Population pharmacokinetics and humanized dosage regimens matching the peak, area, trough, and range of amikacin plasma concentrations in immune-competent murine bloodstream and lung infection models.

Amikacin is an FDA-approved aminoglycoside antibiotic that is commonly used. However, validated dosage regimens that achieve clinically relevant exposure profiles in mice are lacking. We aimed to design and validate humanized dosage regimens for amikacin in immune-competent murine bloodstream and lung infection models of Acinetobacter baumannii. Plasma and lung epithelial lining fluid (ELF) concentrations after single subcutaneous doses of 1.37, 13.7, and 137 mg/kg of body weight were simultaneously modeled via population pharmacokinetics. Then, humanized amikacin dosage regimens in mice were designed and prospectively validated to match the peak, area, trough, and range of plasma concentration profiles in critically ill patients (clinical dose: 25-30 mg/kg of body weight). The pharmacokinetics of amikacin were linear, with a clearance of 9.93 mL/h in both infection models after a single dose. However, the volume of distribution differed between models, resulting in an elimination half-life of 48 min for the bloodstream and 36 min for the lung model. The drug exposure in ELF was 72.7% compared to that in plasma. After multiple q6h dosing, clearance decreased by ~80% from the first (7.35 mL/h) to the last two dosing intervals (~1.50 mL/h) in the bloodstream model. Likewise, clearance decreased by 41% from 7.44 to 4.39 mL/h in the lung model. The humanized dosage regimens were 117 mg/kg of body weight/day in mice [administered in four fractions 6 h apart (q6h): 61.9%, 18.6%, 11.3%, and 8.21% of total dose] for the bloodstream and 96.7 mg/kg of body weight/day (given q6h as 65.1%, 16.9%, 10.5%, and 7.41%) for the lung model. These validated humanized dosage regimens and population pharmacokinetic models support translational studies with clinically relevant amikacin exposure profiles.

Association between maternal employment status and presence of children with major congenital anomalies in Denmark.

IMPORTANCE: The burden of caring for children with complex medical problems such as major congenital anomalies falls principally on mothers, who in turn suffer a variety of potentially severe economic consequences. As well, health consequences of caregiving often further impact the social and economic prospects of mothers of children with major congenital anomalies (MCMCAs). Evaluating the long-term economic consequences of extensive in-home caregiving among MCMCAs can inform strategies to mitigate these effects. OBJECTIVE: To assess whether MCMCAs face reduced employment and increased need for disability benefits over a 20-year period. DESIGN: A population-based matched cohort study. SETTING: Denmark. PARTICIPANTS: All women who gave birth to a singleton child with a major congenital anomaly in Denmark between January 1, 1997 and December 31, 2017 (n = 23,637) and a comparison cohort of mothers matched by maternal age, parity, and infant's year of birth (n = 234,586). EXPOSURES: Liveborn infant with a major congenital anomaly. MAIN OUTCOMES AND MEASURES: The primary outcome was mothers' employment status, stratified by their child's age. Employment status was categorized as employed, outside the workforce (on temporary leave, holding a flexible job, or pursuing education), or unemployed; the number of weeks in each category was measured over time. The secondary outcome was time to receipt of a disability pension, which in Denmark implies permanent exit from the labor market. We used a negative binomial regression model to estimate the number of weeks in each employment category, stratified by the child's age (i.e., 0-1 year, > 1-6 years, 7-13 years, 14-18 years). A Cox proportional hazards regression model was used to compute hazard ratios as a measure of the relative risk of receiving a disability pension. Rate ratios and hazard ratios were adjusted for maternal demographics, pregnancy history, health, and infant's year of birth. RESULTS: During 1-6 years after delivery, MCMCAs were outside the workforce for a median of 50 weeks (IQR, 6-107 weeks), while members of the comparison cohort were outside the workforce for a median of 48 weeks (IQR, 4-98 weeks), corresponding to an adjusted rate ratio [ARR] of 1.05 (95% confidence interval [CI], 1.04-1.07). During the first year after delivery, MCMCAs were more likely to be employed than mothers in the comparison cohort (ARR, 1.08; 95% CI, 1.06-1.10). At all timepoints thereafter, MCMCAs had a lower rate of workforce participation. The rate of being outside the workforce was 5% higher than mothers in the comparison cohort during 1-6 years after delivery (ARR, 1.05; 95% CI, 1.04-1.07), 9% higher during 7-13 years after delivery (ARR, 1.09; 95% CI, 1.06-1.12), and 12% higher during 14-18 years after delivery (ARR, 1.12; 95% CI, 1.07-1.18). Overall, MCMCAs had a 20% increased risk of receiving a disability pension during follow-up than mothers in the matched comparison cohort [incidence rates 3.10 per 1000 person-years (95% CI, 2.89-3.32) vs. 2.34 per 1000 person-years (95% CI, 2.29-2.40), adjusted hazard ratio, 1.20; 95% CI, 1.11-1.29]. CONCLUSION AND RELEVANCE: MCMCAs were less likely to participate in the Danish workforce, less likely to be employed, and more likely to receive disability pensions than mothers of unaffected children. The rate of leaving the workforce intensified as their affected children grew older. The high demands of caregiving among MCMCAs may have long-term employment consequences even in nations with comprehensive and heavily tax-supported childcare systems, such as Denmark.

