Data Disaggregation of Asian-American Family Physicians.

The singular label of "Asian" obscures socioeconomic differences between Asian ethnic groups that affect matriculation into the field of medicine. Using data from American Board of Family Medicine Examination candidates in 2023, we found that compared to the US population, among Asian-American family physicians, Indians were present at higher rates, while Chinese and Filipinos were underrepresented, suggesting the importance of continued disaggregation of Asian ethnicities in medicine.

Evaluating Weight Loss With Semaglutide in Elderly Patients With Type II Diabetes.

Background: Semaglutide is an effective agent indicated for type II diabetes mellitus (T2DM) treatment and weight management. It is unknown if the magnitude of weight loss differs significantly between nonelderly (18-64 years old) and elderly (≥65 years old) patients diagnosed with T2DM. Objective: To determine whether there is a significant difference in percent weight loss between elderly and nonelderly Veterans diagnosed with T2DM and initiating semaglutide. Methods: This institutional review board-approved retrospective cohort study conducted at the VA North Texas Health Care System included adult Veterans with T2DM initiating semaglutide. Veterans with medications, procedures, or conditions that could significantly affect weight were excluded. The primary endpoint was the difference in percent weight loss 3 months after initiating semaglutide. Secondary endpoints were differences in percent weight loss at 6 months and differences of kilogram weight loss at 3 and 6 months. Safety outcomes were significant adverse drug events (ADEs) associated with semaglutide. Results: In total, 177 Veterans were analyzed (n = 111 elderly, n = 66 nonelderly). For the primary endpoint, elderly Veterans lost a mean of 2.02% body weight versus 2.25% in the nonelderly with a mean difference of 0.23% (95% CI, -1.03% to 1.48%; P = 0.72). Secondary endpoints were also not statistically significant. Significant ADEs were gastrointestinal-related, leading to drug discontinuation or dose reduction. Conclusion: Weight loss differences between elderly and nonelderly Veterans diagnosed with T2DM initiating semaglutide were not statistically significant. Age may not be a robust predictor of semaglutide's influence on weight.

The Use of Probiotic Megasphaera elsdenii as a Pre-Harvest Intervention to Reduce Salmonella in Finishing Beef Cattle: An In Vitro Model.

Reducing Salmonella in cattle may mitigate the risk of transmission through the food chain. Megasphaera elsdenii (ME) is a microorganism found naturally in the bovine rumen that can be administered as a probiotic to mitigate ruminal acidosis. Understanding the impact of feeding ME to Salmonella populations in cattle was the objective of this study. Bovine ruminal fluid (RF) and feces were inoculated with antibiotic susceptible or resistant Salmonella and treated with varying concentrations of ME. Salmonella was enumerated at 0, 24, 48, and 72 h using the most probable number (MPN). Volatile fatty acids (VFAs) and pH were recorded from non-inoculated samples. Treating RF with ME did not significantly impact Salmonella concentration or VFA production (p > 0.05). The pH of RF and feces decreased over time (p ≤ 0.05). Salmonella concentration declined in feces, with the largest reduction of 1.92 log MPN/g and 1.05 log MPN/g observed for antibiotic susceptible Salmonella between 0 and 72 h by the 2.5 × 105 CFU/g and control (0.0 CFU/g) concentration of ME, respectively. Treating RF with ME did not impact Salmonella concentration. Salmonella concentration in feces decreased, although ME must be further investigated before a conclusion regarding efficacy in vitro can be determined.

Pharmacological Management of Steroid-Induced Psychosis: A Review of Patient Cases.

