block material (1 × cell block). For 1 × FNAB and 1 × cell block, tissue was processed using FFPE lysis reagent, incubated at 80°C with proteinase K, and followed by addition of 95% or higher ethanol. Quick lysis was processed using FFPE lysis reagent and 95% or higher ethanol, whereas Maui was processed using a proprietary research-use only lysis reagent. The primary outcomes were overall concordance, sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) of STRAT4 as compared with immunohistochemistry or immunohistochemistry plus fluorescence in-situ hybridisation performed on cell blocks using clinically validated protocols in a Clinical Laboratory Improvement Amendments-accredited laboratory at the University of California, San Francisco (San Francisco, CA, USA). Between Nov 29, 2017, and Dec 17, 2020, 208 patients were enrolled. Of 208 cases, 51 (25%) were excluded from analysis because of insufficient tissue in the cell block or absent cell blocks, leaving 157 participants (all female) for analysis. For oestrogen receptor, 1 × FNAB had the best performance, with an overall concordance of 95% (95% CI 90-100), sensitivity of 94% (85-100), specificity of 97% (90-100), and AUC of 0·96 (0·81-1·00). For progesterone receptor, 1 × cell block had the best overall performance (overall concordance 89% [95% CI 84-95], sensitivity 91% [82-99], and specificity 89% [81-97], with an AUC of 0·93 [0·89-0·99]) and 1 × FNAB performed the best among the smear protocols, with a concordance of 84% (95% CI 74-93), sensitivity of 63% (43-82), specificity of 97% (92-100), and AUC of 0·91 (0·72-0·97). For HER2, Maui had the highest agreement, with an overall concordance of 93% (95% CI 89-98), sensitivity of 96% (88-100), specificity of 92% (87-98), and AUC of 0·95 (0·98-1·00). For Ki67, Maui had the best performance of smear protocols, with a concordance of 73% (95% CI 64-82), sensitivity of 70% (58-81), specificity of 81% (66-96), and AUC of 0·80 (0·54-0·82). Processing FNAB samples with STRAT4 is feasible in Tanzania, and performance for the oestrogen receptor is robust. Further optimisation of STRAT4 for FNAB has the potential to improve timely access to breast cancer diagnostics in resource-constrained settings. US National Institutes of Health; UCSF Global Cancer Program, Helen Diller Family Comprehensive Cancer Center; UCSF Department of Pathology; and Cepheid.

Frustrative Nonreward: Behavior, Circuits, Neurochemistry, and Disorders.

The surprising omission or reduction of vital resources (food, fluid, social partners) can induce an aversive emotion known as frustrative nonreward (FNR), which can influence subsequent behavior and physiology. FNR is an integral mediator of irritability/aggression, motivation (substance use disorders, depression), anxiety/fear/threat, learning/conditioning, and social behavior. Despite substantial progress in the study of FNR during the twentieth century, research lagged in the later part of the century and into the early twenty-first century until the National Institute of Mental Health's Research Domain Criteria initiative included FNR and loss as components of the negative valence domain. This led to a renaissance of new research and paradigms relevant to basic and clinical science alike. The COVID-19 pandemic's extensive individual and social restrictions were correlated with increased drug and alcohol use, social conflict, irritability, and suicide, all potential consequences of FNR. This article highlights animal models related to these psychiatric disorders and symptoms and presents recent advances in identifying the brain regions and neurotransmitters implicated.

B-079 Characterization of an isoelectric focusing method for detection of IgG oligoclonal banding in paired cerebrospinal fluid and serum specimens

