National Institutes Of Health Research Articles

Early functional improvements using continuous passive motion therapy after angular-stable plate osteosynthesis of proximal humerus fractures – results of a prospective, randomized trial

BackgroundThe use of continuous passive motion therapy (CPM) has led to promising results in the early phase of rehabilitation after surgical treatment of rotator cuff tears and arthrolysis of the elbow. However, its use has not been proven in other pathologies of the upper extremity. Therefore, the aim of the underlying study was to evaluate the use of CPM therapy after plate osteosynthesis of proximal humeral fractures.Methods95 patients with isolated proximal humerus fractures were enrolled in a prospective, randomized study. Patients were assigned to a treatment group with (n = 48, CPM) or without CPM therapy (n = 47, CG). Four patients (2 of each cohort) violated the study protocol and were excluded. CPM therapy was used for 6 weeks after surgery 2–3 times daily. Functional (range of motion) and patient reported outcomes (PROM, Constant Score [CSS], QuickDASH, subjective shoulder value [SSV], pain on visual analogue scale [VAS]) were evaluated at 6 weeks, 3 and 12months. 60 patients completed the 1-year follow-up.ResultsThe average patient age was 65.3 years (min: 27, max: 88, SD: ± 14.7). Seventy-two patients were female (79%). There was no difference regarding injury severity (2/3/4 part-fracture: 6/32/7 vs. 9/26/11, p = 0.867) and sex (p = 0.08). However, patients in the CPM group were significantly younger (CPM: 67 [min: 34, max: 82], CG: 74 [min: 27, max: 88], p = 0.032). After 6 weeks we observed a better range of motion for forward flexion (CPM: 90° [min: 50°, max: 180°] vs. CG: 80° [min: 20°, max: 170°] p = 0.035) and abduction (CPM: 80° [min: 40°, max: 180°] vs. CG: 70° [min: 20°, max: 180°], p = 0.048) in the CPM group. There was no difference regarding the further planes of motion or the assessed PROMs at 6 weeks. At 3 and 12 months the results between the treatment groups equalized with no further significant differences.ConclusionThe treatment with CPM increases the range of motion after plate osteosynthesis of proximal humerus fractures in the first 6 weeks after surgery. This effect is not sustained after 3 and 12months. The evaluated PROMs are not being influenced by CPM therapy. Hence the results of this prospective randomized study suggest that CPM can be a beneficial asset in the early period of rehabilitation after proximal humerus plate osteosynthesis.Trial registrationThe study protocol was registered in the US National Institutes of Health’s database (http://www.clinicaltrials.gov) registry under NCT 05952622.

A systematic review and meta-analysis of Murray's Law in the Coronary Arterial Circulation.

Murray's law has been viewed as a fundamental law of physiology. Relating blood flow (Q) to vessel diameter (D) (Q µD3), it dictates minimum lumen area (MLA) targets for coronary bifurcation percutaneous coronary intervention (PCI). The cubic exponent (3.0) however, has long been disputed, with alternative theoretical derivations arguing this should be closer to 2.33 (7/3). The aim of this meta-analysis was to quantify the optimum flow-diameter exponent in human and mammalian coronary arteries. We conducted a systematic review and meta-analysis of all articles quantifying an optimum flow-diameter exponent for mammalian coronary arteries within the Cochrane library, PubMed Medline, Scopus, and Embase databases on 20/3/2023. A random-effects meta-analysis was used to determine a pooled flow-diameter exponent. Risk of bias was assessed with the National Institutes of Health (NIH) quality assessment tool, funnel plots and Egger regression. From a total of 4,524 articles, 18 were suitable for meta-analysis. Studies included data from 1,070 unique coronary trees, taken from 372 humans and 112 animals. The pooled flow diameter exponent across both epicardial and transmural arteries was 2.39 (95% CI 2.24 - 2.54, I2 = 99%). The pooled exponent of 2.39 showed very close agreement with the theoretical exponent of 2.33 (7/3) reported by Kassab and colleagues. This exponent may provide a more accurate description of coronary morphometric scaling in human and mammalian coronary arteries, as compared with Murray's original law. This has important implications for the assessment, diagnosis, and interventional treatment of coronary artery disease.

Hematopoietic Cell Transplant (HCT) Referral Barriers for Patients with Hematologic Malignancies: A Retrospective Study at the National Institutes of Health (NIH)

Hematopoietic Cell Transplant (HCT) Referral Barriers for Patients with Hematologic Malignancies: A Retrospective Study at the National Institutes of Health (NIH)

Phenotypic identification of different β-Lactamases in intrinsic and acquired colistin resistant uropathogenic gram negative bacteria

