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We have previously shown that transfer of a mutated dihydrofolate reductase (DHFR) confers resistance to methotrexate (MTX) to infected cells. We report herein the construction of a retrovirus vector, DC/SV6S31tk, which carries the herpes simplex virus thymidine kinase gene (HSVtk) as well as the mutated Serine 31 DHFR (S31) cDNA. 3T3 cells infected with DC/SV6S31tk are more resistant to MTX than cells infected with DC/SV6S31, which carries the S31 and Neor gene. In DC/SV6S31tk-infected cells, a fraction of cells (20–40%) were more resistant to MTX compared with DC/SV6S31-infected cells, and these cells survived a 5-day exposure to 200 μ M of MTX. The mechanism of this augmented resistance is attributed to the salvage of thymidine by HSVtk, as the augmentation is reversed when dialyzed serum is used for cytotoxicity assays. The cells that survive high-dose MTX selection have high levels of expression of S31 DHFR and HSVtk, although copy numbers of the proviral sequences do not increase significantly. Transduction of cells with the DC/SV6S31tk vector also sensitizes cells to ganciclovir (GCV). Co-expression of a metabolically related gene in a retroviral vector to potentiate the resistance imparted by a drug resistance gene may be useful for gene therapy for cancer patients. [ABSTRACT FROM AUTHOR]

Urinary tract infections (UTIs) are among the most common pediatric infections. This study evaluated the antimicrobial susceptibility patterns of 3511 uropathogenic E. coli (UPEC) isolated from pediatric patients in the United States from 2014 to 2023. The database from the SENTRY antimicrobial surveillance program from 89 medical centers was utilized as a data source. The antimicrobial susceptibility was tested using the microbroth dilution technique against 24 antimicrobial agents. MICs were determined using the CLSI/EUCAST/FDA breakpoint criteria. All the antimicrobials reported susceptibility rates above 80% except for tetracycline (76.2%), trimethoprim-sulfamethoxazole (69.7%), and ampicillin-sulbactam (55.7%). During the study period, the susceptibility rates remained stable for most antimicrobial agents. However, significant differences were observed among age, gender, and U.S. census regions, with the Middle Atlantic showing the lowest and the Mountain region the highest susceptibility rates, for most antimicrobials. The incidence of ESBL UPEC increased from 7.1% to 10.8% between 2014 and 2023, while the prevalence of the MDR phenotype remained relatively stable. The prevalence of both ESBL and MDR phenotypes was highest among infants and young children (0-24 months), with the highest resistance rates from the Pacific region. Knowledge of the landscape of antibiotic resistance in pediatric UPEC will help healthcare providers to better tailor empiric treatment regimens for most UTI infections.

Background: Pulmonary function tests (PFTs) have historically used race-specific prediction equations. The recent American Thoracic Society guidelines recommend the use of a race-neutral approach in prediction equations. There are limited studies centering the opinions of practicing pulmonologists on the use of race in spirometry. Provider opinion will impact adoption of the new guideline. The aim of this study was to ascertain the beliefs of academic pulmonary and critical care providers regarding the use of race as a variable in spirometry prediction equations., Methods: We report data from 151 open-ended responses from a voluntary, nationwide survey (distributed by the Association of Pulmonary Critical Care Medicine Program Directors) of academic pulmonary and critical care providers regarding the use of race in PFT prediction equations. Responses were coded using inductive and deductive methods, and a thematic content analysis was conducted., Results: There was a balanced distribution of opinions among respondents supporting, opposing, or being unsure about the incorporation of race in spirometry prediction equations. Responses demonstrated a wide array of understanding related to the concept and definition of race and its relationship to physiology., Conclusions: There was no consensus among providers regarding the use of race in spirometry prediction equations. Concepts of race having biologic implications persist among pulmonary providers and will likely affect the uptake of the Global Lung Function Initiative per the American Thoracic Society guidelines., Competing Interests: The authors have disclosed no conflicts of interest., (Copyright © 2024 by Daedalus Enterprises.)