Abstract Background Qualitative assessment of IgG-specific oligoclonal banding (OCB) in paired serum and cerebrospinal fluid (CSF) samples is useful for evaluating inflammatory conditions of the central nervous system such as multiple sclerosis. Here we characterized the performance of an IgG-specific method using isoelectric focusing on agarose gel matrix for the detection of OCB in paired serum and CSF samples. Methods Specimens of 20 paired, simultaneously collected CSF and serum patient samples were tested on Sebia (Hydrasys 2 System) provided by the National Institutes of Health (NIH) Diagnostic Laboratories. We tested these paired samples using the Helena IgG IFE-20 kit (SPIFE® Touch) method and the results were read by two independent individuals blinded to each other’s assessments. The results were compared to the NIH results for agreement. Positive Percent Agreement (PPA) and Negative Percent Agreement (NPA) were calculated. Analytical sensitivity of the Helena assay was assessed via serial dilutions of a CSF OCB positive sample (total IgG 4.5 mg/dL). Results Figure 1 shows serum and CSF pairs for the control (A), two example positive OCB patients (B &amp; D) and a negative OCB patient (C). The Helena assay was concordant with Sebia for 11/12 positive OCB patients (PPA 91.6%) and 8/8 negative subjects (NPA 100%). 20-fold was the highest dilution that remained positive. Conclusions OCB detection using paired serum and CSF samples and isoelectric focusing electrophoresis is considered the preferred method. The Helena IgG IFE-20 assay is such a method and showed high PPA and NPA concordance with the Sebia System. Thus, the Helena OCB assay can be considered an accurate and analytically sensitive method for assessing OCB in serum and CSF.

The relationship between radiation oncology department NIH funding and institutional community inclusion/investment.

153 Background: Disparities in healthcare access and funding allocation persist among racial minorities and low-income populations. Radiation Oncology departments play a crucial role in cancer treatment, yet the extent to which these departments serve historically underrepresented communities following receipt of National Institutes of Health (NIH) funding remains unclear. This study accessed the relationship between radiation oncology departments that are awarded National Institute of Health (NIH) funding and Lown Institute Hospitals Index rankings for community benefit and inclusivity. Methods: Radiation oncology departments awarded funding from the NIH from 2019-2021 were retrospectively studied. The 2023 Lown Institute Hospital Index rankings for community benefit and inclusivity were examined. The community benefit metric measures financial assistance spending, community investment spending, and Medicaid as a portion of patient revenue. The inclusivity metric measures the similarities of income, race, and education level between the hospital patient population and the surrounding community. Kendall’s correlation coefficient (tau value) and linear regression were used to evaluate the relationship between measures of community benefit and inclusivity and NIH radiation oncology department research funding. Results: Twenty-two radiation oncology departments that received NIH funding (median = $ 419,555.00) were included. A statistically significant positive correlation was observed between the amount of radiation oncology NIH research funding received and institutional rankings for overall community benefit (tau = 0.378; P &lt; 0.034), with a trend towards significance for institutional rankings for community investment spending (tau = 0.497; P &lt; 0.053). No significant correlation was observed between the amount of radiation oncology department funding and institutional rankings for charity care spending (P = 0.430), Medicaid as a portion of patient revenue (P = 0.837), and service of patients from racial and or ethnic minorities (P = 0.505), with low income (P = 0.612), or with lower levels of education (P = 0.700). Conclusions: Our study highlights the relationship between recent NIH funding received by Radiation Oncology departments and their commitment to community health and inclusivity. Our findings indicate a significantly positive correlation between NIH funding received by radiation oncology departments and overall community benefit. This suggests that departments receiving NIH funding may be incentivized to allocate resources towards initiatives to improve community health outcomes beyond direct patient care. This study prompts further exploration into the mechanisms through which NIH-funded radiation oncology departments allocate resources and engage with their surrounding communities.

Investigating the Applications of AI in Oncology from NIH Funded Projects: Case study of Lung Cancer and Pancreatic Cancer

ABSTRACTThis poster aims to conduct an examination of the applications of Artificial Intelligence (AI) in oncology. We collect projects from National Institutes of Health (NIH) which delve into how AI applications and techniques are used in cancer research between 2018 to 2024. Results show AI's ability to enhance lung and pancreatic cancer through novel imaging techniques and data processing. We find that refined medical imaging can be done with AI‐driven techniques such as machine learning or deep learning to improve diagnostic accuracy potentially leading to better survival rates for patients involved. Additionally, this reveals how AI transformed oncology studies underlining the movement toward complex diagnostic algorithms that allow accurate stage assignments. Consequently, these forms of teamwork are essential when determining as well as making reliable Cancer care systems by developing strong AI systems with interpretation abilities using supportive NIH funding.

