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The management of CTEPH has evolved due to advances in diagnosis, treatment, and the adoption of best practice guidelines. However, there is limited information regarding contemporary real-world clinical care. The aim of this survey was to collect clinical practice data from hospital-based medical specialists and to identify unmet needs in CTEPH. CLARITY was developed by an independent committee of international CTEPH experts using the Delphi method. Questions were designed to gather quantitative and qualitative insights on the awareness, diagnosis, and treatment of CTEPH. Twenty-one international, regional, and national scientific societies and other medical organizations have supported the web-survey distribution. Responses were collected from 09.10.2021 to 05.01.2022. 416 questionnaires were collected, 353 of which were suitable to be analyzed. Respondents came from Europe (44%), Asia-Pacific (32%), Latin America (11%), US / Canada (11%), and the Middle East / Africa (2%). Most respondents specialized in pulmonology (44%) or cardiology (41%) and had over 15 years of experience (56%). Around 30% were not working in a pulmonary hypertension or CTEPH expert center and among them, only 30% were affiliated to such a center. The most commonly reported barriers to CTEPH recognition and diagnosis, operability assessment, and treatment by pulmonary endarterectomy (PEA) / balloon pulmonary angioplasty (BPA) were lack of disease awareness and structured pulmonary embolism follow-up, delayed referral, lack of standardized operability criteria and multidisciplinary team/reference center, limited access to PEA / BPA, and insufficient expertise in performing PEA / BPA, respectively (Table). The survey provided global insights on the contemporary management of CTEPH and an understanding of key barriers to optimal care. It may serve as a basis to call for action to improve CTEPH detection and management. [ABSTRACT FROM AUTHOR]

Forkhead box protein 3 (FoxP3)+ regulatory T cells ( Tregs) are important not only in regulating the development of autoimmune conditions, but also in chronic infectious diseases. Given their cardinal function in suppressing immune activation, research has focused upon whether they play a detrimental role in chronic infections, particularly HIV. While the role of Tregs in HIV has been investigated intensively, it remains an unresolved topic. However, it is generally accepted that Tregs are susceptible to HIV infection and are preferentially preserved over conventional CD4+ T cells. It is unknown whether the peripheral-induced or the thymic-derived Tregs are more susceptible to HIV cytotoxicity. It has been recognized that Tregs can be segregated into two subsets based on Helios expression, with the vast majority being Helios+. This study examines the impact of HIV infection on total Tregs and their Helios subsets in a perinatal-acquired HIV-infected paediatric population. The finding indicates a selective expansion or survival of Tregs in association with CD4 depletion and increased viraemia. The Helios+ and Helios− subsets within Tregs appear to be equally affected. However, the Helios+ Tregs seem to be more preserved in patients with low CD4+ ≤ 25% and detectable plasma HIV RNA >20 copies/ml. In this group, the frequencies of Tregs are increased, but their numbers appear insufficient to restrain immune activation. In conclusion, our findings suggest that both Helios subsets of Tregs are susceptible to HIV infection and are preferentially preserved compared to conventional CD4+ T cells. [ABSTRACT FROM AUTHOR]

To evaluate the effect of a multidisciplinary team in the management of patients with chronic thromboembolic pulmonary hypertension (CTEPH) undergoing pulmonary thromboendarterectomy (PTE) (Figure A). From 1997 to 2022, 306 patients underwent PTE for CTEPH. In 2011, a multidisciplinary team was assembled to systematically evaluate, select, and manage patients for PTE based on hemodynamic profile, anatomic scar accessibility, and comorbidities. The cohort was divided into an early era of 62 cases (20%) prior to 2011 and 244 cases (80%) thereafter (recent era). Baseline demographics and hemodynamic profiles were similar between eras, with mean age 53±14 years. More early-era patients were in New York Heart Association class III/IV (64% vs. 40%); however, pulmonary hypertension and pulmonary vascular resistance (PVR) were similar. Recent-era patients had shorter circulatory arrest times (36 vs. 42 min) and more tricuspid valve repairs (22% vs. 3%). Recent-era patients had lower hospital mortality (3% vs. 12%), fewer hospital morbidity, including less prolonged ventilation (32% vs. 59%) and less need for dialysis (1.6% vs. 21%), and shorter length of stay (16 vs. 21 days). Difference in mortality was sustained long-term (12% vs. 30% at 6 years, Figure B). Recent-era patients had lower residual mean pulmonary artery pressures (26 vs. 33 mmHg) and lower residual PVR (2.7 vs. 4.2 Wood units). Establishing a multidisciplinary CTEPH team allows more accurate identification of patients most likely to benefit from PTE surgery, which leads to more complete resolution of pulmonary hypertension and improved survival. A team-based approach for patient selection and perioperative management of these complex patients should be considered standard of care. [ABSTRACT FROM AUTHOR]

