Old reserves and ancient buds fuel regrowth of coast redwood after catastrophic fire.

For long-lived organisms, investment in insurance strategies such as reserve energy storage can enable resilience to resource deficits, stress or catastrophic disturbance. Recent fire in California damaged coast redwood (Sequoia sempervirens) groves, consuming all foliage on some of the tallest and oldest trees on Earth. Burned trees recovered through resprouting from roots, trunk and branches, necessarily supported by nonstructural carbon reserves. Nonstructural carbon reserves can be many years old, but direct use of old carbon has rarely been documented and never in such large, old trees. We found some sprouts contained the oldest carbon ever observed to be remobilized for growth. For certain trees, simulations estimate up to half of sprout carbon was acquired in photosynthesis more than 57 years prior, and direct observations in sapwood show trees can access reserves at least as old. Sprouts also emerged from ancient buds-dormant under bark for centuries. For organisms with millennial lifespans, traits enabling survival of infrequent but catastrophic events may represent an important energy sink. Remobilization of decades-old photosynthate after disturbance demonstrates substantial amounts of nonstructural carbon within ancient trees cycles on slow, multidecadal timescales.

Anastomotic Stricture After Minimally Invasive Esophagectomy.

BACKGROUND: Despite improved outcomes, minimally invasive esophagectomy (MIE) continues to be associated with anastomotic strictures. Most resolve after a single dilation; however, some become refractory. Little is known about strictures after MIE in North America. METHODS: We performed a single-institution retrospective review of MIEs from 2015 to 2019. Primary outcomes were the proportion of patients requiring anastomotic dilation and the dilation rate per year. Univariate analyses of patients undergoing dilation by various risk factors were performed with nonparametric tests, and multivariate analyses of the dilation rate were conducted using generalized linear models. RESULTS: Of 391 included patients, 431 dilations were performed on 135 patients (34.5%, 3.2 dilations per patient who required at least 1 per patient). One complication occurred after dilation. Comorbidities, tumor histology, and tumor stage were not significantly associated with stricture. Three-field MIE was associated with a higher percentage of patients undergoing dilation (48.9% vs 27.1%, P < .001) and a higher rate of dilations (0.944 vs 0.441 dilations per year, P = .007) than 2-field MIE, and this association remained significant after controlling for covariates. When accounting for surgeon variability, this difference was no longer significant. Among patients with 1 or more dilations, those receiving dilation within 100 days of surgery needed more subsequent dilations (2.0 vs 0.6 dilations per year, P < .001). CONCLUSIONS: After controlling for multiple variables, a 3-field MIE approach was associated with a higher rate of repeat dilations in patients undergoing MIE. A shorter interval between esophagectomy and initial dilation is strongly associated with the need for repeated dilations.

Intravenous administration of viral vectors expressing prostate cancer antigens enhances the magnitude and functionality of CD8+ T cell responses.

BACKGROUND: The use of immunotherapeutic vaccination in prostate cancer is a promising approach that likely requires the induction of functional, cytotoxic T cells . The experimental approach described here uses a well-studied adenovirus-poxvirus heterologous prime-boost regimen, in which the vectors encode a combination of prostate cancer antigens, with the booster dose delivered by either the intravenous or intramuscular (IM) route. This prime-boost regimen was investigated for antigen-specific CD8+ T cell induction. METHODS: The coding sequences for four antigens expressed in prostate cancer, 5T4, PSA, PAP, and STEAP1, were inserted into replication-incompetent chimpanzee adenovirus Oxford 1 (ChAdOx1) and into replication-deficient modified vaccinia Ankara (MVA). In four strains of mice, ChAdOx1 prime was delivered intramuscularly, with an MVA boost delivered by either IM or intravenous routes. Immune responses were measured in splenocytes using ELISpot, multiparameter flow cytometry, and a targeted in vivo killing assay. RESULTS: The prime-boost regimen was highly immunogenic, with intravenous administration of the boost resulting in a sixfold increase in the magnitude of antigen-specific T cells induced and increased in vivo killing relative to the intramuscular boosting route. Prostate-specific antigen (PSA)-specific responses were dominant in all mouse strains studied (C57BL/6, BALBc, CD-1 and HLA-A2 transgenic). CONCLUSION: This quadrivalent immunotherapeutic approach using four antigens expressed in prostate cancer induced high magnitude, functional CD8+ T cells in murine models. The data suggest that comparing the intravenous versus intramuscular boosting routes is worthy of investigation in humans.

