In Utero Ultrafine Particulate Exposure Yields Sex- and Dose-Specific Responses to Neonatal Respiratory Syncytial Virus Infection.

Exposure to particulate matter (PM) is associated with lower respiratory tract infections. The role of ultrafine particles (UFPs, ≤0.1 µm) in respiratory disease is not fully elucidated, especially in models of immunologically immature populations. To characterize the effects of maternal UFP exposure on neonatal infection, we exposed time-mated C57Bl/6n mice to filtered air or UFPs at a low dose (LD, ∼55 µg/m3) and high dose (HD, ∼275 µg/m3) throughout gestation. At 5 days of age, offspring were infected with a respiratory syncytial virus (RSV) strain known to mimic infant infection or sham control. Offspring body weights were significantly reduced in response to infection in the LD RSV group, particularly females. Pulmonary gene expression analysis demonstrated significantly increased levels of oxidative stress- and inflammation-related genes in HD-exposed male offspring in sham and RSV-infected groups. In males, the highest grade of inflammation was observed in the HD RSV group, whereas in females, the LD RSV group showed the most marked inflammation. Overall, findings highlight neonatal responses are dependent on offspring sex and maternal UFP dose. Importantly, infant RSV pathology may be enhanced following even low dose UFP exposure signifying the importance of preventing maternal exposure.

Extended-duration letermovir prophylaxis for cytomegalovirus infection after cord blood transplantation in adults.

Cord blood transplantation (CBT) can be complicated by a high incidence of clinically significant cytomegalovirus infection (csCMVi). We have investigated the efficacy of extended letermovir prophylaxis in seropositive adult CBT recipients. The aim was to continue prophylaxis for ≥6 months (insurance permitting). By day 100, the incidence of csCMVi was 0% in 28 patients who received letermovir prophylaxis. Moreover, of 24 patients alive at day 100, none had csCMVi by day 180, having continued prophylaxis for all (n = 20) or part (n = 4) of that period. Overall, 20 patients stopped letermovir at a median of 354 days (range, 119-455 days) posttransplant, with only 5 requiring 1 (n = 4) or 2 (n = 1) courses of valganciclovir (median total duration, 58 days; range, 12-67 days) for postprophylaxis viremia, with no subsequent csCMVi. There were no toxicities attributable to letermovir. Of the 62 historic control subjects who received acyclovir only, 51 developed csCMVi (median onset, 34 days; range, 5-74 days), for a day 100 incidence of 82% (95% confidence interval, 73-92). Seven patients developed proven/probable CMV disease, and 6 died before day 100 (3 with proven/probable CMV pneumonia). Forty-five patients required extended therapy during the first 6 months for 1 (n = 10), 2 (n = 14), or 3/persistent (n = 21) csCMVi, with 43 (84%) of 51 developing significant treatment toxicities. Letermovir is a highly effective, well-tolerated prophylaxis that mitigates CMV infection, CMV-related mortality, and antiviral therapy toxicities in CBT recipients. Our data support prophylaxis duration of at least 6 months after CBT.

NRF2 Protects against Altered Pulmonary T Cell Differentiation in Neonates Following In Utero Ultrafine Particulate Matter Exposure.

Early life exposure to particulate matter (PM) air pollution negatively impacts neonatal health. The underlying mechanisms following prenatal exposure, particularly to ultrafine particles (UFP, diameter ≤ 0.1 µm), are not fully understood; To evaluate the role of Nrf2 in response to in utero UFP exposure, we exposed time-mated Nrf2-deficient (Nrf2-/-) or wildtype (WT) mice to filtered air (FA) or 100 µg/m3 ultrafine PM daily throughout pregnancy. Offspring were evaluated for pulmonary immunophenotypes and pulmonary/systemic oxidative stress on postnatal day 5, a timepoint at which we previously demonstrated viral respiratory infection susceptibility; Nrf2-/- offspring exposed to FA had significantly lower average body weights compared to FA-exposed WT pups. Moreover, PM-exposed Nrf2-/- offspring weighed significantly less than PM-exposed WT pups. Notably, PM-exposed Nrf2-/- offspring showed a decreased pulmonary Th1/Th2 ratio, indicating a Th2 bias. Th17 cells were increased in FA-exposed Nrf2-/- neonates yet decreased in PM-exposed Nrf2-/- neonates. Analysis of oxidative stress-related genes in lung and oxidative stress biomarkers in liver tissues did not vary significantly across exposure groups or genotypes. Collectively, these findings indicate that the lack of Nrf2 causes growth inhibitory effects in general and in response to gestational UFP exposure. Prenatal UFP exposure skews CD4+ T lymphocyte differentiation toward Th2 in neonates lacking Nrf2, signifying its importance in maternal exposure and infant immune responses.