Background: Pulmonary hypertension due to interstitial lung disease (PH-ILD) is associated with high rates of respiratory failure and death. Healthcare resource utilization (HCRU) and cost data are needed to characterize PH-ILD disease burden., Methods: A retrospective cohort analysis of the Truven Health MarketScan ® Commercial Claims and Encounters Database and Medicare Supplemental Database between June 2015 to June 2019 was conducted. Patients with ILD were identified and indexed based on their first claim with a PH diagnosis. Patients were required to be 18 years of age on the index date and continuously enrolled for 12-months pre- and post-index. Patients were excluded for having a PH diagnosis prior to ILD diagnosis or the presence of other non-ILD, PH-associated conditions. Treatment patterns, HCRU, and healthcare costs were compared between the 12 months pre- versus 12 months post-index date., Results: In total, 122 patients with PH-ILD were included (mean [SD] age, 63.7 [16.6] years; female, 64.8%). The same medication classes were most frequently used both pre- and post-index (corticosteroids: pre-index 43.4%, post-index 53.5%; calcium channel blockers: 25.4%, 36.9%; oxygen: 12.3%, 25.4%). All-cause hospitalizations increased 2-fold, with 29.5% of patients hospitalized pre-index vs. 59.0% post-index (P < 0.0001). Intensive care unit (ICU) utilization increased from 6.6 to 17.2% (P = 0.0433). Mean inpatient visits increased from 0.5 (SD, 0.9) to 1.1 (1.3) (P < 0.0001); length of stay (days) increased from 5.4 (5.9) to 7.5 (11.6) (P < 0.0001); bed days from 2.5 (6.6) to 8.0 (16.3) (P < 0.0001); ICU days from 3.8 (2.3) to 7.0 (13.2) (P = 0.0362); and outpatient visits from 24.5 (16.8) to 32.9 (21.8) (P < 0.0001). Mean (SD) total all-cause healthcare costs increased from $43,201 ($98,604) pre-index to $108,387 ($190,673) post-index (P < 0.0001); this was largely driven by hospitalizations (which increased from a mean [SD] of $13,133 [$28,752] to $63,218 [$75,639] [P < 0.0001]) and outpatient costs ($16,150 [$75,639] to $25,604 [$93,964] [P < 0.0001])., Conclusion: PH-ILD contributes to a high HCRU and cost burden. Timely identification, management, and treatment are needed to mitigate the clinical and economic consequences of PH-ILD development and progression., (© 2024. The Author(s).)

Abstract: Chronic thromboembolic pulmonary hypertension (CTEPH) remains significantly underdiagnosed in patients with a history of pulmonary embolism. These patients complain of persistent shortness of breath and present with hypoxemia despite proper anticoagulation. Further investigation reveals evidence of right ventricular dysfunction on echocardiogram, which progresses to right heart failure. CTEPH is associated with a significant increase in patient morbidity and mortality if left untreated. This article offers an approach for the timely recognition of this condition, in addition to suggesting a management protocol with an emphasis on the role of interventional radiology and balloon pulmonary angioplasty., (Copyright © 2022 American Academy of Physician Assistants.)