Mogamulizumab in Combination with Nivolumab in a Phase I/II Study of Patients with Locally Advanced or Metastatic Solid Tumors.

PURPOSE: The aim of the study was to determine safety, antitumor activity, and pharmacodynamic profile of mogamulizumab, an anti-CCR4 monoclonal antibody targeting effector regulatory T cells (Treg) in combination with the checkpoint inhibitor nivolumab in patients with locally advanced or metastatic solid tumors. PATIENTS AND METHODS: This was a multicenter, dose-finding (phase I), and dose expansion (phase II) study (NCT02705105) in patients with locally advanced or metastatic solid tumors. There were no dose-limiting toxicities in phase I with mogamulizumab 1 mg/kg every week for cycle 1 followed by 1 mg/kg every 2 weeks plus nivolumab 240 mg every 2 weeks intravenously, and cohort expansion occurred at this dose level. RESULTS: All 114 patients treated with mogamulizumab 1 mg/kg plus nivolumab 240 mg in phases I (n = 4) and II (n = 110) were assessed for safety and efficacy. Mogamulizumab plus nivolumab showed acceptable safety and tolerability. Objective response rate was 10.5% [95% confidence interval (CI), 5.6-17.7; 3 complete and 9 partial responses]. Disease control rate was 36.8%. Median duration of response was 14.4 months. Median progression-free survival was 2.6 (95% CI, 2.3-3.1) months, and median overall survival was 9.5 (95% CI, 5.9-13.5) months. CONCLUSIONS: Combination of mogamulizumab with nivolumab for treatment of patients with locally advanced or metastatic solid tumors did not result in enhanced efficacy. Tolerability of mogamulizumab 1 mg/kg plus nivolumab 240 mg was acceptable.

Peak and Per-Step Tibial Bone Stress During Walking and Running in Female and Male Recreational Runners.

BACKGROUND: Athletes, especially female athletes, experience high rates of tibial bone stress injuries (BSIs). Knowledge of tibial loads during walking and running is needed to understand injury mechanisms and design safe running progression programs. PURPOSE: To examine tibial loads as a function of gait speed in male and female runners. STUDY DESIGN: Controlled laboratory study. METHODS: Kinematic and kinetic data were collected on 40 recreational runners (20 female, 20 male) during 4 instrumented gait speed conditions on a treadmill (walk, preferred run, slow run, fast run). Musculoskeletal modeling, using participant-specific magnetic resonance imaging and motion data, was used to estimate tibial stress. Peak tibial stress and stress-time impulse were analyzed using 2-factor multivariate analyses of variance (speed*sex) and post hoc comparisons (α = .05). Bone geometry and tibial forces and moments were examined. RESULTS: Peak compression was influenced by speed (P < .001); increasing speed generally increased tibial compression in both sexes. Women displayed greater increases in peak tension (P = .001) and shear (P < .001) than men when transitioning from walking to running. Further, women displayed greater peak tibial stress overall (P < .001). Compressive and tensile stress-time impulse varied by speed (P < .001) and sex (P = .006); impulse was lower during running than walking and greater in women. A shear stress-time impulse interaction (P < .001) indicated that women displayed greater impulse relative to men when changing from a walk to a run. Compared with men, women displayed smaller tibiae (P < .001) and disproportionately lower tibial forces (P≤ .001-.035). CONCLUSION: Peak tibial stress increased with gait speed, with a 2-fold increase in running relative to walking. Women displayed greater tibial stress than men and greater increases in stress when shifting from walking to running. Sex differences appear to be the result of smaller bone geometry in women and tibial forces that were not proportionately lower, given the womens' smaller stature and lower mass relative to men. CLINICAL RELEVANCE: These results may inform interventions to regulate running-related training loads and highlight a need to increase bone strength in women. Lower relative bone strength in women may contribute to a sex bias in tibial BSIs, and female runners may benefit from a slower progression when initiating a running program.

Controlled apneic tracheostomy in patients with coronavirus disease 2019 (COVID-19).