Objective: To review the efficacy and safety of medications used in the management of steroid-induced psychosis. Data Sources: A comprehensive literature search was conducted using PubMed, MEDLINE, ProQuest, and Scopus between May and October 2020 using the following search terminology: "steroid-induced psychosis" OR "corticosteroid-induced psychosis." Study Selection and Data Extraction: Definitive cases, as defined by the Diagnostic and Statistical Manual of Mental Disorders, 5th edition, were included in this review. Geriatric patients >65 years of age, those with a confounding neurological condition such as a traumatic brain or spinal cord injury, or those with active malignancy were excluded. Data Synthesis: A total of 13 patient cases were included in this review, representing 8 male patients and 5 female patients. The mean age at symptom presentation was 42.5 years. Six patients presented with delusions, 5 presented with hallucinations, and 2 presented with both manifestations; 12 patients were managed with an antipsychotic, with haloperidol being the most commonly prescribed, followed by risperidone. One patient was managed with lithium and clonazepam alone. All patients returned to their psychological baseline upon the discontinuation or decreased dose of steroids in combination with Pharmacological intervention, though the time to resolution of symptoms varied significantly. No notable adverse drug events associated with treatments were reported. Conclusions: Steroid-induced psychosis is a serious adverse effect of corticosteroid therapy; however, management strategies that combine a dose reduction or elimination of steroids, in combination with an antipsychotic medication, are effective in resolving this syndrome.

Cortical column and whole-brain imaging with molecular contrast and nanoscale resolution.

Optical and electron microscopy have made tremendous inroads toward understanding the complexity of the brain. However, optical microscopy offers insufficient resolution to reveal subcellular details, and electron microscopy lacks the throughput and molecular contrast to visualize specific molecular constituents over millimeter-scale or larger dimensions. We combined expansion microscopy and lattice light-sheet microscopy to image the nanoscale spatial relationships between proteins across the thickness of the mouse cortex or the entire Drosophila brain. These included synaptic proteins at dendritic spines, myelination along axons, and presynaptic densities at dopaminergic neurons in every fly brain region. The technology should enable statistically rich, large-scale studies of neural development, sexual dimorphism, degree of stereotypy, and structural correlations to behavior or neural activity, all with molecular contrast.

Expansion microscopy: enabling single cell analysis in intact biological systems.

There is a need for single cell analysis methods that enable the identification and localization of different kinds of biomolecules throughout cells and intact tissues, thereby allowing characterization and classification of individual cells and their relationships to each other within intact systems. Expansion microscopy (ExM) is a technology that physically magnifies tissues in an isotropic way, thereby achieving super-resolution microscopy on diffraction-limited microscopes, enabling rapid image acquisition and large field of view. As a result, ExM is well-positioned to integrate molecular content and cellular morphology, with the spatial precision sufficient to resolve individual biological building blocks, and the scale and accessibility required to deploy over extended 3-D objects like tissues and organs.

Deleting HDAC3 rescues long-term memory impairments induced by disruption of the neuron-specific chromatin remodeling subunit BAF53b.

Multiple epigenetic mechanisms, including histone acetylation and nucleosome remodeling, are known to be involved in long-term memory formation. Enhancing histone acetylation by deleting histone deacetylases, like HDAC3, typically enhances long-term memory formation. In contrast, disrupting nucleosome remodeling by blocking the neuron-specific chromatin remodeling subunit BAF53b impairs long-term memory. Here, we show that deleting HDAC3 can ameliorate the impairments in both long-term memory and synaptic plasticity caused by BAF53b mutation. This suggests a dynamic interplay exists between histone acetylation/deacetylation and nucleosome remodeling mechanisms in the regulation of memory formation.

Feasibility of achieving the 2025 WHO global tuberculosis targets in South Africa, China, and India: a combined analysis of 11 mathematical models.

BACKGROUND: The post-2015 End TB Strategy proposes targets of 50% reduction in tuberculosis incidence and 75% reduction in mortality from tuberculosis by 2025. We aimed to assess whether these targets are feasible in three high-burden countries with contrasting epidemiology and previous programmatic achievements. METHODS: 11 independently developed mathematical models of tuberculosis transmission projected the epidemiological impact of currently available tuberculosis interventions for prevention, diagnosis, and treatment in China, India, and South Africa. Models were calibrated with data on tuberculosis incidence and mortality in 2012. Representatives from national tuberculosis programmes and the advocacy community provided distinct country-specific intervention scenarios, which included screening for symptoms, active case finding, and preventive therapy. FINDINGS: Aggressive scale-up of any single intervention scenario could not achieve the post-2015 End TB Strategy targets in any country. However, the models projected that, in the South Africa national tuberculosis programme scenario, a combination of continuous isoniazid preventive therapy for individuals on antiretroviral therapy, expanded facility-based screening for symptoms of tuberculosis at health centres, and improved tuberculosis care could achieve a 55% reduction in incidence (range 31-62%) and a 72% reduction in mortality (range 64-82%) compared with 2015 levels. For India, and particularly for China, full scale-up of all interventions in tuberculosis-programme performance fell short of the 2025 targets, despite preventing a cumulative 3·4 million cases. The advocacy scenarios illustrated the high impact of detecting and treating latent tuberculosis. INTERPRETATION: Major reductions in tuberculosis burden seem possible with current interventions. However, additional interventions, adapted to country-specific tuberculosis epidemiology and health systems, are needed to reach the post-2015 End TB Strategy targets at country level. FUNDING: Bill and Melinda Gates Foundation.