Background: In premature infants, complicated intraabdominal infections (cIAIs) are a leading cause of morbidity and mortality. Although universally prescribed, the safety and effectiveness of commonly used antibiotic regimens have not been established in this population., Methods: Infants ≤33 weeks gestational age and <121 days postnatal age with cIAI were randomized to ≤10 days of ampicillin, gentamicin, and metronidazole (group 1); ampicillin, gentamicin, and clindamycin (group 2); or piperacillin-tazobactam and gentamicin (group 3) at doses stratified by postmenstrual age. Due to slow enrollment, a protocol amendment allowed eligible infants already receiving study regimens to enroll without randomization. The primary outcome was mortality within 30 days of study drug completion. Secondary outcomes included adverse events, outcomes of special interest, and therapeutic success (absence of death, negative cultures, and clinical cure score >4) 30 days after study drug completion., Results: One hundred eighty infants [128 randomized (R), 52 nonrandomized (NR)] were enrolled: 63 in group 1 (45 R, 18 NR), 47 in group 2 (41 R, 6 NR), and 70 in group 3 (42 R, 28 NR). Thirty-day mortality was 8%, 7%, and 9% in groups 1, 2, and 3, respectively. There were no differences in safety outcomes between antibiotic regimens. After adjusting for treatment group and gestational age, mortality rates through end of follow-up were 4.22 [95% confidence interval (CI): 1.39-12.13], 4.53 (95% CI: 1.21-15.50), and 4.07 (95% CI: 1.22-12.70) for groups 1, 2, and 3, respectively., Conclusions: Each of the antibiotic regimens are safe in premature infants with cIAI., Clinical Trial Registration: NCT0199499., Competing Interests: The other authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Metronidazole is frequently used off-label in infants with complicated intra-abdominal infections (cIAI) to provide coverage against anaerobic organisms, but its safety and efficacy in this indication are unknown., Methods: In the Antibiotic Safety in Infants with Complicated Intra-Abdominal Infections open-label multicenter trial infants ≥34 weeks gestation at birth and <121 days postnatal age with cIAIs were administered metronidazole as part of multimodal therapy. Metronidazole safety was evaluated by reporting of adverse events (AEs) and safety events of special interest. Cure from disease was determined by blood cultures and a clinical cure score >4. A blinded adjudication committee reviewed all safety events of special interest., Results: Fifty-five infants were included, median gestational age was 36 weeks (range: 34-41) and postnatal age was 7 days (0-63). The most common additional antibiotics received included gentamicin, piperacillin-tazobactam, ampicillin and vancomycin. Only one AE, a candidal rash, was identified to be potentially caused by metronidazole administration. One infant died of cardiopulmonary failure, which was deemed unrelated to metronidazole. The most common events of special interest included feeding intolerance in 18 (33%) infants, and exploratory laparotomy in 10 (18%) requiring intestinal anastomosis in 7 (13%) infants. There was 1 (2%) intestinal stricture. Fifty-three infants (96%) achieved overall therapeutic success, 54 (98%) were alive through 30 days post-study therapy, and 54 (98%) had 30-day clinical cure score >4., Conclusions: In a cohort of late pre-term and term infants with cIAIs, combination antibiotic therapy that included metronidazole was safe, and therapeutic success was high.

There is limited guidance on how to treat extremely premature infants with HIV infection. This can lead to delay of antiretroviral therapy initiation adversely affecting magnitude of HIV reservoir and disease progression. We report perinatal HIV-1 infection in an extremely low birth weight infant born at 24 5/7 weeks of gestation. Treatment challenges, viral dynamics and clinical outcomes are described.

Objective: In adults, nucleoside reverse transcriptase inhibitor-only antiretroviral regimens (NOARs) with ≥3 nucleoside reverse transcriptase inhibitors are less potent than highly active antiretroviral therapy (HAART). Published pediatric experience with NOARs is limited; thus, we wished to better define the virological, immunological and toxicological effects of NOARs in children and adolescents., Methods: We analyzed data from NOAR-treated participants in LEGACY, a multicenter observational cohort study of HIV-infected children and adolescents. NOAR-treated case-participants were matched to participants without prior NOAR who initiated HAART during the same year for comparison., Results: Of 575 participants with data from time of HIV diagnosis through 2006, 67 (12%) received NOARs for at least 24 weeks; most (46%) received the fixed dose combination of zidovudine/lamivudine/abacavir. NOAR use peaked in 2001 to 2002. NOAR-treated participants were significantly older and more treatment experienced than HAART-treated participants. Virologic outcomes, including the percentage of participants with a plasma HIV RNA viral load <400 copies/mL at week 24 (47% versus 34%) and the mean 24-week change in log10 plasma HIV RNA viral load from baseline (-0.63 versus -1.02), were similar between NOAR- and HAART-treated participants, but virologic rebound was more likely in NOAR-treated participants (77% versus 54%, P = 0.02). Increase in CD4 percentage points from baseline to 24 weeks was negligible in NOAR-treated participants compared with HAART-treated participants (0.95% versus 10.1%, P < 0.001). Anemia and leukopenia were more commonly reported with NOARs than HAART., Discussion: Week 24 virologic outcomes were similar between NOAR- and HAART-treated participants, but NOAR durability was poorer and their use was associated with less immunologic reconstitution. NOARs should play a limited role in pediatric and adolescent antiretroviral therapy.