Academic Metrics and Demographics and National Institutes of Health Grant Funding in IR

The goal of this study was to evaluate whether there is an association between academic productivity and National Institutes of Health (NIH) grant funding among academic interventional radiologists. A database containing board-certified U.S. interventional radiologists was previously created for a study evaluating the Hirsch index (h-index) in 2021. The Scopus database was used to add the h-index values for 2023. The NIH RePORTER system was queried to collect any data on NIH grant funding received by each interventional radiologist. Among the 832 interventional radiologists, 37 physicians received NIH grant funding (33 males and 4 females). Bivariate analysis showed that h-index and length of publication range were both positively and significantly correlated with NIH grant funding (coefficients, $731,696 [P < .001] and $2,957,922 [P < .001], respectively). However, no significant differences in NIH grant funding were found across academic ranks (P = .430) or sexes (P = .906). h-Index was significantly associated with higher NIH grant funding received by interventional radiologists.

Identifying Predictors of Successful Conversion from OREF Grants to Extramural Federal Funding Among Orthopaedic Surgeons

Background: Musculoskeletal diseases are a major contributor to global human disability, but research in this area of medicine contends with chronic underfunding in the United States, receiving &lt;2% of the National Institutes of Health (NIH) budget. The Orthopaedic Research and Education Foundation (OREF) serves as a vital nongovernmental organization, providing essential support for orthopaedic research. This study investigated the translation of various OREF grants into successful extramural federal funding discerning the clinician demographics and OREF award characteristics associated with increased chances of securing federal grants. Methods: We included OREF data from 1994 to 2020, and federal funding from the NIH, the U.S. Department of Defense (DoD), the National Science Foundation (NSF), and the Agency of Healthcare Research and Quality (AHRQ) was queried using publicly available databases: the NIH RePORTER, the DoD Defense Technical Information Center, the NSF search engine, and the AHRQ search engine. Clinician demographics and training were collected from the American Academy of Orthopaedic Surgeons roster and institution departmental websites. The successful translation of OREF grants into federal awards was assessed based on clinician gender, training, and specialty, as well as OREF grant mechanisms and characteristics; multivariable logistic regression was used to determine the likelihood of federal translation based on these predictor variables. Results: Three hundred and forty-eight OREF grants were awarded to 319 different clinicians, 23.5% of whom successfully translated their award into a federal grant. Notably, recipients of the OREF Career Development Grant (CDG) demonstrated a 48.4% translation rate to federal funding. The federal return on investment for all of the OREF grants averaged 503%, translating approximately $34 million in OREF awards into &gt;$200 million in federal funding. Logistic regression revealed that recipients who received CDG funding, as well as orthopaedic oncologists, were more than 3 times as likely to secure federal funding than those who received grants with other mechanisms and those in other subspecialties. Conclusions: OREF fills a vital role in supporting budding orthopaedic research careers, ensuring the field’s competitiveness for federal awards on a national scale. The success rates, particularly for CDG recipients, highlight OREF’s effectiveness in identifying promising surgeon-scientists.

Effectiveness, cost-effectiveness, and positive externalities of integrated chronic care for adults with major depressive disorder in Malawi (IC3D): a stepped-wedge, cluster-randomised, controlled trial