Introduction: Advanced heart failure therapies and heart transplantation (HT) have been underutilized in women. Therefore, we aimed to explore the clinical characteristics and outcomes of HT by sex., Methods: We conducted a retrospective analysis of adult discharges from the National Inpatient Sample (NIS) between 2012 and 2019. International Classification of Disease (ICD) procedure codes were used to identify those who underwent HT., Results: A total of 20,180 HT hospitalizations were identified from 2012-2019. Among them, 28 % were female. Women undergoing HT were younger (mean age 51 vs. 54.5 years, p<0.001). HT hospitalizations among men were more likely to have atrial fibrillation, diabetes, hypertension, renal failure, dyslipidemia, smoking, and ischemic heart disease. HT hospitalizations among women were more likely to have hypothyroidism and valvular heart disease. HT hospitalizations in women were associated with no significant difference in risk of in-hospital mortality (adjusted odds ratio [OR] 0.82; 95 % confidence interval [CI] 0.58-1.16, p=0.271), no significant difference in length of stay or inflation-adjusted cost. Men were more likely to develop acute kidney injury during HT hospitalization (69.2 % vs. 59.7 %, adjusted OR 0.71, 95 % CI 0.61-0.83, p<0.001)., Conclusions: HT utilization is lower in women. However, most major in-hospital outcomes for HT are similar between the sexes. Further studies are need to explore the causes of lower rates of HT in women., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)

Respiratory syncytial virus (RSV) is the leading cause of hospitalization among infants in the United States. In August 2023, CDC's Advisory Committee on Immunization Practices recommended nirsevimab, a long-acting monoclonal antibody, for infants aged <8 months to protect against RSV-associated lower respiratory tract infection during their first RSV season and for children aged 8-19 months at increased risk for severe RSV disease. In phase 3 clinical trials, nirsevimab efficacy against RSV-associated lower respiratory tract infection with hospitalization was 81% (95% CI = 62%-90%) through 150 days after receipt; post-introduction effectiveness has not been assessed in the United States. In this analysis, the New Vaccine Surveillance Network evaluated nirsevimab effectiveness against RSV-associated hospitalization among infants in their first RSV season during October 1, 2023-February 29, 2024. Among 699 infants hospitalized with acute respiratory illness, 59 (8%) received nirsevimab ≥7 days before symptom onset. Nirsevimab effectiveness was 90% (95% CI = 75%-96%) against RSV-associated hospitalization with a median time from receipt to symptom onset of 45 days (IQR = 19-76 days). The number of infants who received nirsevimab was too low to stratify by duration from receipt; however, nirsevimab effectiveness is expected to decrease with increasing time after receipt because of antibody decay. Although nirsevimab uptake and the interval from receipt of nirsevimab were limited in this analysis, this early estimate supports the current nirsevimab recommendation for the prevention of severe RSV disease in infants. Infants should be protected by maternal RSV vaccination or infant receipt of nirsevimab., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. John V. Williams reports institutional support from the National Institutes of Health (NIH); compensation for service on Quidel’s scientific advisory board through 2022 and service on GSK Independent Data Monitoring Committee; honorarium for Infectious Diseases of Children conference lecture; payments for participation on Independent Data Monitoring Committee, GSK, Data Safety Monitoring Board, and National Institute of Allergy and Infectious Diseases IMPAACT study. Janet A. Englund reports institutional support from GSK, and consulting fees from AstraZeneca, Meissa Vaccines, Moderna, and Sanofi Pasteur. Natasha B. Halasa reports grants from Sanofi and Quidel and consulting fees from Genetech. Mary Allen Staat reports institutional support from NIH and receipt of royalties from UpToDate. Geoffrey A. Weinberg reports institutional support from the New York State Department of Health AIDS Institute and honoraria from Merck & Co. for writing and editing textbook chapters in the Merck & Co. Merck Manual. Rangaraj Selvarangan reports grants from Hologic, BioFire, Becton Dickinson, Luminex, and Cepheid and honoraria for serving on a GSK advisory board. Marian G. Michaels reports support from NIH. Elizabeth P. Schlaudecker reports institutional support from Pfizer-BioNTech, support for attending a Pediatric Infectious Diseases Society meeting, uncompensated service on NIH Data Safety Monitoring Board and Division of Microbiology and Infectious Diseases Data Safety Monitoring Board, honorarium from Sanofi Pasteur, uncompensated membership in the World Society of Pediatric Infectious Diseases, and uncompensated service as committee chair for the Pediatric Infectious Diseases Society. Jennifer E. Schuster reports institutional support from NIH, Food and Drug Administration, and State of Missouri; speaking honoraria from the Missouri American Academy of Pediatrics; and payment for participation on the board of the Association of American Medical Colleges Advisory (AAMC) for a grant awarded to AAMC for vaccine confidence. Pedro A. Piedra reports grants or contracts from Icosavax, Mapp Biologics, Merck, Sanofi-Pasteur, GSK, Blue Lake Biotechnology, Shionogi, and IgM Biosciences; and reports consulting fees from Takada, Pfizer, Moderna, Merck, and Sanofi-Pasteur. No other potential conflicts of interest were disclosed.