Objective: Identification of MBL, AmpC and ESBLs in colistin intrinsic and acquired resistant uropathogenic gram negative bacteria. Method: Urine samples were collected from Hayatabad Medical Complex, Peshawar during 17 January to 30 June 2019. Collected urine samples were aseptically transported microbiology lab of Health Research Institution (HRI), National Institute of Health (NIH), Khyber Medical College, Peshawar and streaked on different media. Positive growth was identified by API-10s. Antibiotic sensitivity profile was done by Modified Kirby Bauer disc diffusion method. Detection of metallo βlactamases (MBL) production by Imipenem EDTA synergy test, Double Disc Synergy Test (DDST) for detection of ESBLs and D-test for the detection of inducible AmpC beta lactamases test was used. Colistin resistance was identified via broth micro dilution according to CLSI manual. Colistin resistant bacteria was divided in two categories; acquired and intrinsic resistant bacteria according to CLSI manual. Results: Out of 2000 urine samples, 281(14%) gram-negative bacteria were isolated. Among positive samples, acquired colistin resistant bacteria were 241 and intrinsic resistant bacteria were 40 isolates. MBL was produce by twenty one (11.7%) E.coli and seventeen (40.5%) Pseudomonas aeruginosa. E.coli, Pseudomonas aeruginosa, Klebsiella Pneumoniae, Serratia Oderifora and Proteus Marblis were ESBLs producing bacteria. AmpC production was prevalent in fourteen (7.8%) E. coli and twelve (28.6%) Pseudomonas aeruginosa. Fifty-five samples showed resistance to colistin out of 241 samples. In colistin resistant bacteria, two E.coli were MBL, ESBLs, while one E.coli was ESBLs, AmpC co-producing bacteria. The most prevalent extended drug resistant bacteria were Pseudomonas aeruginosa (28.6%) and Escherichia coli (6.1%), While 155(86.6%) Escherichia coli, 25 (59.5%) Pseudomonas aeruginosa and 22 (95.7%) Serratia Oderifora was multi drug resistant bacteria. Conclusion: Current study concluded that ESBL, MBL AmpC enzymes and their co-expression was observed with colistin resistance in E.coli and Pseudomonas aeruginosa. doi: https://doi.org/10.12669/pjms.40.6.8516 How to cite this: Arif A, Ihasn Ullah, Zaman R, Khan AM. Phenotypic identification of different β-Lactamases in intrinsic and acquired colistin resistant uropathogenic gram negative bacteria. Pak J Med Sci. 2024;40(6):1122-1128. doi: https://doi.org/10.12669/pjms.40.6.8516 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Effect of Psychoeducation on Reducing Burden Among Primary Caregivers of People with Schizophrenia

Schizophrenia is a serious psychological illness that needs long-term treatment. Family members, especially those who care for a patient at home, experience the burden of providing long-term care. Psychoeducational intervention may enhance the caregiver’s outcomes. The major goal of the study was to explore the effect of psychoeducation on reducing the burden among primary carers of people with schizophrenia. In this study, thirty-two participants (32 caregivers) were purposefully selected based on the National Institute of Mental Health (NIMH). A personal information form and the Bangla version of the Zarit Burden Interview scale were administered. Total participants were divided by simple randomization into two groups (i.e., experimental and control groups). Following the baseline evaluation by questionnaire, the experimental group of 16 caregivers received two sessions of psychoeducation, but the control group of the same number of caregivers did not. The effectiveness of psychoeducation was evaluated using a pretest-posttest control group design. Findings suggested that psychoeducation decreased the level of burden, and after the intervention, the mean score of the experimental group was lower than that of the control group. These findings found that the psychoeducation intervention had a positive outcome in reducing the burden on caregivers of patients who deal with schizophrenia. Jagannath University Journal of Life and Earth Sciences, 9(1): 81–94, 2023 (June)

Objective response after immune checkpoint inhibitors in a chemotherapy-refractory pMMR/MSS metastatic rectal cancer patient primed with experimental AlloStim® immunotherapy

BackgroundImmune Checkpoint Inhibitor (ICI) immunotherapy is most effective in immune effector cell infiltrated ‘hot’ tumor lesions, such as occurs in deficient mismatch repair, microsatellite instability high (dMMR/MSI-H) colorectal cancer (CRC). However, most all metastatic CRC tumors are mismatch repair proficient/microsatellite stable (pMMR/MSS) ‘cold’ lesions, without significant immune cell infiltration, and are unresponsive to ICI. AlloStim®, is an experimental, allogeneic immunomodulatory cell therapy designed to convert ‘cold’ metastatic tumor lesions to ‘hot’ inflamed lesions. After AlloStim® immunotherapy, this cold to hot inflammatory mechanism can make it difficult to distinguish between pseudoprogression and actual progression on restaging CT scans, as inflamed metastatic lesions can appear larger and occult disease can appear as new small lesions.MethodsTo explore whether radiological progression after AlloStim® immunotherapy is due to immune-flare or disease progression, we administered a short course of a combination ICI therapy to a pMMR/MSS chemotherapy-refractory metastatic colorectal cancer patient enrolled in the StimVax Phase IIb clinical study that presented with radiological progression after AlloStim® immunotherapy. Our rationale was that an accelerated response to ICI should occur if the lesions were inflamed, while if the enlarged lesions were due to disease progression there would not be a response.ResultsHere we report a rapid, significant reduction in tumor burden in response to ICI administration in an AlloStim® primed pMMR/MSS mCRC patient with retroperitoneal and lung metastases.ConclusionThis rare objective response to ICIs in a pMMR/MSS mCRC patient supports further evaluation of the combination of AlloStim® with ICI immunotherapy in MSS mCRC and other cold or ICI refractory tumors.Trial registrationNational Library of Medicine (NLM) at the National Institutes of Health (NIH). Registered 22 June 2020, https://clinicaltrials.gov/study/NCT04444622.