In low-income and middle-income countries, individuals with major depressive disorder often do not receive screening and treatment. We assessed effectiveness and cost-effectiveness of an integrated care model for treating major depressive disorder in Malawi, accounting for two sets of positive externalities: household benefits and improvements in comorbidities. In this stepped-wedge, cluster-randomised, controlled trial, 14 health facilities in Neno District, Malawi, introduced screening, diagnosis, and treatment for people with major depressive disorder, using a stepped-care model of group Problem Management Plus and antidepressant therapy. Adults (ie, aged ≥18 years) residing in facility catchment areas, newly diagnosed with major depressive disorder, and actively enrolled in an integrated chronic care clinic were eligible for inclusion. People identified with high suicidal risk or psychotic symptoms were excluded. Health facilities were categorised into two strata (ie, health centres or secondary hospitals) and randomly allocated to one of five trial sequences, with intervention initiation staggered across sequences in 3-month periods. Participants were masked to trial sequence, data collectors were masked to treatment assignment, and the chief statistician was masked to treatment assignment until analysis. Services were delivered by counsellors and clinical officers at integrated chronic care clinics, and assessments took place at 3-month intervals over 27 months. Primary outcomes were changes in depressive symptom severity (measured with the Patient Health Questionnaire-9 [PHQ-9]), current depressive episode (PHQ-9 score of >10), and functioning (measured with the WHO Disability Assessment Schedule 2.0) over the 27-month period. Longitudinal mixed-effects regression analyses assessed outcomes from an intention-to-treat perspective. The trial was registered with ClinicalTrials.gov (NCT04777006) and is completed. Between Sept 1, 2021, and April 28, 2022, we conducted 15 562 screenings, resulting in 506 (3%) adults identified with major depressive disorder and 487 (3%) enrolled (395 [81%] women and 92 [19%] men). Assignment to IC3D corresponded to a 2·60-point (95% CI -3·35 to -1·86; d -0·61) reduction in depressive symptoms and 1·69-point (-2·73 to -0·65; -0·27) improvement in functioning, reflecting a reduced odds of depression after treatment roll-out (adjusted odds ratio 0·62, 95% CI 0·51 to 0·74). Integrated care for people with major depressive disorder and chronic health conditions is effective at reducing depressive symptoms, improving functioning, and reducing the odds of depression, and facilitates expansion of services through existing infrastructure. National Institute of Mental Health.

Deep learning assessment of senescence-associated nuclear morphologies in mammary tissue from healthy female donors to predict future risk of breast cancer: a retrospective cohort study

Cellular senescence has been associated with cancer as either a barrier mechanism restricting autonomous cell proliferation or a tumour-promoting microenvironmental mechanism that secretes proinflammatory paracrine factors. With most work done in non-human models and the heterogeneous nature of senescence, the precise role of senescent cells in the development of cancer in humans is not well understood. Furthermore, more than 1 million non-malignant breast biopsies are taken every year that could be a major resource for risk stratification. We aimed to explore the clinical relevance for breast cancer development of markers of senescence in mammary tissue from healthy female donors. In this retrospective cohort study, we applied single-cell deep learning senescence predictors, based on nuclear morphology, to histological images of haematoxylin and eosin-stained breast biopsy samples from healthy female donors at the Komen Tissue Bank (KTB) at the Indiana University Simon Cancer Center (Indianapolis, IN, USA). All KTB participants (aged ≥18 years) who underwent core biopsies for research purposes between 2009 and 2019 were eligible for the study. Senescence was predicted in the epithelial (terminal duct lobular units [TDLUs] and non-TDLU epithelium), stromal, and adipose tissue compartments using validated models, previously trained on cells induced to senescence by ionising radiation (IR), replicative exhaustion (or replicative senescence; RS), or antimycin A, atazanavir-ritonavir, and doxorubicin (AAD) exposures. To benchmark our senescence-based cancer prediction results, we generated 5-year Gail scores-the current clinical gold standard for breast cancer risk prediction-for participants aged 35 years and older on the basis of characteristics at the time of tissue donation. The primary outcome was estimated odds of breast cancer via logistic modelling for each tissue compartment based on predicted senescence scores in cases (participants who had been diagnosed with breast cancer as of data cutoff, July 31, 2022) and controls (those who had not been diagnosed with breast cancer). 4382 female donors (median age at donation 45 years [IQR 34-57]) were eligible for the study. As of data cutoff (median follow-up of 10 years [7-11]), 86 (2·0%) had developed breast cancer a mean of 4·8 years (SD 2·84) after date of donation and 4296 (98·0%) had not received a breast cancer diagnosis. Among the 86 cases, we found significant differences in adipose-specific IR and AAD senescence prediction scores compared with controls. Risk analysis showed that individuals in the upper half (above the median) of scores for the adipose tissue IR model had higher odds of developing breast cancer (odds ratio [OR] 1·71 [95% CI 1·10-2·68]; p=0·019), whereas the adipose AAD model revealed a reduced odds of developing breast cancer (OR 0·57 [0·36-0·88]; p=0·013). For the other tissue compartments and the RS model, no significant associations were found (except for stromal tissue via the IR model, had higher odds of developing breast cancer [OR 1·59, 1·03-2·49]). Individuals with both of the adipose risk factors had an OR of 3·32 (1·68-7·03; p=0·0009). Participants with 5-year Gail scores above the median had an OR for development of cancer of 2·33 (1·46-3·82; p=0·0012) compared with those with scores below the median. When combining Gail scores with our adipose AAD risk model, we found that individuals with both of these predictors had an OR of 4·70 (2·29-10·90; p<0·0001). When combining the Gail score with our adipose IR model, we found that individuals with both predictors had an OR of 3·45 (1·77-7·24; p=0·0002). Assessment of senescence-associated nuclear morphologies with deep learning allows prediction of future cancer risk from normal breast biopsy samples. The combination of multiple models improved prediction of future breast cancer compared with the current clinical benchmark, the Gail model. Our results suggest an important role for microscope image-based deep learning models in predicting future cancer development. Such models could be incorporated into current breast cancer risk assessment and screening protocols. Novo Nordisk Foundation, Danish Cancer Society, and the US National Institutes of Health.