Background: Dementias are a group of gradually progressing neurodegenerative conditions, leading to significant impairment in cognition, functioning, decision-making, capacity and autonomy. With the rise of human rights and patient-centred perspectives in psychogeriatric management, physician-assisted suicide (PAS) has emerged as an important and integral part of end-of-life care in advanced dementias., Methods: With only few original studies in the area, this paper takes a narrative and critical approach to review the global legislations, treatment decisions, debates as well as perspectives from patients, families and medical professionals., Results: PAS and euthanasia are legally allowed in countries like Belgium, Netherlands, Switzerland and few states of the United States (U.S.). Germany has fewer clearer legislations in this regard. The Oregon state requirement and care criteria of the Dutch euthanasia act form the basis of most such laws. Even in the presence of these provisions, PAS is fraught with multiple medical, ethical, moral and legal dilemmas and physicians as well as caregivers are quite heterogenous in their outlook. While right to live with dignity and need to end incurable suffering form the main arguments for PAS, several arguments against it are possibility of undue influence, impaired judgement leading to biased decision-making such as depression and suicidality, inappropriate assessment of capacity, and that all deaths are not necessarily painful. These dilemmas are critically discussed in light of autonomy, decision-making and advanced directives in people living with dementia as well as the rationality of ending life and 'right to live vs right to die'. Based on the findings, certain balanced strategies are highlighted for the health professionals., Conclusion: The 'slippery slope' of PAS needs to be carefully evaluated from a social justice and human rights perspective to improve dignified end-of-life care in dementia. Considerations are also discussed from India, a rapidly-ageing nation with no current provisions for PAS., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) is the most common form of dementia with global burden projected to triple by 2050. It incurs significant biopsychosocial burden worldwide with limited treatment options. Aducanumab is the first monoclonal antibody recently approved by the US-FDA for mild AD through the accelerated approval pathway. It is the first molecule to be approved for AD since 2003 and carries with it a therapeutic promise for the future. As the definition of AD has evolved from a pathological entity to a Clinico-biological construct over the years, the amyloid-β (Aβ) pathway has been increasingly implicated in its pathogenesis. The approval of Aducanumab is based on reduction of the Aβ load in the brain, which forms a surrogate marker for this pathway. The research populace has, however, been globally divided by skepticism and hope regarding this approval. Failure to meet clinical endpoints in the trials, alleged transparency issues, cost-effectiveness, potential adverse effects, need for regular monitoring, and critique of 'amyloid cascade hypothesis' itself are the main caveats concerning the antibody. With this controversy in background, this paper critically looks at antibody research in AD therapeutics, evidence, and evolution of Aducanumab as a drug and the potential clinical implications of its use in future. While the efficacy of this monoclonal antibody in AD stands as a test of time, based on the growing evidence it is vital to rethink and explore alternate pathways of pathogenesis (oxidative stress, neuroinflammation, cholesterol metabolism, vascular factors, etc.) as possible therapeutic targets that may help elucidate the enigma of this complex yet progressive and debilitating neurodegenerative disorder.

