Immune checkpoint blockers in solid organ transplant recipients and cancer: the INNOVATED cohort.

BACKGROUND: Patients with solid organ transplant (SOT) and solid tumors are usually excluded from clinical trials testing immune checkpoint blockers (ICB). As transplant rates are increasing, we aimed to evaluate ICB outcomes in this population, with a special focus on lung cancer. METHODS: We conducted a multicenter retrospective cohort study collecting real data of ICB use in patients with SOT and solid tumors. Clinical data and treatment outcomes were assessed by using retrospective medical chart reviews in every participating center. Study endpoints were: overall response rate (ORR), 6-month progression-free survival (PFS), and grade ≥3 immune-related adverse events. RESULTS: From August 2016 to October 2022, 31 patients with SOT (98% kidney) and solid tumors were identified (36.0% lung cancer, 19.4% melanoma, 13.0% genitourinary cancer, 6.5% gastrointestinal cancer). Programmed death-ligand 1 expression was positive in 29% of tumors. Median age was 61 years, 69% were males, and 71% received ICB as first-line treatment. In the whole cohort the ORR was 45.2%, with a 6-month PFS of 56.8%. In the lung cancer cohort, the ORR was 45.5%, with a 6-month PFS of 32.7%, and median overall survival of 4.6 months. The grade 3 immune-related adverse events rate leading to ICB discontinuation was 12.9%. Allograft rejection rate was 25.8%, and risk of rejection was similar regardless of the type of ICB strategy (monotherapy or combination, 28% versus 33%, P = 1.0) or response to ICB treatment. CONCLUSIONS: ICB could be considered a feasible option for SOT recipients with some advanced solid malignancies and no alternative therapeutic options. Due to the risk of allograft rejection, multidisciplinary teams should be involved before ICB therapy.

Effects of high incubation temperature on tight junction proteins in the yolk sac and small intestine of embryonic broilers.

During the transition from incubation to hatch, the chicks shift from obtaining nutrients from the yolk sac to the intestine. The yolk sac tissue (YST) and small intestine serve as biological barriers between the yolk or gut contents and the blood circulation. These barriers must maintain structural integrity for optimal nutrient uptake as well as protection from pathogens. The objective of this study was to investigate the effect of high incubation temperature on mRNA abundance of the tight junction (TJ) proteins zona occludens 1 (ZO1), occludin (OCLN), claudin 1 (CLDN1), and junctional adhesion molecules A and 2 (JAMA, JAM2) and the heat shock proteins (HSP70 and HSP90) in the YST and small intestine of embryonic broilers. Broiler eggs were incubated at 37.5°C. On embryonic day 12 (E12), half of the eggs were switched to 39.5°C. YST samples were collected from E7 to day of hatch (DOH), while small intestinal samples were collected from E17 to DOH. The temporal expression of TJ protein mRNA from E7 to DOH at 37.5°C and the effect of incubation temperature from E13 to DOH were analyzed by one-way and two-way ANOVA, respectively and Tukey's test. Significance was set at P < 0.05. The temporal expression pattern of ZO1, OCLN, and CLDN1 mRNA showed a pattern of decreased expression from E7 to E13 followed by an increase to DOH. High incubation temperature caused an upregulation of ZO1 and JAM2 mRNA in the YST and small intestine. Using in situ hybridization, OCLN and JAMA mRNA were detected in the epithelial cells of the YST. In addition, JAMA mRNA was detected in epithelial cells of the small intestine, whereas JAM2 mRNA was detected in the vascular system of the villi and lamina propria. In conclusion, the YST expressed mRNA for TJ proteins and high incubation temperature increased ZO1 and JAM2 mRNA. This suggests that the TJ in the vasculature of the YST and intestine is affected by high incubation temperature.

Effect of dermatological consultation on survival in patients with checkpoint inhibitor-associated cutaneous toxicity.