Testing and Evaluation of Health Care Applications of Large Language Models: A Systematic Review.

Importance: Large language models (LLMs) can assist in various health care activities, but current evaluation approaches may not adequately identify the most useful application areas. Objective: To summarize existing evaluations of LLMs in health care in terms of 5 components: (1) evaluation data type, (2) health care task, (3) natural language processing (NLP) and natural language understanding (NLU) tasks, (4) dimension of evaluation, and (5) medical specialty. Data Sources: A systematic search of PubMed and Web of Science was performed for studies published between January 1, 2022, and February 19, 2024. Study Selection: Studies evaluating 1 or more LLMs in health care. Data Extraction and Synthesis: Three independent reviewers categorized studies via keyword searches based on the data used, the health care tasks, the NLP and NLU tasks, the dimensions of evaluation, and the medical specialty. Results: Of 519 studies reviewed, published between January 1, 2022, and February 19, 2024, only 5% used real patient care data for LLM evaluation. The most common health care tasks were assessing medical knowledge such as answering medical licensing examination questions (44.5%) and making diagnoses (19.5%). Administrative tasks such as assigning billing codes (0.2%) and writing prescriptions (0.2%) were less studied. For NLP and NLU tasks, most studies focused on question answering (84.2%), while tasks such as summarization (8.9%) and conversational dialogue (3.3%) were infrequent. Almost all studies (95.4%) used accuracy as the primary dimension of evaluation; fairness, bias, and toxicity (15.8%), deployment considerations (4.6%), and calibration and uncertainty (1.2%) were infrequently measured. Finally, in terms of medical specialty area, most studies were in generic health care applications (25.6%), internal medicine (16.4%), surgery (11.4%), and ophthalmology (6.9%), with nuclear medicine (0.6%), physical medicine (0.4%), and medical genetics (0.2%) being the least represented. Conclusions and Relevance: Existing evaluations of LLMs mostly focus on accuracy of question answering for medical examinations, without consideration of real patient care data. Dimensions such as fairness, bias, and toxicity and deployment considerations received limited attention. Future evaluations should adopt standardized applications and metrics, use clinical data, and broaden focus to include a wider range of tasks and specialties.

First Penicillin-Binding Protein Occupancy Patterns for 15 ß-Lactams and ß-Lactamase Inhibitors in Mycobacterium abscessus.

