Predictors of early mortality after lung transplantation for idiopathic pulmonary arterial hypertension.

Lung transplantation remains an important therapeutic option for idiopathic pulmonary arterial hypertension (IPAH), yet short-term survival is the poorest among the major diagnostic categories. We sought to develop a prediction model for 90-day mortality using the United Network for Organ Sharing database for adults with IPAH transplanted between 2005 and 2021. Variables with a p value ≤ 0.1 on univariate testing were included in multivariable analysis to derive the best subset model. The cohort comprised 693 subjects, of whom 71 died (10.2%) within 90 days of transplant. Significant independent predictors of early mortality were: extracorporeal circulatory support and/or mechanical ventilation at transplant (OR: 3; CI: 1.4-5), pulmonary artery diastolic pressure (OR: 1.3 per 10 mmHg; CI: 1.07-1.56), forced expiratory volume in the first second percent predicted (OR: 0.8 per 10%; CI: 0.7-0.94), recipient total bilirubin >2 mg/dL (OR: 3; CI: 1.4-7.2) and ischemic time >6 h (OR: 1.7, CI: 1.01-2.86). The predictive model was able to distinguish 25% of the cohort with a mortality of ≥20% from 49% with a mortality of ≤5%. We conclude that recipient variables associated with increasing severity of pulmonary vascular disease, including pretransplant advanced life support, and prolonged ischemic time are important risk factors for 90-day mortality after lung transplant for IPAH.

Management of systemic to pulmonary shunts and elevated pulmonary vascular resistance.

Background: Repair of systemic to pulmonary shunts is timed to prevent the development of irreversible pulmonary vascular disease, including in patients with other factors contributing to pulmonary hypertension. This study assessed outcomes of an individualised strategy for managing patients with mild-moderately elevated pulmonary vascular resistance (PVR) deemed borderline eligible for repair. Methods: A retrospective chart review was conducted of patients with systemic to pulmonary shunts and baseline indexed PVR (PVRi) ≥3 WU·m2 treated at a single centre from 1 January 2005 to 30 September 2019. Data included demographics, World Health Organization functional class (WHO FC), medications and haemodynamic data at baseline and serial follow-up. Results: 30 patients (18 females) met criteria for inclusion. Median age at diagnosis of pulmonary arterial hypertension was 1.3 years (range 0.03-54 years) and at surgery was 4.1 years (range 0.73-56 years). Median follow-up time was 5.8 years (range 0.2-14.6 years) after repair. Most patients received at least one targeted pulmonary arterial therapy prior to repair and the majority (80%) underwent fenestrated shunt closure. There was a significant decrease in mean pulmonary arterial pressure (mPAP) (p<0.01), PVRi (p=0.0001) and PVR/systemic vascular resistance (p<0.01) between baseline and preoperative catheterisation and a decrease in PVRi (p<0.005), mPAP (p=0.0001) and pulmonary to systemic flow ratio (p<0.03) from baseline to most recent catheterisation. WHO FC improved from FC II-III at baseline to FC I post repair in most patients (p<0.003). Conclusions: In carefully selected patients with systemic to pulmonary shunts and elevated PVR considered borderline for operability, the use of preoperative targeted therapy in conjunction with fenestrated or partial closure of intracardiac shunts is associated with improvement in WHO FC and clinical outcomes.

Changes in Body Mass Index in Children and Adolescents with Asthma during the COVID-19 Pandemic.

Background: Increased weight gain in children during the COVID-19 pandemic has been reported. Changes in weight in children with asthma during this period have not been well described. Methods: Retrospective review of children with asthma, 6-18 years of age, seen in 2019 and 2020. Mean monthly rates of change in body mass index (BMI) were compared between years. Demographic and asthma-related factors were examined. Results: Two hundred sixty-seven patients were enrolled. BMI increased by 0.128 ± 0.283 kg/m2/month during the pandemic year as compared with 0.084 ± 0.160 kg/m2/month during the previous year (P = 0.03). Patients with baseline overweight or obesity trended toward higher rates of BMI increase than those starting with normal weight, with the greatest BMI increase occurring in the severely obese. Conclusions: In this single-site study of children with asthma, there was a greater monthly rate of BMI gain during the early pandemic as compared with that observed in the previous year.

The relationship between weight and pulmonary outcomes in overweight and obese people with cystic fibrosis: A retrospective observational study.