A model for supporting biomedical and public health researcher use of publicly available All of Us data at Historically Black Colleges and Universities.

The aim of this study was to describe opportunities and challenges associated with the development and implementation of a program for supporting researchers underrepresented in biomedical research. We describe a case study of the All of Us Researcher Academy supported by the National Institutes of Health (NIH), including feedback from participants, instructors, and coaches. Lessons include the importance of inviting role models into learning networks, establishing and maintaining trusted relationships, and making coaches available for technical questions from researcher participants. Although research has focused on learning outcomes in science, technology, engineering, and mathematics at Minority Serving Institutions in the United States, literature tends to lack models for initiatives to improve everyday research experiences of faculty and researchers at such institutions or to encourage researcher use of public-use data such as that available through NIH's All of Us Research Program. The All of Us Researcher Academy offers a model that addresses these needs.

An Epidemiological Study to Assess the Risk Factors and Symptoms of PCOS

The aim to present this study was to assess the most affected age group of girls from PCOD and to make them aware by our questionnaire in this descriptive study, 200 girls were selected randomly from hostels of MMDU, MULLANA. A questionnaire was formulated to obtain information regarding symptoms, changes, dietary patterns, etc. This data was differentiated, tabulated, and tested. The data collected shows that the majority of the respondents who participated in the survey were on the edge of PCOD. Stein and Leventhal are regarded to have been the first investigators of polycystic ovary syndrome however, in 1721 Vallisneri, an Italian scientist; he described a married, infertile woman with shiny ovaries with a white surface, and the size of pigeon eggs. It was not until early 1990 at a national institute of Health (NIH) sponsored conference on PCOD that formal diagnostic criteria were proposed and afterward largely utilized. Many scientists tried to explain the pathophysiology of PCOS and many studies were made. It is now accepted that it is multifactorial, partly genetic, however, a number of candidate genes have been postulated. Insulin resistance has been noted consistently among many women with PCOS, especially in those with Hyperandrogenism, but it is not included in any of the diagnostic criteria. Now there is strong evidence that cardiovascular diseases risk factors and disturbances in carbohydrate metabolism are all increased in patients with PCOS compared to healthy populations. The criteria was established by a group of experts during a conference in ROTTERDAM held in 2003 are obligatory. The subsequent ROTTERDAM CRITERIA incorporated the size and morphology as determined by an ultrasound of the ovary into the diagnostic criteria. The Center for Disease Control and Prevention, obesity among children in the U.S. has tripled since 1980 due to various factors like bad eating habits, and lack of physical exercise, and many more children are getting more and more obese. Many researchers have found that PCOD findings are increasing with time. Finding insulin resistance in obese adolescents gave a different diagnosis of PCOD. Upon further clinical testing, many other symptoms are found like Hirsutism, acne, and menstrual abnormalities. Emans (2005) described PCOS as a diagnosis related to the diagnosis of insulin resistance, not being overweight. For insulin resistance, females don't need to be overweight, they will have insulin resistance even a normal weight female adolescents also have insulin resistance.

Unlocking Health Literacy: The Ultimate Guide to Hypertension Education From ChatGPT Versus Google Gemini.

Background Google Gemini (Google, Mountain View, CA) represents the latest advances in the realm of artificial intelligence (AI) and has garnered attention due to its capabilities similar to the increasingly popular ChatGPT (OpenAI, San Francisco, CA). Accurate dissemination of information on common conditions such as hypertension is critical for patient comprehension and management. Despite the ubiquity of AI, comparisons between ChatGPT and Gemini remain unexplored. Methods ChatGPT and Gemini were asked 52 questions derived from the American College of Cardiology's (ACC) frequently asked questions on hypertension, following a specified prompt. Prompts included: no prompting (Form 1), patient-friendly prompting (Form 2), physician-level prompting (Form 3), and prompting for statistics/references (Form 4). Responses were scored as incorrect, partially correct, or correct. Flesch-Kincaid (FK) grade level and word count were recorded. Results Across all forms, scoring frequencies were as follows: 23 (5.5%) incorrect, 162 (38.9%) partially correct, and 231 (55.5%) correct. ChatGPT showed higher rates of partially correct answers than Gemini (p = 0.0346). Physician-level prompts resulted in a higher word count across both platforms (p < 0.001). ChatGPT showed a higher FK grade level (p = 0.033) in physician-friendly prompting. Gemini exhibited a significantly higher mean word count (p < 0.001); however, ChatGPT had a higher FK grade level across all forms (p > 0.001). Conclusion To our knowledge, this study is the first to compare cardiology-related responses from ChatGPT and Gemini, two of the most popular AI chatbots. The grade level for most responses was collegiate level, which was above average for the National Institutes of Health (NIH) recommendations, but on par with most online medical information. Both chatbots responded with a high degree of accuracy, with inaccuracies being rare. Therefore, it is reasonable that cardiologists suggest either chatbot as a source of supplementary education.