OBJECTIVE: To develop a team-based institutional infrastructure for navigating management of a novel disease, to determine a safe and effective approach for performing tracheostomies in patients with COVID-19 respiratory failure, and to review outcomes of patients and health care personnel following implementation of this approach. METHODS: An interdisciplinary Task Force was constructed to develop innovative strategies for management of a novel disease. A single-institution, prospective, nonrandomized cohort study was then conducted on patients with coronavirus disease 2019 (COVID-19) respiratory failure who underwent tracheostomy using an induced bedside apneic technique at a tertiary care academic institution between April 27, 2020, and June 30, 2020. RESULTS: In total, 28 patients underwent tracheostomy with induced apnea. The median lowest procedural oxygen saturation was 95%. The median number of ventilated days following tracheostomy was 11. There were 3 mortalities (11%) due to sepsis and multiorgan failure; of 25 surviving patients, 100% were successfully discharged from the hospital and 76% are decannulated, with a median time of 26 days from tracheostomy to decannulation (range 12-57). There was no symptomatic disease transmission to health care personnel on the COVID-19 Tracheostomy Team. CONCLUSIONS: Patients with respiratory failure from COVID-19 disease may benefit from tracheostomy. This can be completed effectively and safely without viral transmission to health care personnel. Performing tracheostomies earlier in the course of disease may expedite patient recovery and improve intensive care unit resource use. The creation of a collaborative Task Force is an effective strategic approach for management of novel disease.

Mogamulizumab in Combination with Durvalumab or Tremelimumab in Patients with Advanced Solid Tumors: A Phase I Study.

PURPOSE: The study goal was to determine safety, antitumor activity, and pharmacodynamic profile of mogamulizumab, an anti-C-C chemokine receptor 4 (anti-CCR4) mAb targeting effector regulatory T cells (eTreg), in combination with mAb checkpoint inhibitors durvalumab or tremelimumab. PATIENTS AND METHODS: This was a multicenter, phase I, dose escalation study, followed by disease-specific cohort expansion (NCT02301130). Mogamulizumab dose escalation proceeded with concurrent dose escalation of durvalumab or tremelimumab in patients with advanced solid tumors. Cohort expansion occurred with mogamulizumab 1 mg/kg plus durvalumab 10 mg/kg or tremelimumab 10 mg/kg in patients with advanced pancreatic cancer. RESULTS: Forty patients were enrolled during dose escalation, followed by 24 patients during dose expansion. No dose-limiting toxicities occurred during dose escalation. No new or unexpected toxicities were seen. Tolerability, the primary endpoint, was acceptable utilizing mogamulizumab 1 mg/kg plus durvalumab or tremelimumab 10 mg/kg in the combined dose escalation and dose expansion cohorts (each n = 19). At these doses, the objective response rate was 5.3% (95% confidence interval, 0.1%-26.0%; one partial response) with each combination treatment. At all doses, mogamulizumab treatment led to almost complete depletion of peripheral eTregs, as well as reduction of intratumoral Tregs in the majority of patients. There was no clear correlation of clinical response with peripheral or intratumoral reduction in CCR4+ eTregs or with baseline degree of CCR4+ expression. CONCLUSIONS: Mogamulizumab in combination with durvalumab or tremelimumab did not result in potent antitumor efficacy in patients with advanced solid tumors. Tolerability of mogamulizumab 1 mg/kg combined with durvalumab or tremelimumab 10 mg/kg was acceptable.

Building alliances for improving newborn health in Latin America and the Caribbean.

The regional Latin American and Caribbean (LAC) Neonatal Alliance and national neonatal alliances in Bolivia, El Salvador, and Peru were studied through in-depth interviews and a review of publications. Findings were analyzed to distill successful strategies, structures, and tools for improving neonatal health by working through alliances that can be replicated at the regional or national level. The studies found the following factors were the most critical for successful outcomes from alliance work: inclusion of the Ministry of Health as a leader or primary stakeholder; a committed, diverse, technically expert, and horizontal membership; the presence of champions for neonatal health at the national level; development of a shared work plan based on feasible objectives; the use of shared financing mechanisms; the use of informal and dynamic organizational structures; and a commitment to scientific evidence-based programming. The relationship between the regional and national alliances was found to be mutually beneficial.

Building alliances for improving newborn health in Latin America and the Caribbean / Alianzas para mejorar la salud de los recién nacidos en América Latina y el Caribe

The regional Latin American and Caribbean (LAC) Neonatal Alliance and national neonatal alliances in Bolivia, El Salvador, and Peru were studied through in-depth interviews and a review of publications. Findings were analyzed to distill successful strategies, structures, and tools for improving neonatal health by working through alliances that can be replicated at the regional or national level. The studies found the following factors were the most critical for successful outcomes from alliance work: inclusion of the Ministry of Health as a leader or primary stakeholder; a committed, diverse, technically expert, and horizontal membership; the presence of champions for neonatal health at the national level; development of a shared work plan based on feasible objectives; the use of shared financing mechanisms; the use of informal and dynamic organizational structures; and a commitment to scientific evidence-based programming. The relationship between the regional and national alliances was found to be mutually beneficial.