Background: A major focus in cystic fibrosis (CF) care aims to increase weight gain. Rates of overweight and obese people with CF have gradually increased over the past decade. Obesity could be a risk for restriction of lung volumes and airway obstruction as well as increase rates of pulmonary exacerbations in people with CF. Aim: To assess the relationship between weight categories and pulmonary outcomes in children and adults with CF. Methods: Patients 6 years of age and older were categorized into weight categories based on the Centers for Disease Control and Prevention (CDC) definitions. A retrospective chart review was conducted to obtain lung function testing and other outcomes. Results: One hundred five patients with a median age of 20.6 years were included in this analysis. 8.4%, 64%, 18%, and 10% of patients were underweight, normal/healthy weight, overweight, and obese, respectively. Forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) (% predicted) did not differ between patients with weights in the normal range versus patients in the overweight/obese categories. Linear regression analysis showed a direct correlation between body mass index (BMI) and FEV1 that continued as BMI entered overweight and obese categories in both pediatric and adult patients. Overweight/obese patients did not have increased rates of pulmonary exacerbations compared to those in the normal/healthy weight category. Conclusion: As CF therapies continue to improve, an increasing number of people with CF are exceeding the CDC's normal-weight range. Gaining weight past the normal range does not appear to negatively impact pulmonary health of people with CF. If this trend of increased weight gain continues, it remains to be seen if it will eventually negatively affect lung health.

Vasoreactive phenotype in children with pulmonary arterial hypertension and syncope.

Background: Syncope in Group 1 pulmonary arterial hypertension (PAH) is an independent predictor of poor prognosis in adults, but this is not well studied in children. We hypothesise that syncope in children with PAH often occurs in association with a reactive pulmonary vascular bed with sudden vasoconstriction in response to adverse stimuli. In the current study, we sought to determine the association of syncope with acute vasoresponsiveness and outcomes in children with Group 1 PAH. Methods: A retrospective chart review of children with PAH at a single pulmonary hypertension centre from 1 January 2005 to 31 October 2018 was performed. Data included demographics, symptoms, imaging, haemodynamics, and outcomes at baseline and follow-up. Results: 169 children had Group 1 PAH; 47 (28%) had syncope at presentation or follow-up. Children with significant shunts were excluded from the analysis. Children with syncope were older at diagnosis (7.5 versus 5.0 years; p=0.002) and had a higher incidence of chest pain (p=0.022) and fatigue (p=0.003). They had higher pulmonary vascular resistance at baseline (14.9 versus 9.1 WU·m2; p=0.01). More children with syncope were vasoresponders to inhaled nitric oxide (33% versus 22%; p=0.08-NS). Children with syncope and acute vasoresponsiveness had the highest survival, and non-responders with syncope on medications had the worst long-term survival. Conclusions: Children with syncope had higher rates of vasoreactivity compared to those without. This suggests that in some children with PAH, syncope may simply reflect acute pulmonary vasoconstriction to an adverse stimulus. Larger prospective studies are warranted to further assess syncope as a marker for a vasoreactive phenotype with implications for treatment and long-term outcomes.

Transcriptomic modifications in developmental cardiopulmonary adaptations to chronic hypoxia using a murine model of simulated high-altitude exposure.

Mechanisms driving adaptive developmental responses to chronic high-altitude (HA) exposure are incompletely known. We developed a novel rat model mimicking the human condition of cardiopulmonary adaptation to HA starting at conception and spanning the in utero and postnatal timeframe. We assessed lung growth and cardiopulmonary structure and function and performed transcriptome analyses to identify mechanisms facilitating developmental adaptations to chronic hypoxia. To generate the model, breeding pairs of Sprague-Dawley rats were exposed to hypobaric hypoxia (equivalent to 9,000 ft elevation). Mating, pregnancy, and delivery occurred in hypoxic conditions. Six weeks postpartum, structural and functional data were collected in the offspring. RNA-Seq was performed on right ventricle (RV) and lung tissue. Age-matched breeding pairs and offspring under room air (RA) conditions served as controls. Hypoxic rats exhibited significantly lower body weights and higher hematocrit levels, alveolar volumes, pulmonary diffusion capacities, RV mass, and RV systolic pressure, as well as increased pulmonary artery remodeling. RNA-Seq analyses revealed multiple differentially expressed genes in lungs and RVs from hypoxic rats. Although there was considerable similarity between hypoxic lungs and RVs compared with RA controls, several upstream regulators unique to lung or RV were identified. We noted a pattern of immune downregulation and regulation patterns of immune and hormonal mediators similar to the genome from patients with pulmonary arterial hypertension. In summary, we developed a novel murine model of chronic hypoxia exposure that demonstrates functional and structural phenotypes similar to human adaptation. We identified transcriptomic alterations that suggest potential mechanisms for adaptation to chronic HA.