NRF2-Dependent Placental Effects Vary by Sex and Dose following Gestational Exposure to Ultrafine Particles.

Exposure to ultrafine particles (UFPs, PM0.1) during pregnancy triggers placental oxidative stress and inflammation, similar to fine PM (PM2.5). The Nrf2 gene encodes a redox-sensitive transcription factor that is a major regulator of antioxidant and anti-inflammatory responses. Disruption of NRF2 is known to substantially enhance PM2.5-driven oxidant and inflammatory responses; however, specific responses to UFP exposure, especially during critical windows of susceptibility such as pregnancy, are not fully characterized; To investigate the role of NRF2 in regulating maternal antioxidant defenses and placental responses to UFP exposure, wildtype (WT) and Nrf2-/- pregnant mice were exposed to either low dose (LD, 100 µg/m3) or high dose (HD, 500 µg/m3) UFP mixture or filtered air (FA, control) throughout gestation; Nrf2-/- HD-exposed female offspring exhibited significantly reduced fetal and placental weights. Placental morphology changes appeared most pronounced in Nrf2-/- LD-exposed offspring of both sexes. Glutathione (GSH) redox analysis revealed significant increases in the GSH/GSSG ratio (reduced/oxidized) in WT female placental tissue exposed to HD in comparison with Nrf2-/- HD-exposed mice. The expression of inflammatory cytokine genes (Il1ß, Tnfα) was significantly increased in Nrf2-/- placentas from male and female offspring across all exposure groups. Genes related to bile acid metabolism and transport were differentially altered in Nrf2-/- mice across sex and exposure groups. Notably, the group with the most marked phenotypic effects (Nrf2-/- HD-exposed females) corresponded to significantly higher placental Apoa1 and Apob expression suggesting a link between placental lipid transport and NRF2 in response to high dose UFP exposure; Disruption of NRF2 exacerbates adverse developmental outcomes in response to high dose UFP exposure in female offspring. Morphological effects in placenta from male and female offspring exposed to low dose UFPs also signify the importance of NRF2 in maternal-fetal response to UFPs.

Gestational Exposure to Ultrafine Particles Reveals Sex- and Dose-Specific Changes in Offspring Birth Outcomes, Placental Morphology, and Gene Networks.

Particulate matter (PM) causes adverse developmental outcomes following prenatal exposure, but the underlying biological mechanisms remain uncertain. Here we elucidate the effects of diesel exhaust ultrafine particle (UFP) exposure during pregnancy on placental and fetal development. Time-mated C57Bl/6n mice were gestationally exposed to UFPs at a low dose (LD, 100 µg/m3) or high dose (HD, 500 µg/m3) for 6 h daily. Phenotypic effects on fetuses and placental morphology at gestational day (GD) of 18.5 were evaluated, and RNA sequencing was characterized for transcriptomic changes in placental tissue from male and female offspring. A significant decrease in average placental weights and crown to rump lengths was observed in female offspring in the LD exposure group. Gestational UFP exposure altered placental morphology in a dose- and sex-specific manner. Average female decidua areas were significantly greater in the LD and HD groups. Maternal lacunae mean areas were increased in the female LD group, whereas fetal blood vessel mean areas were significantly greater in the male LD and HD groups. RNA sequencing indicated several disturbed cellular functions related to lipid metabolism, which were most pronounced in the LD group and especially in female placental tissue. Our findings demonstrate the vulnerability of offspring exposed to UFPs during pregnancy, highlighting sex-specific effects and emphasizing the importance of mitigating PM exposure to prevent adverse health outcomes.

Air pollution and children's health-a review of adverse effects associated with prenatal exposure from fine to ultrafine particulate matter.

BACKGROUND: Particulate matter (PM), a major component of ambient air pollution, accounts for a substantial burden of diseases and fatality worldwide. Maternal exposure to PM during pregnancy is particularly harmful to children's health since this is a phase of rapid human growth and development. METHOD: In this review, we synthesize the scientific evidence on adverse health outcomes in children following prenatal exposure to the smallest toxic components, fine (PM2.5) and ultrafine (PM0.1) PM. We highlight the established and emerging findings from epidemiologic studies and experimental models. RESULTS: Maternal exposure to fine and ultrafine PM directly and indirectly yields numerous adverse birth outcomes and impacts on children's respiratory systems, immune status, brain development, and cardiometabolic health. The biological mechanisms underlying adverse effects include direct placental translocation of ultrafine particles, placental and systemic maternal oxidative stress and inflammation elicited by both fine and ultrafine PM, epigenetic changes, and potential endocrine effects that influence long-term health. CONCLUSION: Policies to reduce maternal exposure and health consequences in children should be a high priority. PM2.5 levels are regulated, yet it is recognized that minority and low socioeconomic status groups experience disproportionate exposures. Moreover, PM0.1 levels are not routinely measured or currently regulated. Consequently, preventive strategies that inform neighborhood/regional planning and clinical/nutritional recommendations are needed to mitigate maternal exposure and ultimately protect children's health.

