Modulation of tissue resident memory T cells by glucocorticoids after acute cellular rejection in lung transplantation.

Acute cellular rejection is common after lung transplantation and is associated with an increased risk of early chronic rejection. We present combined single-cell RNA and TCR sequencing on recipient-derived T cells obtained from the bronchoalveolar lavage of three lung transplant recipients with rejection and compare them with T cells obtained from the same patients after treatment of rejection with high-dose systemic glucocorticoids. At the time of rejection, we found an oligoclonal expansion of cytotoxic CD8+ T cells that all persisted as tissue resident memory T cells after successful treatment. Persisting CD8+ allograft-resident T cells have reduced gene expression for cytotoxic mediators after therapy with glucocorticoids but accumulate around airways. This clonal expansion is discordant with circulating T cell clonal expansion at the time of rejection, suggesting in situ expansion. We thus highlight the accumulation of cytotoxic, recipient-derived tissue resident memory T cells within the lung allograft that persist despite the administration of high-dose systemic glucocorticoids. The long-term clinical consequences of this persistence have yet to be characterized.

Maintenance Belatacept-Based Immunosuppression in Lung Transplantation Recipients Who Failed Calcineurin Inhibitors.

BACKGROUND: Traditional immunosuppressive regimens (ISR) used in lung transplantation rely on calcineurin inhibitors (CNI) that occasionally cause severe adverse reactions necessitating discontinuation. Belatacept is a novel costimulation antagonist approved for use in renal transplantation which lacks data in lung transplantation. This series aims to describe the response to belatacept ISR in 11 lung transplantation recipients after CNI failure. METHODS: Single-center, retrospective medical record review of adult lung transplant recipients (LTR) before and after conversion to belatacept-based ISR. Patients were evaluated at fixed time points before and after belatacept initiation. Primary outcome was incidence of acute cellular rejection (ACR). Secondary outcomes included incidence of infection, chronic lung allograft dysfunction (CLAD) progression, death, change in mean arterial pressure, and estimated glomerular filtration rate. RESULTS: Eleven LTRs received belatacept with a mean of 246 (91-1064) days of follow-up after conversion. Four were changed to belatacept for thrombotic thrombocytopenic purpura, 3 for posterior reversible encephalopathy syndrome, 2 for recurrent ACR, 1 for CLAD, and 1 for renal-sparing. ACR was not different before and after belatacept (P = 0.17). Mean estimated glomerular filtration rate was significantly higher postbelatacept (32.53 vs 45.26, P = 0.04). Mean incidence of infections (24.4% vs 16.0%, P = 0.55) and mean arterial pressure (97.5 vs 92.1 P = 0.38) were not different. Progression of CLAD occurred in 2 patients. At the end of follow-up, 7 of 11 patients were alive. CONCLUSIONS: Belatacept-based ISR appear to produce reasonable results in LTRs who fail CNI-based ISR. Larger prospective trials appear warranted in lung transplantation.

Surgical Strategy for Lung Transplantation in Adults With Small Chests: Lobar Transplant Versus a Pediatric Donor.

BACKGROUND: Adult lung transplant recipients with small chests have traditionally received lungs from pediatric donors, placing an additional strain on the already restricted pediatric donor pool. Performing lobar lung transplantation (LLT) can circumvent issues with donor-recipient size mismatch; however, LLT imparts additional risks. Here, we review our experience using LLT and standard lung transplantation using a pediatric donor (PDLT) for adults with small chests. METHODS: We retrospectively reviewed consecutive patients with end-stage lung disease and a height of 65 inches or less who underwent LLT (n = 15) or PDLT (n = 15) between 2006 and 2012 at our institution, a high-volume lung transplant center. RESULTS: Lobar lung transplantation recipients were older (54 ± 10 vs 48 ± 8 years) and had higher pulmonary pressure (57 ± 11 vs 52 ± 27 mmHg) and higher lung allocation scores (70 ± 9 vs 51 ± 8) than PDLT recipients (all P < 0.05). Mean waiting time was 62 days for PDLT and 9 days for LLT. Postoperatively, the incidence of severe primary graft dysfunction and the incidence of acute renal insufficiency were higher, and the mean intensive care unit stay was longer in the LLT group, but the incidence of bronchial anastomotic complications was higher in the PDLT group because of significant size discrepancy in the main bronchus (P < 0.05). Interestingly, long-term functional outcomes and survival rates were similar between the groups. CONCLUSIONS: Both LLT and PDLT are viable surgical options for adult patients with small chests. Because of the potential impact on posttransplant outcomes, the technical complexity of transplantation, decisions regarding the best surgical approach should be made by experienced surgeons.