Psychosocial and mental health concerns among elderly people during COVID-19: Findings from national helpline in India

ABSTRACT Background: WHO reported that the epidemic SARS-CoV-2 spread was a public health emergency of international tension in January 2020 and pandemic in March 2020. In this regard, National Institute of Mental Health and Neuro Sciences (NIMHANS) launched a national helpline with the support of the Ministry of Health and Family Welfare for addressing psychosocial issues and mental health concerns of people during the COVID-19 pandemic. The recorded calls made to the National Psychosocial Support helpline were analysed to elicit the psychosocial issues seen among the elderly during the pandemic. Methods: The data of 70 randomly selected helpline callers were collected by using the sociodemographic data sheet and the semistructured questionnaire. The study employed descriptive research design. Results: In total, 71.1% of callers belonged to the 60-70 years’ age group. 57.1% of callers had approached the helpline by themselves. 38.6% of the callers had reported a preexisting mental illness, of which the majority (33%) reported anxiety and/or sleeplessness. 28.6% of callers complained of comorbid medical issues. Interventions provided to the callers were in the form of supportive psychotherapy (84.28%), the COVID-19-related information (72.85%), referral services (62.9%), lifestyle modifications (41.42%), and behavioural activation (35.71%). Conclusion: Study findings indicate that the older population encountered several mental health issues during COVID-19, and the telephonic interventions were the most feasible, accessible, and helpful method to reach out to them.

Patient-Reported Outcomes in Early Phase Trials for Patients with Myelodysplastic Syndromes

Patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) experience a wide range of symptoms due both to their underlying disease and the effects of treatment. Designing early phase trials to explore effective therapies in these patients should not only examine anti-tumor activity, but also consider the effects of treatments on how patients feel and function. Assessing symptomatic toxicities associated with new therapies in early phase trials from the patient perspective is best measured using patient-reported outcomes (PROs) and offers valuable insight and complementary information to the traditional adverse event reporting in cancer clinical trials. This review describes PROs, highlights their importance in MDS drug development, and outlines the key psychometric properties and practical considerations that make PROs essential and desirable in evaluating the impact of new therapies. We will provide a general overview of PROs and follow with application of PROs in MDS/AML including strategies to be considered in early phase trials. Finally, we describe the creation of the Office of Patient-Centered Outcomes Research at the US National Institutes of Health which has developed a standardized PROs methodology for early phase trials conducted in the Center for Cancer Research at the US National Cancer Institute.