Outpatient clinical pharmacy practice in the face of COVID-19 at a cancer center in New York City.

PURPOSE: With the rapid spread of COVID-19 in New York City since early March 2020, innovative measures were needed for clinical pharmacy specialists to provide direct clinical care safely to cancer patients. Allocating the workforce was necessary to meet the surging needs of the inpatient services due to the COVID-19 outbreak, which had the potential to compromise outpatient services. We present here our approach of restructuring clinical pharmacy services and providing direct patient care in outpatient clinics during the pandemic. DATA SOURCES: We conducted a retrospective review of electronic clinical documentation involving clinical pharmacy specialist patient encounters in 9 outpatient clinics from March 1, 2020 to May 31, 2020. The analysis of the clinical pharmacy specialist interventions and the impact of the interventions was descriptive. DATA SUMMARY: As hospital services were modified to handle the surge due to COVID-19, select clinical pharmacy specialists were redeployed from the outpatient clinics or research blocks to COVID-19 inpatient teams. During these 3 months, clinical pharmacy specialists were involved in 2535 patient visits from 9 outpatient clinics and contributed a total of 4022 interventions, the majority of which utilized telemedicine. The interventions provided critical clinical pharmacy care during the pandemic and omitted 199 in-person visits for medical care. CONCLUSION: The swift transition to telemedicine allowed the provision of direct clinical pharmacy services to patients with cancer during the COVID-19 pandemic.

Letermovir for Prevention of Cytomegalovirus Reactivation in Haploidentical and Mismatched Adult Donor Allogeneic Hematopoietic Cell Transplantation with Post-Transplantation Cyclophosphamide for Graft-versus-Host Disease Prophylaxis.

Cytomegalovirus (CMV) is serious viral infection in allogeneic hematopoietic cell transplantation (allo-HCT) recipients. November 2017, the novel CMV DNA terminase complex inhibitor letermovir was approved for prophylaxis of CMV infection in CMV-seropositive allo-HCT recipients. Here we sought to determine the effectiveness of letermovir in preventing CMV infection in CMV-seropositive patients undergoing haploidentical or mismatched adult unrelated donor allo-HCT using post-transplantation cyclophosphamide-based graft-versus host-disease prophylaxis. Sixty-four patients underwent transplantation between 2014 and 2019, of whom 32 received letermovir and 32 did not receive letermovir. The day 180 cumulative incidence of CMV infection requiring therapy was 45.3% (95% confidence interval [CI], 32.7% to 57.1%) in the entire cohort, 68.8% (95% CI, 48.9% to 82.2%) in the patients who did not receive letermovir, and 21.9% (95% CI, 9.5% to 37.6%; P < .001) in patients who received letermovir. Adjusting for regimen intensity, disease histology, and age, the hazard ratio for CMV infection was .19 (95% CI, .08 to .47; P < .001) in patients who received primary prophylaxis with letermovir. The 1-year cumulative incidence of treatment- related mortality was similar between patients with and without letermovir treatment (16.9% versus 18.9%), as was overall survival (64.0% versus 49.0%). Persistent CMV infection requiring >28 days of therapy was more common in patients who did not receive letermovir (31.2% versus 6.2%; P = .02). In summary, letermovir was effective in preventing CMV infection in this high-risk population of HLA-mismatched allo-HCT recipients.

Letermovir for primary and secondary cytomegalovirus prevention in allogeneic hematopoietic cell transplant recipients: Real-world experience.