Cost-effectiveness and resource implications of aggressive action on tuberculosis in China, India, and South Africa: a combined analysis of nine models.

BACKGROUND: The post-2015 End TB Strategy sets global targets of reducing tuberculosis incidence by 50% and mortality by 75% by 2025. We aimed to assess resource requirements and cost-effectiveness of strategies to achieve these targets in China, India, and South Africa. METHODS: We examined intervention scenarios developed in consultation with country stakeholders, which scaled up existing interventions to high but feasible coverage by 2025. Nine independent modelling groups collaborated to estimate policy outcomes, and we estimated the cost of each scenario by synthesising service use estimates, empirical cost data, and expert opinion on implementation strategies. We estimated health effects (ie, disability-adjusted life-years averted) and resource implications for 2016-35, including patient-incurred costs. To assess resource requirements and cost-effectiveness, we compared scenarios with a base case representing continued current practice. FINDINGS: Incremental tuberculosis service costs differed by scenario and country, and in some cases they more than doubled existing funding needs. In general, expansion of tuberculosis services substantially reduced patient-incurred costs and, in India and China, produced net cost savings for most interventions under a societal perspective. In all three countries, expansion of access to care produced substantial health gains. Compared with current practice and conventional cost-effectiveness thresholds, most intervention approaches seemed highly cost-effective. INTERPRETATION: Expansion of tuberculosis services seems cost-effective for high-burden countries and could generate substantial health and economic benefits for patients, although substantial new funding would be required. Further work to determine the optimal intervention mix for each country is necessary. FUNDING: Bill & Melinda Gates Foundation.

Can China achieve the WHO global targets for TB control by 2035?

To reach the ambitious WHO TB global targets by 2035, it is likely that China will need a comprehensive strategy that builds on its existing high-quality directly observed treatment, short-course program. This will require optimizing the use of existing tools within a changing health system landscape. In addition, new tools are needed to identify and treat TB in high-risk groups and in older people, who are a growing driver of disease incidence. Lastly, strategies are needed to address the proximate risk factors and social determinants that underlie trends in TB burden.

Semi-adaptive response and noise attenuation in bone morphogenetic protein signalling.

Temporal dynamics of morphogen-driven signalling events are critical for proper embryonic development. During development, cells translate extracellular bone morphogenetic protein (BMP) gradients, often subject to noise, into graded intracellular tail-phosphorylated SMAD (TP-SMAD) levels. Using modelling and experimental approaches, we found that BMPs induce TP-SMAD responses in neural precursor cells in a concentration-dependent manner, which are semi-adaptive within a specific intermediate range of BMP concentration. These semi-adaptive TP-SMAD responses involve an intrinsically slow deactivation of BMP receptors, which attenuates noise by prolonging SMAD deactivation time after BMP withdrawal, but increases response time. Interestingly, negative feedback on BMP receptors is also required for semi-adaptation, which benefits both noise attenuation and response time, and therefore balances the trade-off seen with slow BMP receptor deactivation. These results highlight the rich dynamics of SMAD regulation in response to graded BMP concentration, and elucidate general design principles for balancing noise attenuation and activation speed in signalling systems.

Tuberculosis control strategies to reach the 2035 global targets in China: the role of changing demographics and reactivation disease.