Mycobacterium abscessus causes serious infections that often require over 18 months of antibiotic combination therapy. There is no standard regimen for the treatment of M. abscessus infections, and the multitude of combinations that have been used clinically have had low success rates and high rates of toxicities. With ß-lactam antibiotics being safe, double ß-lactam and ß-lactam/ß-lactamase inhibitor combinations are of interest for improving the treatment of M. abscessus infections and minimizing toxicity. However, a mechanistic approach for building these combinations is lacking since little is known about which penicillin-binding protein (PBP) target receptors are inactivated by different ß-lactams in M. abscessus We determined the preferred PBP targets of 13 ß-lactams and 2 ß-lactamase inhibitors in two M. abscessus strains and identified PBP sequences by proteomics. The Bocillin FL binding assay was used to determine the ß-lactam concentrations that half-maximally inhibited Bocillin binding (50% inhibitory concentrations [IC50s]). Principal component analysis identified four clusters of PBP occupancy patterns. Carbapenems inactivated all PBPs at low concentrations (0.016 to 0.5 mg/liter) (cluster 1). Cephalosporins (cluster 2) inactivated PonA2, PonA1, and PbpA at low (0.031 to 1 mg/liter) (ceftriaxone and cefotaxime) or intermediate (0.35 to 16 mg/liter) (ceftazidime and cefoxitin) concentrations. Sulbactam, aztreonam, carumonam, mecillinam, and avibactam (cluster 3) inactivated the same PBPs as cephalosporins but required higher concentrations. Other penicillins (cluster 4) specifically targeted PbpA at 2 to 16 mg/liter. Carbapenems, ceftriaxone, and cefotaxime were the most promising ß-lactams since they inactivated most or all PBPs at clinically relevant concentrations. These first PBP occupancy patterns in M. abscessus provide a mechanistic foundation for selecting and optimizing safe and effective combination therapies with ß-lactams.

Impact of Social Needs Navigation on Utilization Among High Utilizers in a Large Integrated Health System: a Quasi-experimental Study.

BACKGROUND: Programs addressing social determinants of health for high-utilizing patients are gaining interest among health systems as an avenue to promote health and decrease utilization. OBJECTIVE: To evaluate impacts of a social needs screening and navigation program for adult predicted high utilizers on total medical visit utilization. DESIGN: A prospective, quasi-experimental study using an intent-to-treat propensity-weighted difference-in-differences approach. Stratified analyses assessed intervention effects among three low-socioeconomic status sub-samples: patients in low-income areas, in low-education areas, and with Medicaid insurance. PARTICIPANTS: Predicted high utilizers-patients predicted to be in the highest 1% for total utilization in a large integrated health system. INTERVENTION: A telephonic social needs screening and navigation program. MAIN MEASURES: Primary difference-in-difference analyses compared total visit count utilization, including outpatient, emergency department (ED), and inpatient utilization, between the intervention and control groups at both in-network and out-of-network facilities. Prevalence of social needs among sample patients and their connection rates to social needs resources are also described. KEY RESULTS: The study included 34,225 patients (7107 intervention, 27,118 control). Most (53%) patients screened reported social needs, but only a minority (10%) of those with a need were able to connect with resources to address these needs. Primary analysis found total utilization visits decreased 2.2% (95% CI - 4.5%, 0.1%; p = 0.058) in the intervention group. Stratified analyses showed decreases in total utilization for all low-socioeconomic status subgroups receiving the intervention compared with controls: - 7.0% (95% CI - 11.9%, - 1.9%; p = 0.008) in the low-income area group, - 11.5% (- 17.6%, 5.0%; p < 0.001) in the low-education area group, and - 12.1% (- 18.1%, - 5.6%; p < 0.001) in the Medicaid group. CONCLUSIONS: Social needs navigation programs for high-utilizing patients may have modest effects on utilization for the population overall. However, significant decreases in utilization were found among low-socioeconomic status patients more likely to experience social needs.

Expression of ETS1 and LEF1 in salivary glands of Sjögren syndrome patients.

