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Long‐term gout management is based on reducing serum urate by using urate‐lowering therapy (ULT). A lifelong treat‐to‐target approach is advocated, although a ULT (taper to) stop attempt can be considered (treat‐to‐avoid symptoms approach) during remission. Exploring the beliefs of patients with gout on long‐term ULT strategies during remission is important for optimizing gout management. We aimed to identify factors that influence the decision for continuation or discontinuation of ULT and to determine their relative importance according to patients with gout in remission. A mixed‐methods design was used. First, semistructured interviews (substudy 1) were conducted to identify barriers and facilitators for the (dis)continuation of ULT using inductive thematic analysis. Afterwards, these barriers/facilitators were summarized into neutrally phrased items and used in a maximum difference scaling study (substudy 2) to determine their relative importance using the rescaled probability score. Substudies 1 and 2 included 18 and 156 patients, respectively. Substudy 1 yielded 22 items within 10 overarching themes. Substudy 2 revealed that the perceived risk of joint damage and gout flares and that ULT use gives some assurance were the most important items. The costs, ease of receiving ULT, and its practical use were the least important items. These results can aid shared decision‐making and provide input for what is important to discuss with patients with gout in remission when they consider ULT discontinuation. The emphasis should be on the risk of having gout flares and joint damage, not so much on facilitating how easily medication is received.

To investigate the use of remote consultations (RCs) and the influence of consultation, health care provider (HCP), and patient characteristics on the choice for remote or face‐to‐face consultation. A monocenter retrospective cohort study was conducted on follow‐up consultations of patients with rheumatic diseases from January 1, 2019 to January 16, 2023, using data from electronic health records. Trends in the proportion of RCs before, during, and after COVID‐19 were studied. Cross–classified multilevel logistic regression models were built to account for clustering of consultations (level 1) within both patients and HCPs (level 2). The influence of consultation, patient, and HCP characteristics on the type of consultation was assessed. 157,028 consultations of 30,215 unique patients seen by 64 HCPs were included in the data set. After an initial sharp increase in RC use at the beginning of the COVID‐19 pandemic, the proportion of RCs decreased toward a seemingly steady state at around 30%. 90% of the variance in the use of RCs can be attributed to the consultation level, whereas 4% and 6% can be attributed to the patient and HCP level. Longer consultation durations and time since last consultation decreased the odds for a RC, as did higher patient age, shared care, and longer disease duration. Higher travel distance, consultation density, and patient digital access increased the odds for a RC. The COVID pandemic resulted in a structural increase in the use of RCs. Although several patient characteristics are associated with the type of consultation, most variance resulted from consultation characteristics compared with patients and HCPs.

The present study aimed to analyse their independent and cumulative association of the three correlated environmental exposures: air pollution, road traffic noise, and green space with MI. Air pollution, noise, and lack of green space were all independently associated with MI.Risk estimates for air pollution, noise, and lack of green space were similar, indicating that all may be equally relevant targets for regulatory measures.Graphical Abstract

IMPORTANCE: Cancer screening tests are promoted to save life by increasing longevity, but it is unknown whether people will live longer with commonly used cancer screening tests. OBJECTIVE: To estimate lifetime gained with cancer screening. DATA SOURCES: A systematic review and meta-analysis was conducted of randomized clinical trials with more than 9 years of follow-up reporting all-cause mortality and estimated lifetime gained for 6 commonly used cancer screening tests, comparing screening with no screening. The analysis included the general population. MEDLINE and the Cochrane library databases were searched, and the last search was performed October 12, 2022. STUDY SELECTION: Mammography screening for breast cancer; colonoscopy, sigmoidoscopy, or fecal occult blood testing (FOBT) for colorectal cancer; computed tomography screening for lung cancer in smokers and former smokers; or prostate-specific antigen testing for prostate cancer. DATA EXTRACTION AND SYNTHESIS: Searches and selection criteria followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline. Data were independently extracted by a single observer, and pooled analysis of clinical trials was used for analyses. MAIN OUTCOMES AND MEASURES: Life-years gained by screening was calculated as the difference in observed lifetime in the screening vs the no screening groups and computed absolute lifetime gained in days with 95% CIs for each screening test from meta-analyses or single randomized clinical trials. RESULTS: In total, 2 111 958 individuals enrolled in randomized clinical trials comparing screening with no screening using 6 different tests were eligible. Median follow-up was 10 years for computed tomography, prostate-specific antigen testing, and colonoscopy; 13 years for mammography; and 15 years for sigmoidoscopy and FOBT. The only screening test with a significant lifetime gain was sigmoidoscopy (110 days; 95% CI, 0-274 days). There was no significant difference following mammography (0 days: 95% CI, −190 to 237 days), prostate cancer screening (37 days; 95% CI, −37 to 73 days), colonoscopy (37 days; 95% CI, −146 to 146 days), FOBT screening every year or every other year (0 days; 95% CI, −70.7 to 70.7 days), and lung cancer screening (107 days; 95% CI, −286 days to 430 days). CONCLUSIONS AND RELEVANCE: The findings of this meta-analysis suggest that current evidence does not substantiate the claim that common cancer screening tests save lives by extending lifetime, except possibly for colorectal cancer screening with sigmoidoscopy.