Se estudiaron la Alianza de Salud Neonatal para América Latina y el Caribe a escala regional, y las alianzas nacionales de salud neonatal de Bolivia, El Salvador y Perú, mediante entrevistas exhaustivas y un análisis de las publicaciones. Se analizaron los resultados para extraer las estrategias, las estructuras y las herramientas eficaces para mejorar la salud neonatal trabajando mediante alianzas que puedan repetirse a escala regional o nacional. Los estudios descubrieron que los factores más decisivos para obtener resultados exitosos del trabajo mediante alianzas fueron los siguientes: la inclusión de los ministerios de salud como líderes o interesados directos principales; una afiliación comprometida, diversa, técnicamente experta y horizontal; la presencia de promotores de la salud neonatal a escala nacional; la formulación de un plan de trabajo compartido basado en objetivos factibles; la utilización de mecanismos de financiamiento compartido; el uso de estructuras organizativas informales y dinámicas; y un compromiso con la programación científica basada en datos probatorios. Se observó que la relación entre las alianzas regionales y nacionales resultaba mutuamente beneficiosa.

Population pharmacokinetic and pharmacodynamic analysis of tremelimumab in patients with metastatic melanoma.

Tremelimumab, a fully human monoclonal antibody specific for human cytotoxic T-lymphocyte-associated antigen 4, has been studied in clinical trials. We have reported the results of population pharmacokinetics for tremelimumab in 654 metastatic melanoma patients. Population estimates (inter-individual variability [IIV]) for pharmacokinetic parameters in a final model were clearance (CL), 0.26 L/day (31.8%) and central volume of distribution, 3.97 L (20.4%). CL was faster in males, patients with higher values of creatinine clearance and endogenous immunoglobulin, and patients with relatively poor baseline prognostic factors. No dose adjustment was needed based on the magnitude of the change of CL (<30%). The association of CL and overall survival (OS) was investigated. In a Phase 3 trial evaluating tremelimumab as first-line-treatment, median OS for the 147 patients in the fast-CL group (≥ median CL value) was 9.6 months versus 15.8 months for the 146 patients in the slow-CL group (

Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma.

PURPOSE: In phase I/II trials, the cytotoxic T lymphocyte-associated antigen-4-blocking monoclonal antibody tremelimumab induced durable responses in a subset of patients with advanced melanoma. This phase III study evaluated overall survival (OS) and other safety and efficacy end points in patients with advanced melanoma treated with tremelimumab or standard-of-care chemotherapy. PATIENTS AND METHODS: Patients with treatment-naive, unresectable stage IIIc or IV melanoma were randomly assigned at a ratio of one to one to tremelimumab (15 mg/kg once every 90 days) or physician's choice of standard-of-care chemotherapy (temozolomide or dacarbazine). RESULTS: In all, 655 patients were enrolled and randomly assigned. The test statistic crossed the prespecified futility boundary at second interim analysis after 340 deaths, but survival follow-up continued. At final analysis with 534 events, median OS by intent to treat was 12.6 months (95% CI, 10.8 to 14.3) for tremelimumab and 10.7 months (95% CI, 9.36 to 11.96) for chemotherapy (hazard ratio, 0.88; P = .127). Objective response rates were similar in the two arms: 10.7% in the tremelimumab arm and 9.8% in the chemotherapy arm. However, response duration (measured from date of random assignment) was significantly longer after tremelimumab (35.8 v 13.7 months; P = .0011). Diarrhea, pruritus, and rash were the most common treatment-related adverse events in the tremelimumab arm; 7.4% had endocrine toxicities. Seven deaths in the tremelimumab arm and one in the chemotherapy arm were considered treatment related by either investigators or sponsor. CONCLUSION: This study failed to demonstrate a statistically significant survival advantage of treatment with tremelimumab over standard-of-care chemotherapy in first-line treatment of patients with metastatic melanoma.

Safety profile and pharmacokinetic analyses of the anti-CTLA4 antibody tremelimumab administered as a one hour infusion.