Pertussis clinical case definition: Time for change in developing countries?

BACKGROUND: Developing countries still struggle with late detection and mortality from pertussis. A review of clinical case definitions is necessary for early disease detection. This paper aimed to study possible clinical characteristics for earlier pertussis detection in a sporadic setting. METHODS: We conducted a retrospective review of medical and laboratory records in a general paediatric ward of a district hospital in a developing country. Inclusion criteria were all children hospitalised with nasopharyngeal swab taken for Bordetella pertussis. We compared sensitivity and specificity of World Health Organization diagnostic criteria with other clinical characteristics. Polymerase chain reaction Bordetella pertussis was the gold standard used. RESULTS: Out of 207 eligible admissions, the study retrieved 128 complete records. Approximately half of the children were less than 3 months old. The World Health Organization diagnostic criteria had a low sensitivity (15%), but high specificity (92%). In comparison, combinations that included paroxysmal cough, ill contact and facial congestion had higher sensitivity. Increasing cough duration improved specificity while compromising sensitivity. CONCLUSION: Several clinical characteristics such as paroxysmal cough, facial congestion and a history of ill contact have potential for early clinical detection. Conventional emphasis on cough duration may hamper early detection.

Peak post-transplant lung function in bilateral lung transplant recipients using a prediction model based on donor and recipient demographic characteristics.

RATIONALE: There are no reliable methods to predict lung function following lung transplantation. We sought to devise a prediction model of peak pulmonary function testing (PFT) post-transplant based on donor and recipient demographic characteristics. METHODS: Single center retrospective analysis of bilateral lung transplant recipients between 2011 and 2015 without evidence of allograft dysfunction in the first year was performed. Peak PFT post-transplant was determined by serially measured FEV1 and FVC. Using the NHANES III equation, donor demographic characteristics were used to calculate predicted lung function. Multivariable linear regression helped determine which donor and recipient characteristics affected peak lung function and identify the discrepancy between donor predicted and recipient observed PFT post-transplant. RESULTS: 146 donor/recipient patients were analyzed. 80 had obstructive lung disease, 66 had restrictive disease. Peak post-transplant FEV1 and FVC was reached in 64.30 ±â€¯48.96 and 78.14 ±â€¯50.68 weeks, respectively. Spirometry values peaked earlier in restrictive lung disease recipients. Higher peak FEV1 was significantly associated with younger donor age, non-African American donor race, male recipient sex, greater recipient height, underlying obstructive lung disease. Greater absolute differences between donor predicted and observed FEV1 were significantly associated with male donor sex, greater donor height, non-African-American donor race, female recipient sex, greater recipient height. CONCLUSIONS: Donor and recipient characteristics can help predict lung function post-transplant. Patients without complications in the first year post-transplant may take greater than one year to achieve peak lung function. Such predictions can help guide clinical decision making in the right setting.

Management of broncholithiasis.

Broncholithiasis is a condition in which calcified material has entered the tracheobronchial tree, at times causing airway obstruction and inflammation. Broncholiths generally originate as calcified material in mediastinal lymph nodes that subsequently erode into adjacent airways, often as a result of prior granulomatous infection. Disease manifestations range from asymptomatic stones in the airway to life-threatening complications, including massive hemoptysis and post-obstructive pneumonia. Radiographic imaging, particularly computed tomography scanning of the chest, is integral in the evaluation of suspected broncholithiasis and can be helpful to assess involvement of adjacent structures, including vasculature, prior to any planned intervention. Management strategies largely depend on the severity of disease. Observation is warranted in asymptomatic cases, while therapeutic bronchoscopy and surgical interventions may be necessary for cases involving complications. Bronchoscopic extraction is often feasible in cases in which the broncholith is freely mobile within the airway, whereas partially-embedded broncholiths represent additional challenges. Surgical intervention is indicated for advanced cases deemed not amenable to endoscopic management. Complex cases involving complications such as massive hemoptysis and/or bronchomediastinal fistula formation are best managed with a multidisciplinary approach, utilizing expertise from fields such as pulmonology, radiology, and thoracic surgery.

A case report of hepatopulmonary syndrome in hereditary hemorrhagic telangiectasia (HHT): Not all right-to-left shunting in HHT is due to pulmonary arteriovenous malformations.