Re-emergence of Oropouche virus between 2023 and 2024 in Brazil: an observational epidemiological study

Oropouche virus is an arthropod-borne virus that has caused outbreaks of Oropouche fever in central and South America since the 1950s. This study investigates virological factors contributing to the re-emergence of Oropouche fever in Brazil between 2023 and 2024. In this observational epidemiological study, we combined multiple data sources for Oropouche virus infections in Brazil and conducted in-vitro and in-vivo characterisation. We collected serum samples obtained in Manaus City, Amazonas state, Brazil, from patients with acute febrile illnesses aged 18 years or older who tested negative for malaria and samples from people with previous Oropouche virus infection from Coari municipality, Amazonas state, Brazil. Basic clinical and demographic data were collected from the Brazilian Laboratory Environment Management System. We calculated the incidence of Oropouche fever cases with data from the Brazilian Ministry of Health and the 2022 Brazilian population census and conducted age-sex analyses. We used reverse transcription quantitative PCR to test for Oropouche virus RNA in samples and subsequently performed sequencing and phylogenetic analysis of viral isolates. We compared the phenotype of the 2023-24 epidemic isolate (AM0088) with the historical prototype strain BeAn19991 through assessment of titre, plaque number, and plaque size. We used a plaque reduction neutralisation test (PRNT50) to assess the susceptibility of the novel isolate and BeAn19991 isolate to antibody neutralisation, both in serum samples from people previously infected with Oropouche virus and in blood collected from mice that were inoculated with either of the strains. 8639 (81·8%) of 10 557 laboratory-confirmed Oropouche fever cases from Jan 4, 2015, to Aug 10, 2024, occurred in 2024, which is 58·8 times the annual median of 147 cases (IQR 73-325). Oropouche virus infections were reported in all 27 federal units, with 8182 (77·5%) of 10 557 infections occurring in North Brazil. We detected Oropouche virus RNA in ten (11%) of 93 patients with acute febrile illness between Jan 1 and Feb 4, 2024, in Amazonas state. AM0088 had a significantly higher replication at 12 h and 24 h after infection in mammalian cells than the prototype strain. AM0088 had a more virulent phenotype than the prototype in mammalian cells, characterised by earlier plaque formation, between 27% and 65% increase in plaque number, and plaques between 2·4-times and 2·6-times larger. Furthermore, serum collected on May 2 and May 20, 2016, from individuals previously infected with Oropouche virus showed at least a 32-fold reduction in neutralising capacity (ie, median PRNT50 titre of 640 [IQR 320-640] for BeAn19991 vs <20 [ie, below the limit of detection] for AM0088) against the reassortant strain compared with the prototype. These findings provide a comprehensive assessment of Oropouche fever in Brazil and contribute to an improved understanding of the 2023-24 Oropouche virus re-emergence. Our exploratory in-vitro data suggest that the increased incidence might be related to a higher replication efficiency of a new Oropouche virus reassortant for which previous immunity shows lower neutralising capacity. São Paulo Research Foundation, Burroughs Wellcome Fund, Wellcome Trust, US National Institutes of Health, and Brazilian National Council for Scientific and Technological Development. For the Portuguese translation of the abstract see Supplementary Materials section.

The effect of Plasmodium falciparum exposure and maternal anti-circumsporozoite protein antibodies on responses to RTS,S/AS01E vaccination in infants and children: an ancillary observational immunological study to a phase 3, randomised clinical trial