Effects of Alpha Lipoic Acid Supplementation on Slow Skeletal Muscle Mass and Contractile Functions in Type 2 Diabetic Male Sprague Dawley Rats

Objective: To see the Effects of Alpha-Lipoic Acid (ALA) supplementation on slow skeletal muscle mass andcontractile functions in type 2 diabetic male Sprague Dawley rats.Study Design: Quasi-experimental study.Place and Duration of Study: The study was carried out at the Physiology Research Lab, Army MedicalCollege, Rawalpindi, Pakistan from June 2019 to April 2021 in collaboration with the National Institute of Health(NIH) Islamabad, Pakistan.Methods: Sixty adult SD rats were divided into three equal groups. Rats were fed on a standard diet as per NIHprotocols. After 2 weeks type 2 Diabetes mellitus (T2DM) was induced in groups 2 and 3 by injecting low dose35mg of streptozotocin (STZ) in the abdomen intraperitoneally. T2DM was successfully developed andconfirmed by measuring glucose levels through a glucometer. Group 3 was injected with Alpha Lipoic acid30mg/kg/day at the lower abdomen for the next two weeks. After 04 weeks, soleus muscles were dissected.The animal data acquisition unit (iWorx) was used for assessing the contractile functions of soleus.Results: Alpha Lipoic acid group showed improvement in muscle mass, muscle tension strength, and recoveryfrom fatigue after applying fatigue protocol as compared to group 2.Conclusion: Alpha Lipoic acid supplementation improves contractile force and delays fatigue in the soleusmuscles of diabetic rats. How to cite this: Khan BU, Yousef I, Arshad S, Ikram F, Ali A, Ullah I. Effects of Alpha Lipoic Acid Supplementation on Slow Skeletal Muscle Mass and Contractile Functions in Type 2 Diabetic Male Sprague Dawley Rats. Life and Science. 2024; 5(2): 216-221. doi: http://doi.org/10.37185/LnS.1.1.408

Novel Role of Irbesartan in Elevating Serum High Density Lipoprotein in Hypercholesterolemic Animal Model

Objective: To explore the HDL cholesterol-raising capacity of Irbesartan (an antihypertensive drug) in rabbit'sserum.Study Design: Laboratory-based experimental study.Place and Duration of Study: The study was carried out at the Animal House of the National Institute of Health(NIH) Islamabad, Pakistan from January 2023 to November 2023.Methods: This study was conducted on 18 rabbits divided into three groups with six rabbits in each. Leaving one group as a normal control, two out of three groups were made hypercholesterolemic by a high-cholesterol diet. Irbesartan was given to one of the hypercholesteremic groups for 30 days. Blood samples were taken for serum analysis of HDL cholesterol.Results: Results of blood serum levels of all three groups were compared and analyzed on three differentoccasions i.e., on day zero, day 120, and day 150 for HDL cholesterol. Their means were calculated using SPSSVersion 20. The irbesartan-treated group showed obvious elevation in serum HDL cholesterol in comparisonwith the hypercholesteremic control group.Conclusion: It is concluded that Irbesartan, an antihypertensive drug has an additional role of elevating serumhigh-density lipoproteins and can provide the supplementary benefit of improving the lipid profile inhypertension and Hypercholesterolemia. How to cite this: Shakir S, Chaudhry ZR, Atif M, Sadaf R, Chaudhry ER, Chaudhry SR. Novel Role of Irbesartan in Elevating Serum High Density Lipoprotein in Hypercholesterolemic Animal Model. Life and Science. 2024; 5(2): 199-203. doi: http://doi.org/10.37185/LnS.1.1.536

Impact of Short-Term Arsenic Exposure on Hormonal Balance and Fibrosis in Sprague Dawley Rats