BACKGROUND: Cutaneous immune-related adverse events (cirAEs) are a common side-effect of immune checkpoint inhibitors (ICIs). However, prior work examining these toxicities in detail has considered only the fraction of events evaluated by dermatologists. Associations between dermatology referral, cirAE treatment and survival outcomes remain underexplored across care settings. OBJECTIVES: To comprehensively categorize cirAE patterns among all patients treated with immunotherapy at our institution, and to evaluate: (i) the effect of dermatology referral on cirAE treatment and (ii) the impact of cirAE treatment on survival. METHODS: This was a retrospective cohort analysis of patients with cancer who initiated ICI therapy between 1 January 2016 and 8 March 2019 and developed one or more cirAEs, as screened for using International Classification of Diseases 10th revision codes and confirmed via manual chart review (n = 358). All relevant information documented prior to 31 March 2020 was included. RESULTS: CirAEs evaluated by dermatologists were significantly more likely to be treated than cirAEs that were not referred (odds ratio 6·08, P < 0·001). Patients who received any cirAE treatment had improved progression-free survival [hazard ratio (HR) 0·59, P = 0·001] and overall survival (HR 0·58, P = 0·007) compared with those who did not. CONCLUSIONS: CirAEs evaluated by dermatologists were significantly more likely to be treated than cirAEs that were not referred, and patients who received any treatment for a cirAE had improved survival outcomes.

Changes with age in density of goblet cells in the small intestine of broiler chicks.

Goblet cells secrete mucin 2 (Muc2), which is a major component of the mucus that lines the intestinal tract and creates a protective barrier between pathogens and the intestinal epithelial cells and thus are important for chick health. The objectives of this study were to determine the age-specific and intestinal segment-specific expression of Muc2 mRNA and changes in the number of goblet cells from late embryogenesis to early after hatch. Small intestinal samples from the duodenum, jejunum, and ileum were collected from Cobb 500 broilers at embryonic day 19 (e19), day of hatch (doh), and day 2 and 4 after hatch. Cells expressing Muc2 mRNA and mucin glycoprotein were detected by in situ hybridization or alcian blue and periodic acid-Schiff staining, respectively. Along the villi, there were many more cells expressing Muc2 mRNA than those stained for mucin glycoprotein. In the crypt, cells expressing Muc2 mRNA did not stain for mucin glycoprotein. There was an increase in the density of goblet cells in the villi and Muc2 mRNA expressing cells in the crypts of the jejunum and ileum from e19 to doh and day 2 to day 4, with no change between doh and day 2. In contrast, in the duodenum, the density of goblet cells in the villi and Muc2 mRNA expressing cells in the crypts remained constant from e19 to day 4. At day 4, the villi in the ileum had a greater density of goblet cells than the duodenum. In the crypt, the ileum had a greater density of Muc2 mRNA expressing cells than the duodenum at doh, and the ileum and jejunum both had greater densities of Muc2 mRNA expressing cells than the duodenum at day 4. These results indicate that the population of goblet cells has reached a steady state by doh in the duodenum, whereas in the jejunum and ileum, a steady-state population was not reached until after hatch.

Psychological factors that influence traumatic injury occurrence and physical performance.

This 9 month prospective study, conducted at the US Army Sergeants Major Academy (USASGMA), examined the association of selected psychological variables (e.g., measures of tension/anxiety, sleep disturbance, Type A behavior pattern) with injury occurrence and physical performance in 126 soldiers. ANOVA and logistic regression analyses revealed significant relationships between: 1) Traumatic injury occurrence and mean tension/anxiety scores, 2) Mean self-reported sleep disturbance scores and traumatic injury occurrence, 3) The Type A behavior pattern (abbreviated Jenkins Activity Survey) and number of sit-ups repetitions completed in 2 minutes, one component of the Army Physical Fitness Test (APFT), 4) The Type A behavior pattern and total score APFT. No significant associations were found for mean tension/anxiety scores and overuse injuries, or Type A behavior pattern and two mile run time or number of push-up repetitions completed in 2 minutes. These data suggest traumatic injury occurrence is influenced by tension/anxiety and disturbances in sleep habits. Additionally, individuals with higher Jenkins Activity scores (characteristic of the Type A behavior pattern) perform better physically.

Injuries in women associated with a periodized strength training and running program.