BACKGROUND: In the last 20 years, China ramped up a DOTS (directly observed treatment, short-course)-based tuberculosis (TB) control program with 80% population coverage, achieving the 2015 Millennium Development Goal of a 50% reduction in TB prevalence and mortality. Recently, the World Health Organization developed the End TB Strategy, with an overall goal of a 90% reduction in TB incidence and a 95% reduction in TB deaths from 2015-2035. As the TB burden shifts to older individuals and China's overall population ages, it is unclear if maintaining the current DOTS strategy will be sufficient for China to reach the global targets. METHODS: We developed an individual-based computational model of TB transmission, implementing realistic age demographics and fitting to country-level data of age-dependent prevalence over time. We explored the trajectory of TB burden if the DOTS strategy is maintained or if new interventions are introduced using currently available and soon-to-be-available tools. These interventions include increasing population coverage of DOTS, reducing time to treatment, increasing treatment success, and active case finding among elders > 65 years old. We also considered preventative therapy in latently infected elders, a strategy limited by resource constraints and the risk of adverse events. RESULTS: Maintenance of the DOTS strategy reduces TB incidence and mortality by 42% (95% credible interval, 27-59%) and 41% (5-64%), respectively, between 2015 and 2035. A combination of all feasible interventions nears the 2035 mortality target, reducing TB incidence and mortality by 59% (50-76%) and 83% (73-94%). Addition of preventative therapy for elders would enable China to nearly reach both the incidence and mortality targets, reducing incidence and mortality by 84% (78-93%) and 92% (86-98%). CONCLUSIONS: The current decline in incidence is driven by two factors: maintaining a low level of new infections in young individuals and the aging out of older latently infected individuals who contribute incidence due to reactivation disease. While further reducing the level of new infections has a modest effect on burden, interventions that limit reactivation have a greater impact on TB burden. Tools that make preventative therapy more feasible on a large scale and in elders will help China achieve the global targets.

Calibration of an intrahost malaria model and parameter ensemble evaluation of a pre-erythrocytic vaccine.

BACKGROUND: A pre-erythrocytic vaccine could provide a useful tool for burden reduction and eventual eradication of malaria. Mathematical malaria models provide a mechanism for evaluating the effective burden reduction across a range of transmission conditions where such a vaccine might be deployed. METHODS: The EMOD model is an individual-based model of malaria transmission dynamics, including vector lifecycles and species-specific behaviour, coupled to a mechanistic intrahost model of malaria parasite and host immune system dynamics. The present work describes the extension of the EMOD model to include diagnoses of severe malaria and iterative calibration of the immune system parameters and parasite antigenic variation to age-stratified prevalence, incidence and severe disease incidence data obtained from multiple regions with broadly varying transmission conditions in Africa. An ensemble of calibrated model parameter sets is then employed to evaluate the potential impact of routine immunization with a pre-erythrocytic vaccine. RESULTS: The reduction in severe malaria burden exhibits a broad peak at moderate transmission conditions. Under sufficiently intense transmission, a vaccine that reduces but does not eliminate the probability of acquisition from a single challenge bite may delay infections but produces minimal or no net reduction. Conversely, under sufficiently weak transmission conditions, a vaccine can provide a high fractional reduction but avert a relatively low absolute number of cases due to low baseline burden. CONCLUSIONS: Roll-out of routine immunization with pre-erythrocytic malaria vaccines can provide substantial burden reduction across a range of transmission conditions typical to many regions in Africa.

Convection and retro-convection enhanced delivery: some theoretical considerations related to drug targeting.

Delivery of drugs and macromolecules into the brain is a challenging problem, due in part to the blood-brain barrier. In this article, we focus on the possibilities and limitations of two infusion techniques devised to bypass the blood-brain barrier: convection enhanced delivery (CED) and retro-convection enhanced delivery (R-CED). CED infuses fluid directly into the interstitial space of brain or tumor, whereas R-CED removes fluid from the interstitial space, which results in the transfer of drugs from the vascular compartment into the brain or tumor. Both techniques have shown promising results for the delivery of drugs into large volumes of tissue. Theoretical approaches of varying complexity have been developed to better understand and predict brain interstitial pressures and drug distribution for these techniques. These theoretical models of flow and diffusion can only be solved explicitly in simple geometries, and spherical symmetry is usually assumed for CED, while axial symmetry has been assumed for R-CED. This perspective summarizes features of these models and provides physical arguments and numerical simulations to support the notion that spherical symmetry is a reasonable approximation for modeling CED and R-CED. We also explore the potential of multi-catheter arrays for delivering and compartmentalizing drugs using CED and R-CED.