Circulating cardiac troponins are markers of myocardial injury. We sought to determine whether cardiac troponin I (cTnI), measured by a sensitive assay, is associated with disease severity and prognosis in pulmonary arterial hypertension (PAH). cTnI was measured in 68 patients with PAH diagnostic category 1 in a research-based sensitive immunoanalyser with a lower limit of detection of 0.008 ng · mL(-1). The associations between cTnI and PAH severity and clinical outcomes were assessed using Chi-squared and Wilcoxon rank sum tests, Kaplan-Meier analysis and Cox regression models. cTnI was detected in 25% of patients. Patients with detectable cTnI had more advanced functional class symptoms, a shorter 6-min walk distance, more pericardial effusions, larger right atrial area, and higher B-type natriuretic peptide and C-reactive protein levels. 36-month transplant-free survival was 44% in patients with detectable cTnI versus 85% in those with undetectable cTnI. cTnI was associated with a 4.7-fold increased risk of death related to right ventricular failure or transplant (hazard ratio 4.74, 95% CI 1.89-11.89; p<0.001), even when adjusted individually for known parameters of PAH severity. Elevated plasma cTnI, even at subclinically detectable levels, is associated with more severe disease and worse outcomes in patients with PAH.

Background: Hematogenous Candida meningoencephalitis (HCME) is a relatively frequent manifestation of disseminated candidiasis in neonates and is associated with significant mortality and neurodevelopmental abnormalities. The outcome after antifungal therapy is often suboptimal, with few therapeutic options. Limited clinical data suggest that echinocandins may have role to play in the treatment of HCME., Methods: We studied the pharmacokinetics and pharmacodynamics of micafungin in a rabbit model of neonatal HCME and bridged the results to neonates by use of population pharmacokinetics and Monte Carlo simulation., Results: Micafungin exhibited linear plasma pharmacokinetics in the range of 0.25-16 mg/kg. Micafungin penetrated most compartments of the central nervous system (CNS), but only with doses >2 mg/kg. Micafungin was not reliably found in cerebrospinal fluid. With few exceptions, drug penetration into the various CNS subcompartments was not statistically different between infected and noninfected rabbits. A dose-microbiological response relationship was apparent in the brain, and near-maximal effect was apparent with doses of 8 mg/kg. Monte Carlo simulations revealed that near-maximal antifungal effect was attained at human neonatal doses of 12-15 mg/kg., Conclusions: These results provide a foundation for clinical trials of micafungin in neonates with HCME and a model for antimicrobial bridging studies from bench to bedside in pediatric patients.

We report the development of Campylobacter jejuni enteritis in a patient with preexisting humoral and cellular immune recognition of C. jejuni antigens. This is one of few studies in which the immunologic status of a person with regard to C. jejuni before and after C. jejuni infection is directly compared, and it is the only study of which we are aware that includes measurements of cellular immunity. The findings may be important to Campylobacter vaccine development efforts.

A preterm breast-fed infant had three episodes of type Ia/c group B streptococcus septicemia. After the second episode rifampin was given to the infant, but further Ia/c exposure to maternal breast milk ensued. We propose rifampin treatment for both the mother and infant in cases of recurrent group B streptococcus disease.

Shigella sonnei infection resulting from oral administration of 500 colony-forming units was followed in 11 volunteers with the objective of studying the immune response and pathogenesis. Characterization of infection included recording of signs and symptoms, excretion of S. sonnei in stool, measurement of humoral tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), interferon-gamma (IFN-gamma), C-reactive protein, IL-2 receptor, soluble CD8, antibody-antigen complexes, and endotoxin. Measurements were also made of the immune response including lymphocytes secreting antibody to S. sonnei O antigen and serum antibody to this antigen. Six of the volunteers developed typical shigellosis with excretion of bacteria in stool and systemic signs and symptoms, three excreted bacteria but did not show illness, and two showed no evidence of infection or illness. Shigellosis was characterized by excretion in stool of S. sonnei beginning on average 1.3 days after ingestion. Excretion of S. sonnei (mean of time of the first positive cultures) was followed in sequence by the onset of increases in TNF-alpha (10 hr), liquid stools (14 hr), fever and dysentery (18 hr), IFN-gamma (22 hr), and C-reactive protein (34 hr). A S. sonnei-specific immune response was demonstrated somewhat later, between days 4 and 7 postinfection by antibody-secreting cells, and between days 7 and 14 postinfection by humoral antibody. Shigellosis was not associated with increased humoral IL-1 beta, endotoxin, or antigen-antibody complexes.

To address the hypothesis that increased infectious morbidity is associated with iron supplementation, 783 randomly selected infants were provided with a powdered full fat cow's milk (non-fortified group) and 872 with a powdered acidified full fat cow's milk fortified with 15 mg of iron as ferrous sulfate (fortified group). All infants were followed from birth to 15 months of age with a monthly home visit by a nurse who recorded morbidity occurring during the previous 30 days. At 9 months of age, 15% of infants in each cohort were receiving breast milk only; data for these infants were segregated to make the third group. Episodes (mean +/- SD) of diarrhea/infant/year were 1.06 +/- 1.29, 1.14 +/- 1.37, and 0.82 +/- 1.04 for the fortified, non-fortified and breast-fed groups, respectively; the fortified and non-fortified bottle-fed groups had a very similar incidence of respiratory illness; 2.66 +/- 2.07 and 2.74 +/- 2.24 episodes/infant/year, respectively. The incidence of respiratory illness for both bottle-fed groups was significantly higher than that for the breast-fed group (2.22 +/- 1.84 respiratory episodes/infant/year). We conclude that for the infants the tested form of iron fortified milk, which is sufficient to lower iron deficiency anemia, does not result in an increased incidence of diarrhea or respiratory illness.