The RTS,S/AS01E malaria vaccine showed lower antibody response and protective efficacy in infants aged 6-12 weeks compared with children aged 5-17 months (for whom this vaccine is recommended). We aimed to study the effect of previous Plasmodium falciparum exposure on the antibody responses to RTS,S/AS01E vaccination in infants and children, and the mediating effect of baseline (including maternal) anti-circumsporozoite protein (CSP) antibodies. In this observational study, we included children and infants from six African countries (Burkina Faso, Gabon, Ghana, Kenya, Mozambique, and Tanzania) enrolled in the MAL067 immunology ancillary study of the RTS,S/AS01E phase 3 clinical trial from March 27, 2009, to Jan 21, 2011. We used comparator-vaccinated infants and children to identify antibody-based signatures of previous P falciparum exposure, which were later applied to RTS,S/AS01E-vaccinated infants and children. In these participants, we explored the relationship between vaccine antibody immunoglobulin G (IgG) responses measured by ELISA and pre-vaccination serological markers of malaria exposure by assessing the IgG levels against 1000 P falciparum antigens using partial proteome microarrays. We included 718 comparator-vaccinated infants (348 [48%]) and children (370 [52%]) and 606 RTS,S/AS01E-vaccinated infants (329 [54%]) and children (277 [46%]). Anti-CSP IgG responses to primary vaccination did not correlate with a baseline signature of previous exposure in children, suggesting that prior P falciparum exposure does not significantly affect antibody immunogenicity in children (Pearson's r=-0·02 [95% CI -0·13 to 0·10]). By contrast, high P falciparum exposure signature levels at the time of vaccination in infants, presumably driven by maternally transferred antibodies and declining within the initial 6-12 months of life, correlated with reduced RTS,S/AS01E responses (r=-0·17 [-0·27 to -0·06]). This negative correlation was stronger for anti-CSP IgG than for the exposure signature or any other more immunogenic blood stage P falciparum antigens (r=-0·42 [-0·50 to -0·33]), persisted after adjustment by baseline levels of the exposure signature (semi-partial correlation r=-0·44 [-0·55 to -0·33]), and involved antibodies to the central NANP region (r=-0·39 [-0·49 to -0·28]) but not the C-terminal region (r=0·02 [-0·10 to 0·15]) of CSP. The negative effect of maternal anti-CSP IgG in infants did not appear to be confounded by other malaria transmission-dependent variables. Interference between passive immunity and vaccine response is clinically significant and might affect the implementation of next-generation CSP-based vaccines for young infants and mothers as well as passive immunisation with human monoclonal antibodies. US National Institutes of Health, National Institute of Allergy and Infectious Diseases; PATH-Malaria Vaccine Initiative; Spanish Ministerio de Economía y Competitividad (Instituto de Salud Carlos III), European Regional Development Fund and European Social Fund; Fundación Ramón Areces; Spanish Ministry of Science and Innovation; and Generalitat de Catalunya (CERCA Program).

Effectiveness of Integrating Suicide Care in Primary Care : Secondary Analysis of a Stepped-Wedge, Cluster Randomized Implementation Trial.

Primary care encounters are common among patients at risk for suicide. To evaluate the effectiveness of implementing population-based suicide care (SC) in primary care for suicide attempt prevention. Secondary analysis of a stepped-wedge, cluster randomized implementation trial. (ClinicalTrials.gov: NCT02675777). 19 primary care practices within a large health care system in Washington State, randomly assigned launch dates. Adult patients (aged ≥18 years) with primary care visits from January 2015 to July 2018. Practice facilitators, electronic medical record (EMR) clinical decision support, and performance monitoring supported implementation of depression screening, suicide risk assessment, and safety planning. Clinical practice and patient measures relied on EMR and insurance claims data to compare usual care (UC) and SC periods. Primary outcomes included documented safety planning after population-based screening and suicide risk assessment and suicide attempts or deaths (with self-harm intent) within 90 days of a visit. Mixed-effects logistic models regressed binary outcome indicators on UC versus SC, adjusted for randomization stratification and calendar time, accounting for repeated outcomes from the same site. Monthly outcome rates (percentage per 10 000 patients) were estimated by applying marginal standardization. During UC, 255 789 patients made 953 402 primary care visits and 228 255 patients made 615 511 visits during the SC period. The rate of safety planning was higher in the SC group than in the UC group (38.3 vs. 32.8 per 10 000 patients; rate difference, 5.5 [95% CI, 2.3 to 8.7]). Suicide attempts within 90 days were lower in the SC group than in the UC group (4.5 vs. 6.0 per 10 000 patients; rate difference, -1.5 [CI, -2.6 to -0.4]). Suicide care was implemented in combination with care for depression and substance use. Implementation of population-based SC concurrent with a substance use program resulted in a 25% reduction in the suicide attempt rate in the 90 days after primary care visits. National Institute of Mental Health.