Objective: To evaluate the toxic effects of arsenic exposure on the female reproductive tract and endocrinesystem.Study Design: A laboratory-based experiment.Place and Duration of Study: The study was carried out at the Laboratory of the National Institute of Health(NIH) Islamabad, Pakistan from 1st January 2019 to 4th January 2020.Methods: non-probability convenient sampling technique was employed and 60 female healthy SpragueDawley rats were included in the study at the National Institute Islamabad. Animals were randomly allocatedinto control and experimental groups (n=30 each). In the first week, animals were acclimatized to the animalhouse of the College of Physicians and Surgeons Pakistan. In the second week, the control and experimentalgroups were given 10 ml of distilled water by oral gavage daily and 4μg of sodium arsenite dissolved in 10 ml ofdistilled water daily for two weeks respectively. After the experimental period, animals were taken to theanimal lab of the National Institute of Health Islamabad for blood sampling and tissue dissection. Rats wereeuthanized by chloroform inhalation and blood was drawn by single intracardiac puncture and stored in clotactivator vials at 4 0C for further workup. The female reproductive tract was dissected, and the tissue was stored in 10 % formalin for histological studies. Serum Gonadotropin-releasing hormone (GnRH) levels were assessed via the Enzyme-Linked Immunosorbent Assay (ELISA) method. Whereas histological effects of arsenic were observed under a microscope by tissue processing and staining with Masson trichrome stain. Mean ± SD of serum GnRH levels and percentage of fibrosis in uterine tissue of control and experimental groups wereevaluated by the software Statistical Package for Social Sciences version 22.0. Comparison of means evaluatedby Student T-test. The significant p-value was ≤ 0.05.Results: The experimental group showed significant elevation of serum GnRH levels and fibrotic changes withhigh collagen deposition (p ≤ 0.05).Conclusion: Exposure to arsenic via contaminated drinking water is disruptive for the female reproductive tractand endocrine system. How to cite this: Mir A, Mir UZ, Hussain W, Irfan A, Butt HA, Sarwar U. Impact of Short-Term Arsenic Exposure on Hormonal Balance and Fibrosis in Sprague Dawley Rats. Life and Science. 2024; 5(2): 187-192. doi: http://doi.org/10.37185/LnS.1.1.64

A Scholarly Dialog on Recent Trends in National Institutes of Health's Funding for the Thyroid Field.

Background: The National Institutes of Health (NIH) is the major funding agency for biomedical research in the United States. To initiate a scholarly dialog about research and career development in the thyroid field, here we reviewed recent trends in NIH funding for this area. We used the Research Portfolio Online Reporting Tool database to estimate the level of NIH extramural support during 2013-2022 (number of active grants/year and $amount/year weighed by the total number of active grants/year and $amount/year), provided by the NIH to the thyroid field. We determined that in 2013, the NIH supported ∼140 grants/year, totaling almost $50 million/year, the majority in the form of R01 grants. Within the thyroid field, support was evenly split between thyroid cancer and thyroid hormone metabolism and action subareas. In the subsequent years (2014-2022), the total number of active grants peaked at 150/year ($55 million) in 2014 but progressively decreased to about 100 active grants/year ($30 million) in 2022. This trend occurred while the NIH budget increased from $29 to $46 billion/year. Globally, the number of thyroid-related publications increased by ∼70% during the study period, and the fractional contribution of several countries remained relatively stable, except for China which increased by ∼600%. Remarkably, the fraction of thyroid-related publications in the United States sponsored by the NIH decreased from 5.5% to 3.1% of the global number. Conclusion: These results constitute a very concerning scenario for research and education in the thyroid field. We appeal to the NIH, the professional societies in endocrinology and thyroidology, and all other relevant stakeholders such as thyroid-related professionals and thyroid patients to engage in further discussions to identify the root causes of this trend and implement an action plan to stabilize and eventually reverse this situation.

Fear, defense, and emotion: A neuroethological understanding of the negative valence research domain criteria.

We describe the close correspondence between predatory imminence continuum theory (PICT) and the National Institute of Mental Health's Research Domain Criteria (RDoC) for negative valence. RDoC's negative valence constructs relate aversively motivated behavioral reactions to various levels of threat. PICT divides defensive responses into distinct modes that vary along a continuum of the psychological closeness of predatory threat. While there is a close correspondence between PICT modes and negative valence threat constructs, based on PICT, we describe some potential elaborations of RDoC constructs. Both have consonant views of fear and anxiety and provide explicit distinctions between these emotional states, relating them to specific defensive behaviors and functions. We describe recent data that causally implicate human subjective emotional states with amygdala activity, which is also critical for defensive behavior. We conclude that attention to neuroethological views of defense can advance our understanding of the etiology and treatment of anxiety and stress disorders. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Federal and foundational research funding trends for cerebrovascular neurosurgeons: the decline of the cerebrovascular surgeon-scientist?