HIV TAT peptide modifies the distribution of DNA nanolipoparticles following convection-enhanced delivery.

We evaluated gene transfer using PEGylated bioresponsive nanolipid particles (NLPs) containing plasmid DNA administered by convection-enhanced delivery (CED) into orthotopically implanted U87-MG tumors in rat brain. We hypothesized that attachment of the human immunodeficiency virus trans-acting transcriptional activator peptide (TATp) to pH-sensitive, reduction-sensitive NLPs would increase gene transfer. TATp was attached either directly to a phospholipid (TATp-lipid) or via a 2-kd polyethylene glycol (PEG) to a lipid (TATp-PEG-lipid). Incorporation of 0.3 mol% TATp-PEG into pH-sensitive NLPs improved transfection 100,000-fold compared to NLPs in culture. In the brain or implanted tumors, the TATp-PEG restricted NLP convection to regions adjacent to the infusion catheter. Gene transfer in the brain from TATp-PEG NLPs, measured by green fluorescent protein (GFP) expression, was substantially greater than from NLPs adjacent to the catheter. Gene transfer using TATp-PEG NLPs, measured by luciferase expression, was 8-12-fold greater than from a 1,2-dioleoyl-3-trimethylammonium-propane/cholesterol cationic lipoplex but 13-27-fold less than from the NLPs. Brain luciferase expression was localized in perivascular macrophages. Thus a cationic ligand, such as the TATp-PEG-lipid, can dramatically increase gene expression in culture, in the normal brain, and in implanted tumors; however, restriction of NLP distribution to the vicinity of the infusion catheter reduces the absolute level of gene transfer.

Retro-convection enhanced delivery to increase blood to brain transfer of macromolecules.

A retro-convection enhanced delivery (R-CED) method has been developed to improve the entry of intravenously administered therapeutics within solid brain tumors. R-CED uses an osmotic gradient to withdraw brain interstitial fluid (ISF) in a controlled manner via an implanted microdialysis catheter. Withdrawal of ISF increases the local tissue specific gravity in normal brain and increases twofold the extravasation of intravenous Evans blue (EB) albumin in normal brain and in an orthotopic 9L tumor. R-CED also increases the extravasation of 70 nm fluorescent liposomes fivefold in the 9L tumor. Thus the transmembrane osmotic gradient induces movement of substances in the blood into the tissue parenchyma. Following probe removal, the magnitude of the R-CED effect on EB-albumin extravasation decreases to control values within 1.5 h in normal brain; however, the effect persists beyond 6 h in the tumor. There was no evidence of histologic damage to the neurons at either 6 h or 2 weeks after R-CED. These studies establish the feasibility of applying R-CED to increase the distribution of systemically administered drugs in both the normal tissue-tumor margin as well as in the central tumor core, holding forth the possibility of improved antitumor drug efficacy.

Barriers to carrier mediated drug and gene delivery to brain tumors.

Brain tumor patients face a poor prognosis despite significant advances in tumor imaging, neurosurgery and radiation therapy. Potent chemotherapeutic drugs fail when used to treat brain tumors because biochemical and physiological barriers limit drug delivery into the brain. In the past decade a number of strategies have been introduced to increase drug delivery into the brain parenchyma. In particular, direct drug administration into the brain tumor has shown promising results in both animal models and clinical trials. This technique is well suited for the delivery of liposome and polymer drug carriers, which have the potential to provide a sustained level of drug and to reach cellular targets with improved specificity. We will discuss the current approaches that have been used to increase drug delivery into the brain parenchyma in the context of fluid and solute transport into, through and from the brain, with a focus on liposome and polymer drug carriers.