Safety and immunogenicity of a delayed booster dose of the rVSVΔG-ZEBOV-GP vaccine for prevention of Ebola virus disease: a multicentre, open-label, phase 2 randomised controlled trial

rVSVΔG-ZEBOV-GP is the first approved vaccine with clinical efficacy against Ebola virus disease. Although a seroprotective threshold has not been defined for those at occupational risk of exposure, the current vaccine strategy is to attain a sustained high level of antibody titres. The aim of this trial was to explore the effects of delayed boosting upon both the height and duration of antibody titres following primary immunisation. In this open-label phase 2 randomised controlled trial, we compared antibody titres at month 36in participants who had received a homologous booster dose at month 18following primary immunisation with those who had received no booster. From Oct 25, 2016, to Jan 29, 2020, healthy adults aged 18years or older deemed at occupational risk of exposure to Ebola virus due to laboratory work, clinical duties, or travel to an active endemic region were recruited from four hospital clinics in the USA and one hospital clinic in Canada and received primary vaccination with 2×107 plaque-forming unit per mL of VSVΔG-ZEBOV-GP. 18months later, individuals who consented and were still eligible were randomly assigned 1:1 to receive either a homologous booster dose or no booster. Study visits for safety and serial blood collections for antibody titres were done on enrolled participants at months 0, 1, 3, 6, 12, 18, 19, 24, 30, and 36. Through July, 2021, a web-based application was used for randomisation, including assignments with schedules for each of the five sites using mixed permuted blocks. The trial was not masked to participants or site staff. The primary endpoint was a comparison of geometric mean titres (GMTs) of anti-Ebola virus glycoprotein IgG antibody at month 36 (ie, 18months after randomisation) for all randomly assigned participants who completed the 36months of follow-up (primary analysis cohort). Investigators were aware of antibody titres from baseline (enrolment) through month 18but were masked to summary data by randomisation group after month 18. This study is registered with ClinicalTrials.gov (NCT02788227). Of the 248participants who enrolled and received their primary immunisation, 114proceeded to the randomisation step at month 18. The two randomisation groups were balanced: 57participants (24 [42%] of whom were female; median age was 42years [IQR 35-50]) were randomly assigned to the booster group and 57 (24 [42%] of whom were female; median age was 42years [IQR 36-51]) to the no-booster group. Of those randomly assigned, 92participants (45 in the booster group and 47in the no-booster group) completed 36months of follow-up. At 18months after primary immunisation, GMTs in the no-booster group increased from a baseline of 10ELISA units (EU)/mL (95% CI 7-14) to 1451EU/mL (1118-1882); GMTs in the booster group increased from 9EU/mL (6-16) to 1769EU/mL (1348-2321). At month 19, GMTs were 31 408EU/mL (23 181-42 554) for the booster group and 1406EU/mL (1078-1833) for the no-booster group; at month 36, GMTs were 10 146EU/mL (7960-12 933) for the booster group and 1240EU/mL (984-1563) for the no-booster group. Accordingly, the geometric mean ratio (GMR) of antibody titres had increased almost 21-fold more in the booster versus no-booster group at 1month after booster administration (GMR 20·6; 95% CI 18·2-23·0; p<0·0001) and was still over 7-fold higher at month 36 (GMR 7·8; 95% CI 5·5-10·2; p<0·0001). Consistent with previous reports of this vaccine's side-effects, transient mono-articular or oligo-articular arthritis was diagnosed in 18 (9%) of 207primary vaccination recipients; after randomisation, arthritis was diagnosed in one (2%)of 57participants in the no-booster group. No new cases of arthritis developed after booster administration. Four serious adverse events occurred following randomisation: one (epistaxis) in the booster group and three (gastrointestinal haemorrhage, prostate cancer, and tachyarrhythmia) in the no-booster group. None of the serious adverse events was judged attributable to the booster vaccination assignment. In addition to no new safety concerns and in marked contrast to earlier trials evaluating short-term boosting, delaying a rVSVΔG-ZEBOV-GP booster until month 18resulted in an increase in GMT that remained several-fold above the no-booster group GMT for at least 18months. These findings could have implications for defining the optimal timing of booster doses as pre-exposure prophylaxis in populations at ongoing risk for Ebola virus exposure. The Division of Intramural Research and the Division of Clinical Research of the National Institute of Allergyand Infectious Diseases at the US National Institutes of Health, Canadian Immunization Research Network through the Public Health Agency of Canada, Canadian Institutes of Health Research, and the US Defense Threat Reduction Agency.