Forty-five women participated in a 24-week physical training program designed to improve lifting, load carriage, and running performance. Activities included weightlifting, running, backpacking, lift and carry drills, and sprint running. Physicians documented by passive surveillance all training-related injuries. Thirty-two women successfully completed training program. Twenty-two women (48.9%) suffered least 1 injury during training, but only 2 women had to drop out of the study because of injuries. The rate of injury associated with lost training time was 2.8 injuries per 1,000 training hours of exposure. Total clinic visits and days lost from training were 89 and 69, respectively. Most injuries were the overuse type involving the lower back, knees, and feet. Weightlifting accounted for a majority of the lost training days. A combined strength training and running program resulted in significant performance gains in women. Only 2 out of 45 participants left the training program cause of injuries.

Injuries and risk factors in a 100-mile (161-km) infantry road march.

BACKGROUND: Light infantry soldiers (N = 218) completed a 161-km cross-country march over 5 days carrying an average +/- SD load mass (i.e., the weight of all equipment and clothing) of 47 +/- 5 kg. METHODS: Prior to the march, height, weight, body fat, and physical fitness (3.2-km run, sit-ups, push-ups) were measured. Soldiers completed a demographic questionnaire which included questions on age and tobacco use history. RESULTS: Thirty-six percent (78/218) of the soldiers suffered one or more injuries. Of the total injuries, 48% presented were blisters and 18% were foot pain (not otherwise specified). Eight percent (17/218) of the soldiers were unable to complete the march because of injuries. Thirty-five percent (27/78) of the injured soldiers had 1 or more limited duty days for a total of 69 days. Risk of injury was higher among smokers (risk ratio = 1.8, P = 0.03 compared to nonsmokers) and lower among older soldiers (risk ratio = 3.2, P = 0.02, < 20 years compared to > 24 years). CONCLUSIONS: Carrying heavy loads over long distances can result in a high injury incidence to the lower body, since 36% of soldiers were injured during the 161-km march. Smoking and younger age (< 20 years) were independent risk factors for injuries.

Friction blisters. Pathophysiology, prevention and treatment.

Blisters occur frequently, especially in vigorously active populations. Studies using respective rubbing techniques show that blisters result from frictional forces that mechanically separate epidermal cells at level of the stratum spinosum. Hydrostatic pressure causes the area of the separation to fill with a fluid that is similar in composition to plasma but has a lower protein level. About 6 hours after formation of the blister, cells in the blister base begin to take amino acids and nucleosides; at 24 hours, there is high mitotic activity in the basal cells; at 48 and 120 hours, new stratum granulosum and stratum corneum, respectively, can be seen. The magnitude of frictional forces (Ff) and the number of times that an object cycles across the skin determine the probability of blister development - the higher the Ff, the fewer the cycles necessary to produce a blister. Moist skin increases Ff, but very dry or very wet skin necessary to produce a blister. Moist skin increases Ff, but very dry or very wet skin decreases Ff. Blisters are more likely in skin areas that have a thick horny layer held tightly to underlying structures (e.g. palms of the hands or soles of the feet). More vigorous activity and the carrying of heavy loads during locomotion both appear to increase the likelihood of foot blisters. Antiperspirants with emollients and drying powders applied to the foot do not appear to decrease the probability of friction blisters. There is some evidence that foot blister incidence can be reduced by closed cell neoprene insoles. Wearing foot socks composed of acrylic results in fewer foot blisters in runners. A thin polyester sock, combined with a thick wool or polypropylene sock that maintains its bulk when exposed to sweat and compression reduces blister incidence in Marine recruits. Recent exposure of the skin to repeated low intensity Ff results in a number of adaptations including cellular proliferation and epidermal thickening, which may reduce the likelihood of blisters. More well-designed studies are necessary to determine which prevention strategies actually decrease blister probability. Clinical experience suggests draining intact blisters and maintaining the blister roof results in the least patient discomfort and may reduce the possibility of secondary infection. Treating deroofed blisters with hydrocolloid dressings provides pain relief and may allow patients to continue physical activity if necessary. There is no evidence that antibiotics influence blister healing. Clinical trials are needed to determine the efficacy of various blister treatment methods.(ABSTRACT TRUNCATED AT 250 WORDS)

Cigarette smoking, physical fitness, and injuries in infantry soldiers.