OBJECTIVE: Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease affecting exocrine glands, thereby causing dry mouth and eyes (sicca). Our objective was to determine the expression of pSS pathogenic biomarker MMP9 and its putative transcription factors ETS1 and LEF1, in labial salivary glands of pSS patients. METHODS: Sicca patients were assigned to three groups based on focus score (FS): non-pSS sicca (i.e., GR1 [FS = 0] and GR2 [0 < FS < 1]) and pSS (i.e., GR3 [FS ≥ 1]). We determined the mRNA and protein expression of MMP9, ETS1, and LEF1 in salivary gland biopsies. Also, ETS1-CD4 and LEF1-CD4 co-expression analyses were performed. RESULTS: The mRNA expression of MMP9, ETS1, and LEF1 was upregulated in GR3 compared to GR1 (p < 0.01). Most GR3 salivary gland areas had moderate to high MMP9, ETS1, and LEF1 protein expression compared to GR1 and GR2. Further, ETS1-CD4 and LEF1-CD4 dual staining demonstrated that both salivary gland epithelial cells and lymphocytic infiltrates had increased levels of ETS1 and LEF1. Moreover, there was a strong correlation between ETS1(+)-CD4(-) and LEF1(+)-CD4(-) cells. CONCLUSION: These results suggest, for the first time, a concerted increase in ETS1 and LEF1 expression in salivary gland epithelial cells of pSS patients that is reflective of the etiopathogenesis of pSS.

Segmentation of High-Cost Adults in an Integrated Healthcare System Based on Empirical Clustering of Acute and Chronic Conditions.

BACKGROUND: High-cost patients are a frequent focus of improvement projects based on primary care and other settings. Efforts to characterize high-cost, high-need patients are needed to inform care planning, but such efforts often rely on a priori assumptions, masking underlying complexities of a heterogenous population. OBJECTIVE: To define recognizable subgroups of patients among high-cost adults based on clinical conditions, and describe their survival and future spending. DESIGN: Retrospective observational cohort study. PARTICIPANTS: Within a large integrated delivery system with 2.7 million adult members, we selected the top 1% of continuously enrolled adults with respect to total healthcare expenditures during 2010. MAIN MEASURES: We used latent class analysis to identify clusters of alike patients based on 53 hierarchical condition categories. Prognosis as measured by healthcare spending and survival was assessed through 2014 for the resulting classes of patients. RESULTS: Among 21,183 high-cost adults, seven clinically distinctive subgroups of patients emerged. Classes included end-stage renal disease (12% of high-cost population), cardiopulmonary conditions (17%), diabetes with multiple comorbidities (8%), acute illness superimposed on chronic conditions (11%), conditions requiring highly specialized care (14%), neurologic and catastrophic conditions (5%), and patients with few comorbidities (the largest class, 33%). Over 4 years of follow-up, 6566 (31%) patients died, and survival in the classes ranged from 43 to 88%. Spending regressed to the mean in all classes except the ESRD and diabetes with multiple comorbidities groups. CONCLUSIONS: Data-driven characterization of high-cost adults yielded clinically intuitive classes that were associated with survival and reflected markedly different healthcare needs. Relatively few high-cost patients remain persistently high cost over 4 years. Our results suggest that high-cost patients, while not a monolithic group, can be segmented into few subgroups. These subgroups may be the focus of future work to understand appropriateness of care and design interventions accordingly.

Uses of electronic health records for public health surveillance to advance public health.

Public health surveillance conducted by health departments in the United States has improved in completeness and timeliness owing to electronic laboratory reporting. However, the collection of detailed clinical information about reported cases, which is necessary to confirm the diagnosis, to understand transmission, or to determine disease-related risk factors, is still heavily dependent on manual processes. The increasing prevalence and functionality of electronic health record (EHR) systems in the United States present important opportunities to advance public health surveillance. EHR data have the potential to further increase the breadth, detail, timeliness, and completeness of public health surveillance and thereby provide better data to guide public health interventions. EHRs also provide a unique opportunity to expand the role and vision of current surveillance efforts and to help bridge the gap between public health practice and clinical medicine.

The wired patient: patterns of electronic patient portal use among patients with cardiac disease or diabetes.