Cytomegalovirus (CMV) is associated with significant morbidity and mortality in allogeneic hematopoietic cell transplantation (HCT) patients. We evaluated the efficacy of letermovir as primary and secondary prophylaxis in 53 CMV-seropositive hematopoietic stem cell transplant recipients. 70% of patients were at high risk for CMV reactivation and disease (primarily ex vivo T-cell-depleted HCT [n = 18; 34%] or haploidentical T-replete HCT [n = 12; 23%]). This was a retrospective, single-center study which identified patients transplanted between January 2018 and June 2018. Patients were followed through September 2018. The primary outcome was the incidence of clinically significant CMV infection (CMV viremia requiring preemptive treatment or CMV disease). Primary letermovir prophylaxis started at a median of 7 days (range, 7-40) after allo-HCT. The median duration of primary letermovir prophylaxis was 116 days (range, 12-221). With primary prophylaxis in 39 patients, the observed CMV reactivation rate was 5.1%. Twenty-nine patients continued primary prophylaxis beyond 14 weeks with a reactivation rate of 3.4%. No recurrent reactivation was seen with secondary prophylaxis of an additional 14 patients. Our experience demonstrates the efficacy of letermovir in a real-world setting for CMV prevention for the first 14 weeks and continued efficacy when given longer than 14 weeks after allogeneic stem cell transplantation or as secondary prophylaxis.

In utero ultrafine particulate matter exposure causes offspring pulmonary immunosuppression.

Early life exposure to fine particulate matter (PM) in air is associated with infant respiratory disease and childhood asthma, but limited epidemiological data exist concerning the impacts of ultrafine particles (UFPs) on the etiology of childhood respiratory disease. Specifically, the role of UFPs in amplifying Th2- and/or Th17-driven inflammation (asthma promotion) or suppressing effector T cells (increased susceptibility to respiratory infection) remains unclear. Using a mouse model of in utero UFP exposure, we determined early immunological responses to house dust mite (HDM) allergen in offspring challenged from 0 to 4 wk of age. Two mice strains were exposed throughout gestation: C57BL/6 (sensitive to oxidative stress) and BALB/C (sensitive to allergen exposure). Offspring exposed to UFPs in utero exhibited reduced inflammatory response to HDM. Compared with filtered air (FA)-exposed/HDM-challenged mice, UFP-exposed offspring had lower white blood cell counts in bronchoalveolar lavage fluid and less pronounced peribronchiolar inflammation in both strains, albeit more apparent in C57BL/6 mice. In the C57BL/6 strain, offspring exposed in utero to FA and challenged with HDM exhibited a robust response in inflammatory cytokines IL-13 and Il-17. In contrast, this response was lost in offspring exposed in utero to UFPs. Circulating IL-10 was significantly up-regulated in C57BL/6 offspring exposed to UFPs, suggesting increased regulatory T cell expression and suppressed Th2/Th17 response. Our results reveal that in utero UFP exposure at a level close to the WHO recommended PM guideline suppresses an early immune response to HDM allergen, likely predisposing neonates to respiratory infection and altering long-term pulmonary health.

Analysis of the Student Experience in an Attending Pharmacist Model General Medicine Advanced Pharmacy Practice Experience.

Objective. To characterize and determine the quality of the student experience in an attending pharmacist model (APM). Methods. In-depth interviews were conducted with students completing an advanced pharmacy practice experience (APPE) at two general medicine services using the APM over a 2-year time period. Quantitative information about student learning and interprofessional interactions were extracted from student evaluations of the site. Data from the mixed model were analyzed to identify strengths of the APM and areas needing improvement. Results. Strengths of the APM included positive student interaction with the pharmacy resident and more students reporting full integration in and accountability to the interprofessional team for patient outcomes compared to students in non-teaching models. A few students at one site reported a need for greater delineation of expectations, more initial support from preceptors, and initial responsibility for fewer patients. These factors were modified before the second APM year and subsequent reports from students at this site were uniformly positive. Students at the second site did not note areas needing improvement. The APM increased student capacity at both sites. Conclusion. The attending pharmacist model provided a high quality learning experience for students, particularly with regard to integration into and accountability for patient outcomes to the interprofessional team. Qualitative research methods enabled precise detection of areas needing improvement at one site and confirmed that changes made at that site improved the student experience.

The effect of horticultural therapy on the quality of life of palliative care patients.

Palliative care patients experience a variety of needs and perceive their quality of life as being only fair. This study adopted a single-group repeated-measure design to investigate the effect of horticultural therapy on the quality of life of palliative care patients using the Quality of Life Concern in End of Life Questionnaire. Significant differences in the domains of "existential distress" and "health care concern" were observed immediately postintervention and at 4 weeks postintervention, respectively. No other significant differences were seen in the other domains or in the total mean score of the outcome measure.

Acquired epidermodysplasia verruciformis in an HIV-positive patient.

Epidermodysplasia verruciformis (EV) is a rare dermatological manifestation of the human papillomavirus (HPV) infection, which causes distinctive skin lesions in sun-exposed areas. Both inherited and acquired forms exist. Immunocompromised individuals, such as HIV patients, are at risk of acquired EV. EV poses challenges in its management and variable responses are seen in different individuals. In addition, EV carries a significant risk of skin malignancy with certain HPV types that require skin surveillance. A case of acquired EV in a HIV-positive patient is presented in this report.