BACKGROUND: CTLA4 blocking monoclonal antibodies provide a low frequency but durable tumor responses in patients with metastatic melanoma, which led to the regulatory approval of ipilimumab based on two randomized clinical trials with overall survival advantage. The similarly fully human anti-CTLA4 antibody tremelimumab had been developed in the clinic at a fixed rate infusion, resulting in very prolonged infusion times. A new formulation of tremelimumab allowed testing a shorter infusion time. METHODS: A phase 1 multi-center study to establish the safety and tolerability of administering tremelimumab as a 1-hour infusion to patients with metastatic melanoma. Secondary endpoints included pharmacokinetic and clinical effects of tremelimumab. RESULTS: No grade 3 or greater infusion-related adverse events or other adverse events preventing the administration of the full tremelimumab dose were noted in 44 treated patients. The overall side effect profile was consistent with prior experiences with anti-CTLA4 antibodies. Objective tumor responses were noted in 11% of evaluable patients with metastatic melanoma, which is also consistent with the prior experience with CTLA4 antagonistic antibodies. CONCLUSIONS: This study did not identify any safety concerns when tremelimumab was administered as a 1-hour infusion. These data support further clinical testing of the 1-hour infusion of tremelimumab. (Clinical trial registration number NCT00585000).

Modified French-window thoracotomy for exposure of the anterior thoracic spine.

Due to the limited exposure, technical challenges, and postoperative pain of thoracic spine surgery, open thoracotomy and video-assisted thoracic surgery (VATS) are associated with significant morbidity and mortality. The modified French-window thoracotomy approach with the aid of a thoracoscope is a useful technique for approaching diseases of the anterior spinal. This approach allows for specific exposure of the spine with a reduction in postoperative pain, morbidity, and mortality and avoids the limitations of VATS.

Phase II trial of tremelimumab (CP-675,206) in patients with advanced refractory or relapsed melanoma.

PURPOSE: This phase II study assessed the antitumor activity of tremelimumab, a fully human, anti-CTL-associated antigen 4 monoclonal antibody, in patients with melanoma. EXPERIMENTAL DESIGN: Patients with refractory/relapsed melanoma received 15 mg/kg tremelimumab every 90 days. After 4 doses, patients with tumor response or stable disease were eligible to receive < or =4 additional doses. Primary endpoint was best overall tumor response assessed by an independent endpoint review committee, and secondary endpoints included duration of response, overall survival, progression-free survival, and safety. RESULTS: Of 251 patients enrolled, 246 (241 response-evaluable) received tremelimumab. Objective response rate was 6.6% (16 partial responses); duration of response was 8.9 to 29.8 months. Eight (50%) objective responses occurred in patients with stage IV M(1c) disease, and 11 (69%) were ongoing at last tumor assessment. Eight (3.3%) patients achieved responses in target lesions (Response Evaluation Criteria in Solid Tumors) despite progressive disease within the first cycle. All 8 survived for >20 months; 5 (63%) remained alive. Clinical benefit rate (overall response + stable disease) was 21% (16 partial responses and 35 stable disease), and median overall survival was 10.0 months. Progression-free survival at 6 months was 15%, and survival was 40.3% at 12 months and 22% at 24 months. Common treatment-related adverse events were generally mild to moderate, and grade 3/4 adverse events included diarrhea (n = 28, 11%), fatigue (n = 6, 2%), and colitis (n = 9, 4%). There were 2 (0.8%) treatment-related deaths. CONCLUSIONS: Tremelimumab showed an objective response rate of 6.6%, with all responses being durable > or =170 days since enrollment, suggesting a potential role for tremelimumab in melanoma.

San Antonio Mental Health Disaster Consortium: Hurricanes Katrina and Rita, a personal perspective.

TOPIC: This is the personal perspective of the author's experience during Hurricanes Katrina and Rita. As a member of a professional mental health volunteer organization, this chronicles 3 months' experience in the local shelters. PURPOSE: Difficulties with organizational support and structure hampered the effectiveness and functioning of this volunteer organization in the shelters. To identify lessons learned from this experience. CONCLUSIONS: It is essential to identify where each mental health volunteer group fits into the organizational structure and what the role of each is. Volunteers need to be scheduled and relieved at regular intervals to rest so as to prevent stress reactions.

Trait aggressiveness and situational provocation: a test of the traits as situational sensitivities (TASS) model.

In this article, the authors propose and test an interactionist model of personality functioning. The model maintains that many traits function in a threshold-like manner, such that less situational strength is needed to evoke a trait-relevant response in people who are high on the trait than in those who are low on the trait. Because of these different sensitivities, people who are high on a trait are more reactive to moderate provocation than are those who are low on a trait, but the opposite is true when strong provocation is compared to moderate provocation. Three studies are reported showing how the model can be used to understand the nature of aggression.