BACKGROUND: As providers develop an electronic health record-based infrastructure, patients are increasingly using Web portals to access their health information and participate electronically in the health care process. Little is known about how such portals are actually used. OBJECTIVE: In this paper, our goal was to describe the types and patterns of portal users in an integrated delivery system. METHODS: We analyzed 12 months of data from Web server log files on 2282 patients using a Web-based portal to their electronic health record (EHR). We obtained data for patients with cardiovascular disease and/or diabetes who had a Geisinger Clinic primary care provider and were registered "MyGeisinger" Web portal users. Hierarchical cluster analysis was applied to longitudinal data to profile users based on their frequency, intensity, and consistency of use. User types were characterized by basic demographic data from the EHR. RESULTS: We identified eight distinct portal user groups. The two largest groups (41.98%, 948/2258 and 24.84%, 561/2258) logged into the portal infrequently but had markedly different levels of engagement with their medical record. Other distinct groups were characterized by tracking biometric measures (10.54%, 238/2258), sending electronic messages to their provider (9.25%, 209/2258), preparing for an office visit (5.98%, 135/2258), and tracking laboratory results (4.16%, 94/2258). CONCLUSIONS: There are naturally occurring groups of EHR Web portal users within a population of adult primary care patients with chronic conditions. More than half of the patient cohort exhibited distinct patterns of portal use linked to key features. These patterns of portal access and interaction provide insight into opportunities for electronic patient engagement strategies.

Oncolytic vesicular stomatitis virus in an immunocompetent model of MUC1-positive or MUC1-null pancreatic ductal adenocarcinoma.

Vesicular stomatitis virus (VSV) is a promising oncolytic agent against various malignancies. Here, for the first time, we tested VSV in vitro and in vivo in a clinically relevant, immunocompetent mouse model of pancreatic ductal adenocarcinoma (PDA). Our system allows the study of virotherapy against PDA in the context of overexpression (80% of PDA patients) or no expression of human mucin 1 (MUC1), a major marker for poor prognosis in patients. In vitro, we tested three VSV recombinants, wild-type VSV, VSV-green fluorescent protein (VSV-GFP), and a safe oncolytic VSV-ΔM51-GFP, against five mouse PDA cell lines that either expressed human MUC1 or were MUC1 null. All viruses demonstrated significant oncolytic abilities independent of MUC1 expression, although VSV-ΔM51-GFP was somewhat less effective in two PDA cell lines. In vivo administration of VSV-ΔM51-GFP resulted in significant reduction of tumor growth for tested mouse PDA xenografts (+MUC1 or MUC1 null), and antitumor efficacy was further improved when the virus was combined with the chemotherapeutic drug gemcitabine. The antitumor effect was transient in all tested groups. The developed system can be used to study therapies involving various oncolytic viruses and chemotherapeutics, with the goal of inducing tumor-specific immunity while preventing premature virus clearance.

Redesigning the regulatory framework for ambulatory care services in New York.

UNLABELLED: Policy Points: The landscape of ambulatory care services in the United States is rapidly changing on account of payment reform, primary care transformation, and the rise of convenient care options such as retail clinics. New York State has undertaken a redesign of regulatory policy for ambulatory care rooted in the Triple Aim (better health, higher-quality care, lower costs)-with a particular emphasis on continuity of care for patients. Key tenets of the regulatory approach include defining and tracking the taxonomy of ambulatory care services as well as ensuring that convenient care options do not erode continuity of care for patients. CONTEXT: While hospitals remain important centers of gravity in the health system, services are increasingly being delivered through ambulatory care. This shift to ambulatory care is giving rise to new delivery structures, such as retail clinics and urgent care centers, as well as reinventing existing ambulatory care capacity, as seen with the patient-centered medical home model and the movement toward team-based care. To protect the public's interests, oversight of ambulatory care services must keep pace with these rapid changes. With this purpose, in January 2013 the New York Public Health and Health Planning Council undertook a redesign of the regulatory framework for the state's ambulatory care services. This article describes the principles undergirding the framework as well as the regulatory recommendations themselves. METHODS: We explored and analyzed the regulation of ambulatory care services in New York in accordance with the available gray and peer-reviewed literature and legislative documents. The deliberations of the Public Health and Health Planning Council informed our review. FINDINGS: The vision of high-performing ambulatory care should be rooted in the Triple Aim (better health, higher-quality care, lower costs), with a particular emphasis on continuity of care for patients. There is a pressing need to better define the taxonomy of ambulatory care services. From the state government's perspective, this clarification requires better reporting from new health care entities (eg, retail clinics), connections with regional and state health information technology hubs, and coordination among state agencies. A uniform nomenclature also would improve consumers' understanding of rights and responsibilities. Finally, the regulatory mechanisms employed-from mandatory reporting to licensure to regional planning to the certificate of need-should remain flexible and match the degree of consensus regarding the appropriate regulatory path. CONCLUSIONS: Few other states have embarked on a wide-ranging assessment of their regulation of ambulatory care services. By moving toward adopting the regulatory approach described here, New York aims to balance sound oversight with pluralism and innovation in health care delivery.