RATIONALE: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by abnormal vessel growth that results in telangiectasias and arteriovenous malformations (AVMs) in the skin, mucosa, and viscera. Up to 30% of patients with HHT exhibit pulmonary AVMs (PAVMs), clinically manifesting as right-to-left shunting and hypoxemia. PATIENT CONCERNS: We report an unusual and novel case of a patient with HHT who lacked clinical sequelae of portal hypertension but presented to clinic with hypoxemia without dyspnea. DIAGNOSES: Diagnostic workup revealed noncardiac right-to-left shunting due to hepatopulmonary syndrome (HPS) from HHT-induced portal hypertension rather than PAVMs. The diagnosis was confirmed by the absence of PAVMs on chest computed tomography and evidence of elevated portal pressures as noted by the presence of small esophageal varices on upper endoscopy and histologic findings on liver biopsy. INTERVENTION: Due to the patient's mild symptoms, no further intervention was required. He was closely followed up in the outpatient setting for changes in symptoms and underwent annual screening for development of PAVMs. OUTCOMES: The patient continues to do well clinically. He has not experienced worsening hypoxemia or dyspnea and has not developed PAVMs. LESSONS: Given that management of hypoxemia in HPS drastically differs from that of hypoxemia due to PAVMs, this case demonstrates the importance of evaluating HHT patients for HPS if they exhibit impaired oxygenation and noncardiac right-to-leftshunting in the setting of hepatic arteriovenous shunting.

Sphingolipid regulation of lung epithelial cell mitophagy and necroptosis during cigarette smoke exposure.

The mechanisms by which lung structural cells survive toxic exposures to cigarette smoke (CS) are not well defined but may involve proper disposal of damaged mitochondria by macro-autophagy (mitophagy), processes that may be influenced by pro-apoptotic ceramide (Cer) or its precursor dihydroceramide (DHC). Human lung epithelial and endothelial cells exposed to CS exhibited mitochondrial damage, signaled by phosphatase and tensin homolog-induced putative kinase 1 (PINK1) phosphorylation, autophagy, and necroptosis. Although cells responded to CS by rapid inhibition of DHC desaturase, which elevated DHC levels, palmitoyl (C16)-Cer also increased in CS-exposed cells. Whereas DHC augmentation triggered autophagy without cell death, the exogenous administration of C16-Cer was sufficient to trigger necroptosis. Inhibition of Cer-generating acid sphingomyelinase reduced both CS-induced PINK1 phosphorylation and necroptosis. When exposed to CS, Pink1-deficient ( Pink1-/-) mice, which are protected from airspace enlargement compared with wild-type littermates, had blunted C16-Cer elevations and less lung necroptosis. CS-exposed Pink1-/- mice also exhibited significantly increased levels of lignoceroyl (C24)-DHC, along with increased expression of Cer synthase 2 ( CerS2), the enzyme responsible for its production. This suggested that a combination of high C24-DHC and low C16-Cer levels might protect against CS-induced necroptosis. Indeed, CerS2-/- mice, which lack C24-DHC at the expense of increased C16-Cer, were more susceptible to CS, developing airspace enlargement following only 1 month of exposure. These results implicate DHCs, in particular, C24-DHC, as protective against CS toxicity by enhancing autophagy, whereas C16-Cer accumulation contributes to mitochondrial damage and PINK1-mediated necroptosis, which may be amplified by the inhibition of C24-DHC-producing CerS2.-Mizumura, K., Justice, M. J., Schweitzer, K. S., Krishnan, S., Bronova, I., Berdyshev, E. V., Hubbard, W. C., Pewzner-Jung, Y., Futerman, A. H., Choi, A. M. K., Petrache, I. Sphingolipid regulation of lung epithelial cell mitophagy and necroptosis during cigarette smoke exposure.

A preliminary study of a cloud-computing model for chronic illness self-care support in an underdeveloped country.