The number of cerebrovascular (CV) surgeons has grown with the rise of endovascular neurosurgery. However, it is unclear whether the number of CV surgeon-scientists has concomitantly increased. With increasing numbers of CV neurosurgeons in the US workforce, the authors analyzed associated changes in National Institutes of Health (NIH) and Neurosurgery Research and Education Foundation (NREF) funding trends for CV surgeons over time. Publicly available data were collected on currently practicing academic CV surgeons in the US. Inflation-adjusted NIH funding between 2009 and 2021 was surveyed using NIH RePORTER and Blue Ridge Institute for Medical Research data. The K12 Neurosurgeon Research Career Development Program and NREF grant data were queried for CV-focused grants. Pearson R correlation, chi-square analysis, and the Mann-Whitney U-test were used for statistical analysis. From 2009 to 2021, NIH funding increased: in total (p = 0.0318), to neurosurgeons (p < 0.0001), to CV research projects (p < 0.0001), and to CV surgeons (p = 0.0018). During this time period, there has been an increase in the total number of CV surgeons (p < 0.0001), the number of NIH-funded CV surgeons (p = 0.0034), and the percentage of CV surgeons with NIH funding (p = 0.370). Additionally, active NIH grant dollars per CV surgeon (p = 0.0398) and the number of NIH grants per CV surgeon (p = 0.4257) have increased. Nevertheless, CV surgeons have been awarded a decreasing proportion of the overall pool of neurosurgeon-awarded NIH grants during this time period (p = 0.3095). In addition, there has been a significant decrease in the number of K08, K12, and K23 career development awards granted to CV surgeons during this time period (p = 0.0024). There was also a significant decline in the proportion of K12 (p = 0.0044) and downtrend in early-career NREF (p = 0.8978) grant applications and grants awarded during this time period. Finally, NIH-funded CV surgeons were more likely to have completed residency less recently (p = 0.001) and less likely to have completed an endovascular fellowship (p = 0.044) as compared with non-NIH-funded CV surgeons. The number of CV surgeons is increasing over time. While there has been a concomitant increase in the number of NIH-funded CV surgeons and the number of NIH grants awarded per CV surgeon in the past 12 years, there has also been a significant decrease in CV surgeons with K08, K12, and K23 career development awards and a downtrend in CV-focused K12 and early-career NREF applications and awarded grants. The latter findings suggest that the pipeline for future NIH-funded CV surgeons may be in decline.

Safety and immunogenicity of a single dose of Tdap compared to Td in pregnant women in Mali and 3 its effect on infant immune responses: a single-centre, randomised, double-blind, active-controlled phase 2 study

While maternal pertussis vaccination is a strategy to reduce infant morbidity, safety and immunogenicity data are limited in sub-Saharan Africa. We aimed to evaluate the safety of a single dose of tetanus, diphtheria and acellular pertussis vaccine (Tdap) vaccine compared to tetanus and diphtheria vaccine (Td) vaccine in pregnant women in Bamako, Mali and to assess the pertussis toxin (PT) antibody response at birth. In this phase 2, single-centre, randomised, double-blind, active-controlled study, from 23 January 2019 to 10 July 2019, healthy 18-39 year old women in the second trimester of a singleton pregnancy were randomised 2:1 to receive Tdap or Td. Blood was tested for serum immunoglobulin G (IgG) against PT and other vaccine antigens using a qualified Meso Scale Discovery multiplex immunoassay. The co-primary objectives evaluated safety and birth anti-PT levels. Infant immune responses to whole-cell pertussis vaccine (DTwP) were assessed. Statistical analysis was descriptive. This trial is registered with clinicaltrials.gov, NCT03589768. 133 women received Tdap and 67 received Td, with 126 and 66 livebirths, respectively. In the Tdap group, 22 serious adverse events (SAEs) including one maternal death occurred in 20 participants (15·0%), with 10 SAEs in 10 participants (14·9%) in the Td group. Among infants, 18 events occurred among 13 participants (10.3%) and 8 SAEs in 6 participants (9.1%), including three and two infant deaths, occurred in Tdap and Td groups, respectively. None were related to study vaccines. Anti-PT geometric mean concentration (GMC) at birth in the Tdap group was higher than in the Td group (55.4 [46.2-66.6] IU/ml vs 7.9 [5.4-11.5] IU/ml). One month after the third dose of DTwP, the GMC in infants born to mothers in the Tdap group were lower compared to the Td group (20.2 [13.7-29.9] IU/ml vs 77.2 [32.2-184.8] IU/ml). By 6 months of age, the anti- PT GMCs were 17.3 [12.8-23.4] IU/ml and 67.1 [35.5-126.7] IU/ml in Tdap and Td groups, respectively. At birth, anti-tetanus toxin (TT) GMCs were higher in infants in the Td vs Tdap group (5.9 [5.0-7.0] IU/ml vs 4.1 [3.5-4.8] IU/ml). Anti-diphtheria toxin GMCs were similar in both groups. Tdap administered to pregnant women in Mali is safe and well-tolerated. Infants of mothers who received Tdap were born with high PT and protective anti-TT antibody levels. By six months of age, after primary vaccination, the PT levels were lower in the Tdap group compared to the Td group. The blunted immune responses to primary DTwP vaccination in the Tdap infant group warrant further study. This project was funded by National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), under contract numbers 75N93021C00012 (The Emmes Company), and HHSN27220130000221 (University of Maryland, Baltimore). Dr. Susana Portillo was supported by NIH award no. T32AI007524. NIAID, NIH provided Tdap vaccine (BOOSTRIX).