Integrating public health education in a public health practice setting: the experience of the School of Public Health, University at Albany and the New York State Department of Health.

The New York State Department of Health (DOH) has a long history of biomedical research, public health policy and program development, peer-reviewed scholarship, and teaching. Its evolution as an academic health department advanced significantly when the University at Albany and DOH formed the School of Public Health Sciences in 1985 to further develop these functions while formally training the next generation of public health workers. The School, renamed in 1990 as the School of Public Health (SPH), was initially located within the DOH with its staff as the founding faculty. The curriculum was heavily influenced by public health practice imperatives. The SPH has evolved to have an independent campus and full-time academic faculty, but the DOH remains closely linked. The relationship is governed by a memorandum of understanding that commits both partners to provide substantial and continuing resources to the SPH. The SPH brings value to the DOH's mission to improve the health of the state's citizens by providing an academic focus to problems faced in health department practice settings. The opportunity to teach and be involved in an academic environment increases the DOH's ability to recruit, retain, and improve the skill level of its professional and scientific staff and thereby improve its ability to assess health problems and to design and evaluate public health programs. The SPH also provides training and support to county health departments and nongovernment organizations, which further the DOH's mission, through continuing education programs and an online MPH degree program. International exchanges including those with China, Vietnam, and the Republic of Georgia have enriched the academic environment. Challenges include maintaining sufficient full-time faculty members, the need for the SPH to take on broader public health issues than those applicable to New York, and the shrinkage of the DOH's workforce and departure of many senior scientists who served as faculty.

Integrating Public and Population Health Into Medical Education Curricula: Opportunities and Challenges for Reform.

ABSTRACT: In a review of U.S. medical education curricular guidance, from premedical studies through to continuing medical education, Maeshiro and colleagues found limited examples of public and population health topics. In this Commentary, the authors emphasize the importance of including public and population health in the curriculum, pointing to curricular reform efforts to integrate these topics into teaching of basic sciences and clinical studies. In addition, they consider the expectations placed on physicians to meet the needs of the population and argue that policies that support public health funding, infrastructure, and workers are also critical to improving the health of communities.

Improving value for underserved populations with a community-based intervention: a retrospective cohort study.

BACKGROUND: Healthcare inequity drives high costs, worse outcomes and is heavily influenced by social determinants of health (SDOH). Addressing health behaviors and SDOH through a culturally competent community-based exposure may be effective in improving value for Medicaid enrollees. This study aims to evaluate whether such an exposure lowers costs at equal or improved quality. METHODS: A retrospective cohort study leveraging claims data was conducted in Detroit, Michigan from April 2021 to April 2022 to examine the impact of a community-based peer support program on clinical, utilization and financial outcomes. A one-to-one propensity matching of 738 pairs of African American Medicaid enrollees was generated, and compared the difference of differences between inpatient, emergency department, prescription and outpatient paid amounts, utilization, and available claims-based quality metrics. RESULTS: Compared to controls, peer support recipients generated significantly lower per member per month costs ($115, (95% CI $20.2 to $210)). Recipients showed a significant increase in the Adult Access to Preventative/Ambulatory Health Services 20-44 year old quality metric (8.31% (95% CI 0.35-16.3%)). Member retention in the health insurance plan was significantly higher for peer support recipients vs. the control group by 3.62% (p < 0.05). Peer support recipients displayed non-significant improvement on all other utilization and actuarial measures. No significant difference was found for any of the other examined quality metrics. CONCLUSIONS: Among a population of African American Medicaid enrollees, a culturally competent community-based intervention was associated with lower cost and better member retention with preserved or improved quality.