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.

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.

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.

Bacteremia associated with decubitus ulcers.

We studied 104 episodes of bacteremia in 102 patients with decubitus ulcers observed over five years in the hospitals of one metropolitan area. The ulcers were considered to be the "probable" source of bacteremia in 49% of episodes. Another site of infection was documented in 86% of patients. Proteus mirabilis, Staphylococcus aureus, and Escherichia coli were the most frequent blood isolates in these patients, but only Bacteroides species correlated with "probable" origin of bacteremia from the ulcers. The overall mortality was 55%, with 51% of deaths being attributed to infection. These findings emphasize the importance of decubitus ulcers as potential sources of bacteremia in hospitalized patients.

Bacteremia in diabetic patients: comparison of incidence and mortality with nondiabetic patients.

We determined the incidence of bacteremia and associated mortality in diabetic and nondiabetic patients in the four major hospitals of one metropolitan area over the 5-yr period 1977-1981. Mortality rates, based on episodes of bacteremia, were similar in diabetic and nondiabetic patients in most instances. Diabetic patients experienced lower mortality rates from Enterobacteriaceae bacteremia compared with nondiabetic patients; this finding was explained by a greater tendency for diabetic patients to have Escherichia coli bacteremia due to community-acquired urinary tract infection. However, the incidence of bacteremia due to all microorganisms was increased twofold in diabetic patients and the incidence of Enterobacteriaceae bacteremia was increased threefold. Because of their increased incidence of bacteremia, diabetic patients in this population were nearly twice as likely to die as a result of bacteremia compared with nondiabetic patients. Thus, the frequent occurrence of bacteremia among patients with diabetes mellitus represents a significant problem.

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.

Bacteremia in obstetrics and gynecology.

Surveillance of all episodes of bacteremia in the four major hospitals of a metropolitan area of 400,000 population between 1977 and 1981 revealed that bacteremia was documented in only 92 patients on obstetrics and gynecology services. Death was attributed to bacteremia in only four of these patients, three of whom had severe underlying diseases. These data confirm that death due to bacteremia in present-day obstetric and gynecology practice is extremely uncommon.

Bacteroides bacteremia. Analysis of 142 episodes from one metropolitan area.

Overall mortality for 142 patients with Bacteroides bacteremia encountered in the four hospitals of one metropolitan area between 1977 and 1982 was 41%. Only 43% of deaths of these patients, however, were attributed directly to Bacteroides infection according to the criteria used in this study. Deaths of patients with Bacteroides bacteremia, compared with deaths of patients with bacteremia due to aerobic gram-negative rods, were less likely to occur early after onset of bacteremia. Choice of antimicrobial therapy had no obvious relationship to eventual outcome. Nonobstetrical Bacteroides bacteremia identifies a group of patients at high risk of death during hospitalization. The diversity of both clinical and microbiologic features of these infections, however, makes specific recommendations regarding optimum therapy difficult to formulate.

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.

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.

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.

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)

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.

Community-acquired bacteremic urinary tract infection: epidemiology and outcome.

We studied 313 episodes of community-acquired bacteremic urinary tract infection in 4 hospitals of 1 metropolitan area from 1977 to 1981. Although over-all mortality rate for these patients was 13.7 percent, only 15 deaths were attributed directly to bacteremic urinary tract infection according to the criteria used in this study. Of these 15 deaths 13 occurred among patients on medical services, all but 1 of whom had alcoholic liver disease, malignancy and/or chronic neurologic disease. The other patient had brittle diabetes mellitus with renal papillary necrosis and chronic renal failure. In this population 10.4 episodes of community-acquired bacteremic urinary tract infection occurred per 10,000 patients. However, these infections appeared to explain the deaths only of patients with severe underlying diseases.

Hospital-acquired bacteremic urinary tract infection: epidemiology and outcome.

Analysis of 221 episodes of hospital-acquired bacteremic urinary tract infection in 4 hospitals of 1 metropolitan area from 1977 to 1981 revealed an over-all mortality rate of 30.8 per cent. The mortality rate attributed specifically to bacteremic urinary tract infection was 12.7 per cent. Of the 28 patients whose deaths were attributed directly to hospital-acquired bacteremic urinary tract infection 19 were on medical services and all had focal or diffuse central nervous system disease, malignancy, alcoholic liver disease or cirrhosis, advanced arteriosclerosis with renal failure and/or diabetes mellitus with obliterative peripheral vascular disease. Extrapolation of these data suggests that 3,520 deaths in the United States each year are directly caused by hospital-acquired bacteremic urinary tract infection but that these deaths may be limited virtually to high risk patients with poor prognoses from underlying diseases.