Three siblings with alloimmune neonatal neutropenia are presented. An immunoglobulin G (IgG) antineutrophil antibody specific for NA-2 antigen was demonstrated in maternal serum and in both of the three affected infants who were studied as neonates. The mother's neutrophils were negative for NA-2 antigen. The father and all four children, including the three known to be affected, had neutrophils that expressed NA-2 antigen. One patient studied sequentially demonstrated an inverse relationship between the antineutrophil antibody titer and the absolute neutrophil count. Exchange transfusions did not appear to benefit two of the infants.

We tested in the field an extruded rice flour, fortified with a bovine haemoglobin concentrate (Fe:14 mg/100 g of powder). This cereal has a high iron bioavailability, good protein quality and amino acid score. Healthy, term breast-fed infants were prospectively studied. One group (n = 92) received the fortified cereal (from 4 to 12 months of age). As control, 96 infants received regular solid foods (cooked vegetables and meat) from age 4 months. At the end of the field trial, a subsample of infants in both groups was supplemented with 45 mg Fe during 90 d. Iron nutrition status was determined at 9, 12 and 15 months. At 12 months, iron deficiency anaemia was present in 17 per cent of controls, in 10 per cent of fortified infants as a whole, but only in 6 per cent of the babies who consumed over 30 g of cereal/d. In addition, this latter group did not show any significant changes in iron nutrition status after the supplementation trial. Results demonstrate that the consumption of a haemoglobin fortified cereal is effective in markedly reducing the incidence of iron deficiency in breast-fed infants.

1. Serum thymic hormone was assayed in genetically-obese (C57B1/6J ob/ob) mice and lean controls (+/+, +/-) of the same strain. 2. The thymic hormone activity was higher in the majority of the obese animals compared with non-obese mice. 3. The number of antibody-forming cells in the spleen expressed as a proportion of the total mononuclear cells was increased in the obese mice. 4. It is suggested that obesity is associated with significant changes in the thymic hormone levels which may alter the relative proportion of lymphocyte subsets and cell-mediated immunity.

In a double-blind, controlled, crossover study involving 47 subjects documented with seasonal allergic rhinitis, repeated intranasal administration of 4% sodium cromoglycate solution was associated with significant reduction in symptoms and decrease in consumption of antihistaminic drugs. Side effects were mild and transitory. It is concluded that intranasal sodium cromoglycate administration is an efficacious preventive and therapeutic approach in the management of patients with seasonal allergic rhinitis.

The thymic factor (TF) activity and lymphocyte stimulation response to phytohemagglutinin (PHA) was studied in calorie-restricted rats. Sprague-Dawley rats (28 days old) were fed a calorie-restricted diet (30% of the average food intake of control) for 4 weeks. The control group was allowed food ad libitum. After this period the body weight was 232.9 +/- 41.8 g for control rats and 66.1 +/- 4.5 g for the calorie-restricted group. The mean thymus weight was 0.699 +/- 0.153 g and 0.099 +/- 0.030 g for the control and experimental groups respectively. The TF activity was makedly reduced in the calorie-restricted group compared with the control. There was an overlap between lymphocyte stimulation responses of the two groups; however, the mean number of counts per minute (cpm) of stimulated cultures with PHA was lower and the mean cpm of unstimulated cultures without PHA was higher in the starved animals. Thus, the stimulation index was significantly lower in the deprived rats. It is suggested that deficiency of thymic inductive factors may be important in the pathogenesis of impaired cell-mediated immunity in nutritional deficiency states.

Cell-mediated immunity is invariably impaired in protein-energy malnutrition. The effect of selected nutrient deficiencies on serum thymic factor activity was assessed in deprived rats and pair-fed controls. Deficits of calories, zinc or pyridoxine resulted in significant lowering of serum thymic factor activity whereas vitamin A deficiency did not have any effect. It is suggested that variants nutrients modulate different steps of cell-mediated immunity and that reduced thymic hormone activity may be the underlying mechanism of imparied immunity in some but not all nutritional deficiencies.