Student-Valued Measurable Teaching Behaviors of Award-Winning Pharmacy Preceptors.

OBJECTIVE: To identify specific preceptor teaching-coaching, role modeling, and facilitating behaviors valued by pharmacy students and to develop measures of those behaviors that can be used for an experiential education quality assurance program. METHODS: Using a qualitative research approach, we conducted a thematic analysis of student comments about excellent preceptors to identify behaviors exhibited by those preceptors. Identified behaviors were sorted according to the preceptor's role as role model, teacher/coach, or learning facilitator; measurable descriptors for each behavior were then developed. RESULTS: Data analysis resulted in identification of 15 measurable behavior themes, the most frequent being: having an interest in student learning and success, making time for students, and displaying a positive preceptor attitude. Measureable descriptors were developed for 5 role-modeling behaviors, 6 teaching-coaching behaviors, and 4 facilitating behaviors. CONCLUSION: Preceptors may need to be evaluated in their separate roles as teacher-coach, role model, and learning facilitator. The developed measures in this report could be used in site quality evaluation.

Cardiomyocyte-specific expression of lamin a improves cardiac function in Lmna-/- mice.

Lmna(-/-) mice display multiple tissue defects and die by 6-8 weeks of age reportedly from dilated cardiomyopathy with associated conduction defects. We sought to determine whether restoration of lamin A in cardiomyocytes improves cardiac function and extends the survival of Lmna(-/-) mice. We observed increased total desmin protein levels and disorganization of the cytoplasmic desmin network in ~20% of Lmna(-/-) ventricular myocytes, rescued in a cell-autonomous manner in Lmna(-/-) mice expressing a cardiac-specific lamin A transgene (Lmna(-/-); Tg). Lmna(-/-); Tg mice displayed significantly increased contractility and preservation of myocardial performance compared to Lmna(-/-) mice. Lmna(-/-); Tg mice attenuated ERK1/2 phosphorylation relative to Lmna(-/-) mice, potentially underlying the improved localization of connexin43 to the intercalated disc. Electrocardiographic recordings from Lmna(-/-) mice revealed arrhythmic events and increased frequency of PR interval prolongation, which is partially rescued in Lmna(-/-); Tg mice. These findings support our observation that Lmna(-/-); Tg mice have a 12% median extension in lifespan compared to Lmna(-/-) mice. While significant, Lmna(-/-); Tg mice only have modest improvement in cardiac function and survival likely stemming from the observation that only 40% of Lmna(-/-); Tg cardiomyocytes have detectable lamin A expression. Cardiomyocyte-specific restoration of lamin A in Lmna(-/-) mice improves heart-specific pathology and extends lifespan, demonstrating that the cardiac pathology of Lmna(-/-) mice limits survival. The expression of lamin A is sufficient to rescue certain cellular defects associated with loss of A-type lamins in cardiomyocytes in a cell-autonomous fashion.

A small-molecule probe induces a conformation in HIV TAR RNA capable of binding drug-like fragments.

The HIV-1 transactivation response (TAR) element-Tat interaction is a potentially valuable target for treating HIV infection, but efforts to develop TAR-binding antiviral drugs have not yet yielded a successful candidate for clinical development. In this work, we describe a novel approach toward screening fragments against RNA that uses a chemical probe to target the Tat-binding region of TAR. This probe fulfills two critical roles in the screen: by locking the RNA into a conformation capable of binding other fragments, it simultaneously allows the identification of proximal binding fragments by ligand-based NMR. Using this approach, we have discovered six novel TAR-binding fragments, three of which were docked relative to the probe-RNA structure using experimental NMR restraints. The consistent orientations of functional groups in our data-driven docked structures and common electrostatic properties across all fragment leads reveal a surprising level of selectivity by our fragment-sized screening hits. These models further suggest linking strategies for the development of higher-affinity lead compounds for the inhibition of the TAR-Tat interaction.

Child prostitution in Thailand.

Child prostitution is an old, global and complex phenomenon, which deprives children of their childhood, human rights and dignity. Child prostitution can be seen as the commercial sexual exploitation of children involving an element of forced labour, and thus can be considered as a contemporary form of slavery. Globally, child prostitution is reported to be a common problem in Central and South America and Asia. Of all the south-east Asian nations, the problem is most prolific in Thailand. In Thailand, there appears to be a long history of child prostitution, and this article explores the factors that underpin the Thai child sex industry and the lessons and implications that can be drawn for health care and nursing around the world.