Reliable data on the impact of physical training on light infantry units in terms of injuries and time loss are sparse. This study evaluated a light infantry unit (n = 181) prospectively and followed it throughout one year of infantry training and operations. Fifty-five percent of the soldiers (n = 101) experienced one or more injuries. Eighty-eight percent of the injuries were training-related conditions, which resulted in 1,103 days of limited duty. Lower extremity overuse injuries were the most common type of injury documented. Fractures accounted for the greatest number of days of limited duty. Risk factors for training-related injuries identified by this study were cigarette smoking, high percentage of body fat, extremely high or low body mass index, low endurance levels, and low muscular endurance levels (sit-ups). Logistic regression showed that cigarette smoking and low endurance levels were independent risk factors for training injuries. These data indicate that the incidence of training-related injuries in infantry units is high. A number of modifiable injury risk factors were identified, suggesting that many of these injuries may be preventable.

Validity of self-assessed physical fitness.

This study compared self-ratings of components of physical fitness with objective measures of physical fitness. We made comparisons in two groups of male infantry soldiers (n = 96 and n = 276) and one group of older male military officers (n = 241). To obtain self-ratings of physical fitness, we asked subjects, "Compared to others of your age and sex, how would you rate your (a) endurance, (b) sprint speed, (c) strength, (d) flexibility?" Subjects responded to each of the four questions on a five-point scale. Self-ratings of endurance were systematically related to three measures of aerobic capacity, including VO2max, peak VO2, and two-mile run time (r = 0.29 to 0.53). Self-ratings of sprint speed showed only weak relationships to measures of anaerobic capacity assessed by the Wingate test, push-ups, and sit-ups (r = 0.10 to 0.17). Strength ratings were systematically related to measures of maximal strength (r = 0.28 to 0.53). Upper body strength measures were more closely associated with the self-ratings of strength than were measures of lower body strength. Responses to the flexibility question were systematically related to measures of hip/low back flexibility (r = 0.30 and 0.48) but not to other measures of flexibility. Apparently, physically active subjects can approximately classify their aerobic capacity, muscle strength, and some types of flexibility.

Physiological responses to prolonged treadmill walking with external loads.

Limited information is available regarding the physiological responses to prolonged load carriage. This study determined the energy cost of prolonged treadmill walking (fixed distance of 12 km) at speeds of 1.10 m.s-1, 1.35 m.s-1, and 1.60 m.s-1, unloaded (clothing mass 5.2 kg) and with external loads of 31.5 and 49.4 kg. Fifteen male subjects performed nine trials in random order over a 6-week period. Oxygen uptake (VO2) was determined at the end of the first 10 min and every 20 min thereafter. A 10-min rest period was allowed following each 50 min of walking. No changes occurred in VO2 over time in the unloaded condition at any speed. The 31.5 and 49.4 kg loads, however, produced significant increases (ranging from 10 to 18%) at the two fastest and at all three speeds, respectively, even at initial exercise intensities less than 30% VO2max. In addition, the 49.4 kg load elicited a significantly higher (P less than 0.05) VO2 than did the 31.5 kg load at all speeds. The measured values of metabolic cost were also compared to those predicted using the formula of Pandolf et al. In trials where VO2 increased significantly over time, predicted values underestimated the actual metabolic cost during the final minute by 10-16%. It is concluded that energy cost during prolonged load carriage is not constant but increases significantly over time even at low relative exercise intensities. It is further concluded that applying the prediction model which estimates energy expenditure from short-term load carriage efforts to prolonged load carriage can result in significant underestimations of the actual energy cost.

The effects of graded exercise on plasma proenkephalin peptide F and catecholamine responses at sea level.