Ventilatory responses to hypoxia and high altitude during sleep in Aconcagua climbers.

BACKGROUND/OBJECTIVE: We examined the changes in ventilation during sleep at high altitude using the LifeShirt monitoring system on 2 climbers who were attempting to summit Mount Aconcagua (6956 m). METHODS: Prior to the summit attempt, we measured cardiovascular and pulmonary function at 401 m (Rochester, MN) and gathered respiratory and cardiovascular data during sleep using the LifeShirt monitoring system with exposure to normobaric normoxia and normobaric hypoxia (simulated 4300 m). We then monitored the ventilatory response during sleep at 3 altitudes (4100 m, 4900 m, and 5900 m). RESULTS: During normoxic sleep, subjects had normal oxygen saturation (O(2sat)), heart rate (HR), respiratory rate (RR), tidal volume (V(T)) and minute ventilation (V(E)), and exhibited no periodic breathing (O(2sat) = 100 +/- 2%, HR = 67 +/- 1 beats/min, RR = 16 +/- 3 breaths/min, V(T) = 516 +/- 49 mL, and V(E) = 9 +/- 1 L/min, mean +/- SD). Sleep during simulated 4300 m caused a reduction in O(2sat), an increase in HR, RR, V(T), and V(E), and induced periodic breathing in both climbers (O(2sat) = 79 +/- 4%, HR = 72 +/- 14 beats/min, RR = 20 +/- 3 breaths/min, V(T) = 701 +/- 180 mL, and V(E) = 14 +/- 3 L/min). All 3 levels of altitude had profound effects on O(2sat), HR, and the ventilatory strategy during sleep (O(2sat) = 79 +/- 2, 70 +/- 8, 60 +/- 2%; HR = 70 +/- 12, 76 +/- 6, 80 +/- 3 beats/min; RR = 17 +/- 6, 18 +/- 4, 20 +/- 6 breaths/min; V(T) = 763 +/- 300, 771 +/- 152, 1145 +/- 123 mL; and V(E) = 13 +/- 1, 14 +/- 0, 22 +/- 4 L/min; for 4100 m, 4900 m, and 5900 m, respectively). There were strong negative correlations between O(2sat) and V(E) and ventilatory drive (V(T)/T(i), where T(i) is the inspiratory time) throughout the study. CONCLUSIONS: Interestingly, the changes in ventilatory response during simulated altitude and at comparable altitude on Aconcagua during the summit attempt were similar, suggesting reductions in FiO(2), rather than in pressure, alter this response.

Serviços públicos no Brasil: mudanças e perspectivas: concessão, regulamentação, privatização e melhoria da gestão pública / Public services in Brazil

Realiza o exame das propostas em discussão para tentar extrair os elementos plausíveis em cada alternativa apresentada e compô-las num todo consistente. Tais propostas são examinadas a partir de amplo pano de fundo teórico e histórico que ajuda a identificar virtudes e vícios das alternativas hoje em pauta. Convém prevenir que o resultado final não é a exposição de um "modelo" acabado para o regime de concessões para a exploração de serviços de utilidade pública, pois este, se existir, deverá ser fruto de difícil e prolongado processo de reflexão, experiências e negociações.