BACKGROUND: Although interactive voice response (IVR) calls can be an effective tool for chronic disease management, many regions of the world lack the infrastructure to provide these services. PURPOSE: This study evaluated the feasibility and potential impact of an IVR program using a cloud-computing model to improve diabetes management in Honduras. METHODS: A single-group, pre-post study was conducted between June and August 2010. The telecommunications infrastructure was maintained on a U.S. server, and calls were directed to patients' cell phones using VoIP. Eighty-five diabetes patients in Honduras received weekly IVR disease management calls for 6 weeks, with automated follow-up e-mails to clinicians, and voicemail reports to family caregivers. Patients completed interviews at enrollment and a 6-week follow-up. Other measures included patients' glycemic control (HbA1c) and data from the IVR calling system. RESULTS: A total of 53% of participants completed at least half of their IVR calls and 23% of participants completed 80% or more. Higher baseline blood pressures, greater diabetes burden, greater distance from the clinic, and better medication adherence were related to higher call completion rates. Nearly all participants (98%) reported that because of the program, they improved in aspects of diabetes management such as glycemic control (56%) or foot care (89%). Mean HbA1c's decreased from 10.0% at baseline to 8.9% at follow-up (p<0.01). Most participants (92%) said that if the service were available in their clinic they would use it again. CONCLUSIONS: Cloud computing is a feasible strategy for providing IVR services globally. IVR self-care support may improve self-care and glycemic control for patients in underdeveloped countries.

The lowest-dose, extended-cycle combined oral contraceptive pill with continuous ethinyl estradiol in the United States: a review of the literature on ethinyl estradiol 20 µg/levonorgestrel 100 µg + ethinyl estradiol 10 µg.

Extended-cycle oral contraceptives (OCs) are increasing in popularity in the United States. A new extended-cycle OC that contains the lowest doses of ethinyl estradiol (EE) and levonorgestrel (LNG) + continuous EE throughout the cycle is now available. It provides 84 days of a low-dose, combined active pill containing levonorgestrel 100 µg and ethinyl estradiol 20 µg. Instead of 7 days of placebo following the active pills, the regimen delivers 7 days of ethinyl estradiol 10 µg. Existing studies reveal a similar efficacy and adverse effect profile compared with other extended-regimen OCs. Specifically, the unscheduled bleeding profile is similar to other extended-cycle OCs and improves with the increase in the duration of use. Although lower daily doses of hormonal exposure have potential benefit, to our knowledge, there are no published studies indicating that this specific regimen offers a lower incidence of hormone-related side effects or adverse events. In summary, this new extended-cycle OC provides patients a low-dose, extended-regimen OC option without sacrificing efficacy or tolerability.

Nonmedical influences on the use of cholinesterase inhibitors in dementia care.

We examined primary care physicians' (PCPs) attitudes toward cholinesterase inhibitors (ChEI) to better understand nonmedical factors influencing prescribing decisions in dementia care. In a cross-sectional, qualitative study, 40 PCPs were interviewed concerning their general approach to managing patients with dementia, and their care for a particular dementia case. Three readers independently identified and categorized themes associated with prescribing ChEI. Physicians' attitudes toward ChEI were also coded. Physicians were predominantly ambivalent (51%) or negative (31%) about prescribing ChEI for their patients with dementia. Nonmedical factors affecting prescribing included lack of knowledge, dependence on specialists, influence of family wishes and involvement, and physicians' values. PCPs reported that lack of knowledge and experience made prescribing decisions for ChEI challenging. Physicians reported feeling pressured by families to prescribe ChEI. Under these ambiguous conditions, some physicians prescribed medications simply to be able to offer "something" to patients.

Cervical cancer incidence in a prevaccine era in the United States, 1998-2002.

OBJECTIVE: To report the incidence of cervical cancer by geography, race or ethnicity, and histology. METHODS: We examined combined data from the National Program of Cancer Registries and the Surveillance, Epidemiology, and End Results Program covering 87% of the U.S. population. We calculated the age-adjusted incidence of cervical cancer by age, race or ethnicity, histology, and stage by region or state. RESULTS: Rates of invasive cancer per 100,000 females declined from 10.2 in 1998 to 8.5 in 2002. Incidence rates by state ranged from 6.6 to 12.3 per 100,000. Rates were especially high among Hispanic women aged 40 years or older (26.5 or more) and African-American women aged older than 50 years (23.5 or more). Rates of squamous cell carcinoma were significantly higher among African-American and Hispanic women than among their white counterparts. In contrast, rates of adenocarcinoma (18% of all cases) were significantly lower among African-American women than in white women (rate ratio 0.88, P<.05). Rates of adenocarcinoma were significantly higher among Hispanic women than among non-Hispanics (rate ratio 1.71, P<.05). Although no regional differences were noted for adenocarcinoma, rates of squamous cell carcinoma were higher in the South than in other regions. CONCLUSION: Despite intense screening in the past decade, higher rates of cervical cancer persist among women in the South and women who are African American or Hispanic. This information could guide more focused interventions to increase access to screening with cervical cytology as well as vaccination against human papillomavirus. LEVEL OF EVIDENCE: III.