The SNX17-Retriever endosomal recycling pathway is a key regulator of synaptic function and plasticity in hippocampal neurons

The insertion and removal of integral membrane proteins is a key mechanism for the regulation of synaptic function. Once surface proteins are internalized, they can either be routed to lysosomes for degradation or can be recycled back to the cell surface. Two recycling protein complexes - the SNX27-Retromer complex and the recently discovered SNX17-Retriever complex - are the main drivers in recycling internalized cargoes in non-neuronal cells. In neurons, the SNX27-Retromer pathway has been shown to regulate surface expression of AMPA-type glutamate receptors (AMPARs) during long-term potentiation (LTP), but almost nothing is known regarding the role of the SNX17-Retriever pathway at synapses. Here, using cultured hippocampal neurons, we demonstrate that the SNX17-Retriever pathway localizes to both synaptic and extra-synaptic sites and that RNAi-mediated disruption of this pathway leads to the functional and structural loss of excitatory synapses. Moreover, we find that synaptic stimulation leads to the recruitment of SNX17 to synaptic sites in a manner that depends on Ca2+ influx through NMDARs, activation of CaMKII, and Retriever complex binding. Knockdown of either SNX17 or the Retriever subunit DSCR3 prevents structural plasticity of dendritic spines during LTP. Finally, this loss of structural plasticity is associated with altered traffcking of the cell adhesion molecule β1 Integrin, which is a SNX17 cargo in non-neuronal cells and as we show, in neurons as well. Additionally, SNX17-Retriever is shown to not play a role in AMPAR recycling. Preliminary studies suggest that SNX27 and SNX17 sort distinct cargos in neurons, suggesting that these two recycling pathways each play important, but unique, roles at synaptic sites. National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health (NIH) under award numbers R01-NS129198 to L.S. Weisman and M.A. Sutton, R01-NS099340 and R01- NS064015 to L.S. Weisman, R01-NS097498 to M.A. Sutton, and R21-NS125449, and R01-NS116008 to S. Iwase, by the National Institute of Mental Health (NIMH) of the NIH under award number R21-MH127485 to S. Iwase. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Use of melatonin supplements and risk of type 2 diabetes and cardiovascular diseases in the USA: insights from three prospective cohort studies

Use of melatonin supplements has been increasing substantially in both children and adults in the USA; however, their long-term cardiometabolic effects remain unclear. We aimed to assess the associations between regular use of melatonin supplements and the risk of developing type 2 diabetes or cardiovascular disease in adults. In this study, we included individuals from three US cohorts: the Nurses' Health Study (women only), the Health Professionals Follow-up Study (men only), and the Nurses' Health Study II (women only). Women aged 25-55 years and men aged 45-75 years at baseline, who had no diagnosis of cancer at baseline, and who responded to the question about melatonin supplement use (yes or no) were included. We excluded baseline prevalent cardiovascular disease and baseline prevalent type 2 diabetes for the main analyses. The main outcomes were cardiovascular disease and type 2 diabetes incidence. In secondary analyses, we stratified by duration of rotating night shift work in the Nurses' Health Study and Nurses' Health Study II to examine whether the associations with melatonin supplement use differed by rotating night shift work. For the cardiovascular disease analysis, we included 67 202 women from the Nurses' Health Study (follow-up 1998-2019, mean age at baseline: 63·6 years [SD 7·1]), 26 629 men from the Health Professionals Follow-up Study (1998-2020, 62·9 years [8·8], and 65 241 women from the Nurses' Health Study II (2003-19, 48·2 years [4·7]). Follow-up for incident type 2 diabetes was from 1998 to June 30, 2021, for the Nurses' Health Study; 2003 to Jan 31, 2023, for the Nurses' Health Study II; and from 1998 to Jan 31, 2020, for the Health Professionals' Follow-up Study. Melatonin supplement use in the study cohorts doubled over recent decades from less than 2% in 1998-2007 to 4% or higher in 2014-15 (4·0% in men and 5·3% in women). We documented 16 917 incident cardiovascular disease events during 2 609 068 person-years of follow-up and 12 730 incident cases of type 2 diabetes during 2 701 830 person-years of follow-up. In a pooled analysis of the three cohorts, comparing users with non-users of melatonin supplements, the pooled multivariable-adjusted hazard ratios were 0·94 (95% CI 0·83-1·06, p=0·32) for cardiovascular disease and 0·98 (0·86-1·12, p=0·80) for type 2 diabetes. In secondary analyses, melatonin supplement use appeared to attenuate the positive association between long-term shift work (>5 years) and risk of cardiovascular disease (pinteraction=0·013) among the female nurses. With up to 23 years of follow-up of three large prospective cohorts of middle-aged and older men and women, self-reported melatonin supplement use was not associated with risk of type 2 diabetes or cardiovascular disease. Further research is warranted to assess if melatonin supplement use could mitigate the potential risks of type 2 diabetes and cardiovascular disease associated with rotating night shift work. US National Institutes of Health.