The purpose of this study was to evaluate the effects of graded treadmill exercise on plasma preproenkephalin peptide F immunoreactivity and concomitant catecholamine responses at sea level (elevation, 50 m). Few data exist regarding the sea-level responses of plasma peptide F immunoreactivity to exercise. thirty-five healthy men performed a graded exercise test on a motor-driven treadmill at the relative exercise intensities of 25, 50, 75, and 100% of maximum oxygen consumption (VO2max). Significant (P less than 0.05) increases above rest were observed for plasma peptide F immunoreactivity and norepinephrine at 75 and 100% of the VO2 max and at 5 min into recovery. Significant increases in plasma epinephrine were observed at 75 and 100% of VO2max. Whole blood lactate significantly increased above resting values at 50, 75, and 100% of the VO2max and at 5 min into recovery. These data demonstrate that exercise stress increases plasma peptide F immunoreactivity levels at sea level. While the exercise response patterns of peptide F immunoreactivity are similar to catecholamines and blood lactate responses, no bivariate relationships were observed. These data show that sea-level response patterns to graded exercise are similar to those previously observed at moderate altitude (elevation, 2200 m).

Influence of demographic factors on cyclosporine pharmacokinetics in adult uremic patients.

The causes of variability in cyclosporine (CS) clearance (CL) are mostly unknown. The pharmacokinetics of CS were studied in 30 adult uremic patients after single intravenous and oral doses by analyzing serial concentrations in serum by radioimmunoassay (SR) and in whole blood by radioimmunoassay (WR) and high pressure liquid chromatography (WH). Bioavailability (F) and CL were calculated by noncompartmental models and were significantly different depending upon the assay method except for FSR = FWR: FSR = 43.2 +/- 21.7%; FWR = 43.5 +/- 18.5%; FWH = 36.4 +/- 17.3%; CLSR = 849 +/- 363 ml/min; CLWR = 380 +/- 156 ml/min; CLWH = 559 +/- 174 ml/min. The age of the patients and parameters describing body size such as weight, surface area and percent of ideal weight were not correlated with CL. The height of the patients correlated with CLWH but not CLSR or CLWR. Parameters responsible for CS binding in blood such as cholesterol, triglyceride, hemoglobin concentration or hematocrit did not explain variability in CL. Of the factors indicative of liver function alanine transaminase activity but not aspartate transaminase, lactate dehydrogenase, alkaline phosphatase activity nor total bilirubin concentration in serum was correlated with CL. F was not correlated with any of the demographic factors except for alanine transaminase. None of the significant correlations explained enough of the variability to afford a reliable prediction of CL or F.

An integrated system for interstitial 192Ir implants.

An efficient system for preparing, afterloading, and removing interstitial 192Ir strands has been developed. Use of the system reduces the risk of personnel exposure and eliminates some patient discomfort. The system is "integrated" in that all aspects of the implantation process are considered, from source preparation to source removal. Strand preparation is facilitated by an "assembly line" process using shielded equipment. Components include a handling block for measuring and cutting active strands, a mirror, and a transport container. Afterloading and removal techniques use quick release devices and several forms of afterloading tubing and catheters, each terminated by a Luer lock adapter. Both blind-end and through-and-through implants are possible. Each 192Ir strand, threaded through an injection cap that mates with the Luer lock adapter, is quickly inserted into its tubing or catheter and locked into place. No crimping is required and no additional positioning of the sources is needed. Strand removal is easily accomplished by unlocking and removing the injection cap. The strands receive no mechanical damage and can be reused after appropriate cleaning. More than 100 cases have been performed without incident. Applications include head/neck, breast, and template and non-template vaginal wall treatments.

Promptness of antibiotic therapy in acute bacterial meningitis.

We reviewed 135 cases of acute community-acquired bacterial meningitis at a municipal teaching hospital during a six-year period, with special emphasis on promptness of initial antimicrobial therapy. Overall mortality was 5% for the 121 childhood cases, compared to 43% for the 14 adult cases (P less than .001). The mean duration between arrival in the emergency department and the administration of appropriate antibiotics was 2.1 hours for the pediatric cases, compared to 4.9 hours for the adult cases (P less than .02). Factors that may contribute to delays in institution of appropriate antimicrobial therapy for adult patients with meningitis include the relative infrequency of this condition, the presence of concomitant disease processes, and the frequent practice of obtaining a computed tomography scan prior to performing lumbar puncture. Prompt institution of antimicrobial therapy for acute meningitis, especially for adult pneumococcal meningitis, remains a major challenge for emergency physicians.