In the absence of culturally and linguistically appropriate disaster preparedness plans, several linguistically isolated and culturally diverse population groups are disproportionately disadvantaged in the United States. The communication gap poses challenges to emergency preparedness planners and response personnel in predisaster communication and postdisaster response efforts. Houston Department of Health and Human Services aimed to develop practical recommendations for local emergency response personnel so as to improve dissemination of emergency information and equitable delivery of services to linguistically isolated communities in the greater Houston area. Sixteen focus group discussions were conducted among linguistically isolated immigrant populations living in the greater Houston metropolitan area who primarily spoke one of the Spanish, Chinese, Vietnamese, and Somali languages. Our questions focused on general knowledge and understanding of disasters and explored experiences during Houston's most recent disaster, Hurricane Ike. We found that (a) understanding of disaster and preparedness is contextual, (b) awareness of preparedness needs and actual plans among LIPs is inadequate, and (c) word of mouth is the preferred information source for linguistically isolated groups. Disaster preparedness plans of a given jurisdiction should reflect the culturally and linguistically appropriate components addressing the needs, concerns, context-based knowledge or awareness, and perceptions of linguistically isolated populations.

Aim: Cardiovascular complications are common in patients with chronic kidney disease in the general population. The study aims to investigate the prevalence and prognosis of CKD stages 3-5 in the veterans affairs (VA) population, which is sicker with more co-morbid conditions., Methods: In this case-controlled study of 6,432 men the associations of risk factors with CKD and its risk of mortality were estimated using, primarily, logistic regression analysis., Results: The 1,045 (16.2%) patients with CKD stages 3-5 were older (72 +/- 10 vs. 59 +/- 13 years, P < 0.0001) with more hypertension (53.6 vs. 39.6%, P < 0.0001), diabetes (24.9 vs. 19.8%, P < 0.0002), and CVD (35.3 vs. 17.8%, P < 0.0001) at baseline. Age > or =65 years (odds ratio [95% CI]) (4.95 [4.22-5.82]), hypertension (1.56 [1.34-1.79]), diabetes mellitus (1.21 [1.03-1.43]), CVD (1.71 [1.47-2.00]), and White not Hispanic (1.57 [1.32-1.85]) were independently associated with CKD. The prevalence of CVD at baseline increased with decreasing renal function. Old age (1.98 [1.66-2.35]), CKD (1.94 [1.61-2.33], CVD (1.46 [1.23-1.74]) and tobacco use (1.91 [1.05-3.47]) were independently associated with the 750 (11.7%) deaths., Conclusion: Among veterans, traditional cardiovascular risk factors, CVD, and CKD are highly prevalent. CKD is associated with increased risk of baseline CVD and follow-up mortality.

A well-executed occupational pulmonary history should be part of the evaluation of workers presenting with respiratory illnesses or symptoms. In this article, we review the scope of occupational lung disease and detail the essential elements of the occupational pulmonary history.

The results of various experiments which characterise the optically stimulated luminescence (OSL) signals from polymineral fine grains of a Martian soil simulant sample (JSC Mars-1) are presented. The blue-green stimulated luminescence signal has greater thermal stability than the infrared stimulated luminescence signal for pre-heat temperatures between 250 degrees C and 400 degrees C. Fading tests over a 2 month storage period at 20 degrees C indicate that in some aliquots of JSC Mars-1 both the blue-green stimulated luminescence and the infrared stimulated luminescence signals fade by as much as 50%, whereas in others there is no evidence of significant fading. Dose recovery experiments demonstrate that equivalent dose (measured/given) ratio varies from aliquot to aliquot, and the underestimation in dose is less than 5% for at least one aliquot, for both the infrared and blue-green stimulated luminescence signals.