Ultra-processed food consumption and mortality among patients with stages I–III colorectal cancer: a prospective cohort study

Ultra-processed foods (UPFs) are emerging as a risk factor for colorectal cancer (CRC), yet how post-diagnostic UPF intake may impact CRC prognosis remains unexplored. Data collected from food frequency questionnaires were used to estimate intakes of total UPFs and UPF subgroups (serving/d) at least 6 months but less than 4 years post-diagnosis among 2498 patients diagnosed with stages I-III CRC within the Nurses' Health Study and Health Professionals Follow-up Study during 1980-2016. Hazard ratios (HR) and 95% confidence intervals (CIs) of all-cause, CRC- and cardiovascular disease (CVD)-specific mortality in association with UPF consumption were estimated using an inverse probability weighted multivariable Cox proportional hazards regression model, adjusted for confounders. The mean (SD) age of patients at diagnosis was 68.5 (9.4) years. A total of 1661 deaths were documented, including 321 from CRC and 335 from CVD. Compared to those in the lowest quintile (median=3.6 servings/d), patients in the highest quintile (median=10 servings/d) of post-diagnostic UPF intake had higher CVD mortality (HR=1.65, 95% CI=1.13-2.40) but not CRC or all-cause mortality. Among UPF subgroups, higher consumption of fats/condiments/sauces was associated with a higher risk of CVD-specific mortality (highest vs. lowest quintile of intake, HR=1.96, 95% CI=1.41-2.73), and higher intake of ice cream/sherbet was associated with an increased risk of CRC-specific mortality (highest vs. lowest quintile, HR=1.86, 95% CI: 1.33-2.61). No statistically significant association was found between UPF subgroups and overall mortality. Higher post-diagnostic intake of total UPFs and fats/condiments/sauces in CRC survivors is associated with higher CVD mortality, and higher ice cream/sherbet intake is linked to higher CRC mortality. US National Institutes of Health and the American Cancer Society.

Safety and immunogenicity of a polyvalent DNA–protein HIV vaccine with matched Env immunogens delivered as a prime–boost regimen or coadministered in HIV-uninfected adults in the USA (HVTN 124): a phase 1, placebo-controlled, double-blind randomised controlled trial

An effective HIV vaccine will most likely need to have potent immunogenicity and broad cross-subtype coverage. The aim of the HIV Vaccine Trials Network (HVTN) 124 was to evaluate safety and immunogenicity of a unique polyvalent DNA-protein HIV vaccine with matching envelope (Env) immunogens. HVTN 124 was a randomised, phase 1, placebo-controlled, double-blind study, including participants who were HIV seronegative and aged 18-50 years at low risk for infection. The DNA vaccine comprised five plasmids: four copies expressing Env gp120 (clades A, B, C, and AE) and one gag p55 (clade C). The protein vaccine included four DNA vaccine-matched GLA-SE-adjuvanted recombinant gp120 proteins. Participants were enrolled across six clinical sites in the USA and were randomly assigned to placebo or one of two vaccine groups (ie, prime-boost or coadministration) in a 5:1 ratio in part A and a 7:1 ratio in part B. Vaccines were delivered via intramuscular needle injection. The primary outcomes were safety and tolerability, assessed via frequency, severity, and attributability of local and systemic reactogenicity and adverse events, laboratory safety measures, and early discontinuations. Part A evaluated safety. Part B evaluated safety and immunogenicity of two regimens: DNA prime (administered at months 0, 1, and 3) with protein boost (months 6 and 8), and DNA-protein coadministration (months 0, 1, 3, 6, and 8). All randomly assigned participants who received at least one dose were included in the safety analysis. The study is registered with ClinicalTrials.gov (NCT03409276) and is closed to new participants. Between April 19, 2018 and Feb 13, 2019, 60 participants (12 in part A [five men and seven women] and 48 in part B [21 men and 27 women]) were enrolled. All 60 participants received at least one dose, and 14 did not complete follow-up (six of 21 in the prime-boost group and eight of 21 in the coadminstration group). 11 clinical adverse events deemed by investigators as study-related occurred in seven of 48 participants in part B (eight of 21 in the prime-boost group and three of 21 in the coadministration group). Local reactogenicity in the vaccine groups was common, but the frequency and severity of reactogenicity signs or symptoms did not differ between the prime-boost and coadministration groups (eg, 20 [95%] of 21 in the prime-boost group vs 21 [100%] of 21 in the coadministration group had either local pain or tenderness of any severity [p=1·00], and seven [33%] vs nine [43%] had either erythema or induration [p=0·97]), nor did laboratory safety measures. There were no delayed-type hypersensitivity reactions or vasculitis or any severe clinical adverse events related to vaccination. The most frequently reported systemic reactogenicity symptoms in the active vaccine groups were malaise or fatigue (five [50%] of ten in part A and 17 [81%] of 21 in the prime-boost group vs 15 [71%] of 21 in the coadministration group in part B), headache (five [50%] and 18 [86%] vs 12 [57%]), and myalgia (four [40%] and 13 [62%] vs ten [48%]), mostly of mild or moderate severity. Both vaccine regimens were safe, warranting evaluation in larger trials. US National Institutes of Health and US National Institute of Allergy and Infectious Diseases.