IMPORTANCE: Otologic disease is common among people with primary ciliary dyskinesia (PCD), yet little is known about its spectrum and severity. OBJECTIVE: To characterize otologic disease among participants with PCD using data from the Ear-Nose-Throat Prospective International Cohort. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional analysis of baseline cohort data from February 2020 through July 2022 included participants from 12 specialized centers in 10 countries. Children and adults with PCD diagnoses; routine ear, nose, and throat examinations; and completed symptom questionnaires at the same visit or within 2 weeks were prospectively included. EXPOSURES: Potential risk factors associated with increased risk of ear disease. MAIN OUTCOMES AND MEASURES: The prevalence and characteristics of patient-reported otologic symptoms and findings from otologic examinations, including potential factors associated with increased risk of ear inflammation and hearing impairment. RESULTS: A total of 397 individuals were eligible to participate in this study (median [range] age, 15.2 [0.2-72.4] years; 186 (47%) female). Of the included participants, 204 (51%) reported ear pain, 110 (28%) reported ear discharge, and 183 (46%) reported hearing problems. Adults reported ear pain and hearing problems more frequently when compared with children. Otitis media with effusion—usually bilateral—was the most common otoscopic finding among 121 of 384 (32%) participants. Retracted tympanic membrane and tympanic sclerosis were more commonly seen among adults. Tympanometry was performed for 216 participants and showed pathologic type B results for 114 (53%). Audiometry was performed for 273 participants and showed hearing impairment in at least 1 ear, most commonly mild. Season of visit was the strongest risk factor for problems associated with ear inflammation (autumn vs spring: odds ratio, 2.40; 95% CI, 1.51-3.81) and age 30 years and older for hearing impairment (41-50 years vs ≤10 years: odds ratio, 3.33; 95% CI, 1.12-9.91). CONCLUSION AND RELEVANCE: In this cross-sectional study, many people with PCD experienced ear problems, yet frequency varied, highlighting disease expression differences and possible clinical phenotypes. Understanding differences in otologic disease expression and progression during lifetime may inform clinical decisions about follow-up and medical care. Multidisciplinary PCD management should be recommended, including regular otologic assessments for all ages, even without specific complaints.

Cutaneous T-cell lymphoma (CTCL) is a devastating lymphoid malignancy characterized by the accumulation of malignant T cells in the dermis and epidermis. Skin lesions cause serious symptoms that hamper quality of life and are entry sites for bacterial infection, a major cause of morbidity and mortality in advanced diseases. The mechanism driving the pathological processes that compromise the skin barrier remains unknown. Here, we report increased transepidermal water loss and compromised expression of the skin barrier proteins filaggrin and filaggrin-2 in areas adjacent to TOX-positive T cells in CTCL skin lesions. Malignant T cells secrete mediators (including cytokines such as interleukin 13 [IL-13], IL-22, and oncostatin M) that activate STAT3 signaling and downregulate filaggrin and filaggrin-2 expression in human keratinocytes and reconstructed human epithelium. Consequently, the repression of filaggrins can be counteracted by a cocktail of antibodies targeting these cytokines/receptors, small interfering RNA–mediated knockdown of JAK1/STAT3, and JAK1 inhibitors. Notably, we show that treatment with a clinically approved JAK inhibitor, tofacitinib, increases filaggrin expression in lesional skin from patients with mycosis fungoides. Taken together, these findings indicate that malignant T cells secrete cytokines that induce skin barrier defects via a JAK1/STAT3-dependent mechanism. As clinical grade JAK inhibitors largely abrogate the negative effect of malignant T cells on skin barrier proteins, our findings suggest that such inhibitors provide novel treatment options for patients with CTCL with advanced disease and a compromised skin barrier.

The increasing aging of the human population is currently and for the coming decades a major public health issue in many countries, requiring the implementation of global public health policies promoting healthy and successful aging. Individuals are not equal in the face of aging and some can present exceptional healthspan and/or lifespan, which are notably influenced by both genetic and environmental factors. Research and studies on human aging, healthy aging and longevity should rely in particular on cohorts of long-lived individuals, also including biological samples allowing studies on the biology of aging and longevity. In this manuscript, we provide for the first time a complete description of the CEPH (Centre d’Etude du Polymophisme Humain) Aging cohort, an exceptional cohort recruited during the 90s to 2000s, including more than 1700 French long-lived individuals (≥ 90 years old) born between 1875 and 1916 as well as for some of them their siblings and offspring. Among the participants, 1265 were centenarians, including 255 semi-supercentenarians ([105–110] years old) and 25 supercentenarians (≥ 110 years old). The available anthropometric, epidemiologic and clinical data for the cohort participants are described and especially the collection of blood-derived biological samples associated with the cohort which includes DNA, cryopreserved cells and cell lines, plasma, and serum. This biological collection from the first cohort of centenarians in the world is an inestimable resource for ongoing and future molecular, cellular, and functional studies aimed at deciphering the mechanisms of human (successful) aging and longevity.

Current methods of characterizing plastic debris use arbitrary, predetermined categorizations and assume that the properties of particles are independent. Here we introduce Gaussian mixture models (GMM), a technique suitable for describing non-normal multivariate distributions, as a method to identify mutually exclusive subsets of floating macroplastic and microplastic particles (latent class analysis) based on statistically defensible categories. Length, width, height and polymer type of 6,942 particles and items from the Atlantic Ocean were measured using infrared spectroscopy and image analysis. GMM revealed six underlying normal distributions based on length and width; two within each of the lines, films, and fragments categories. These classes differed significantly in polymer types. The results further showed that smaller films and fragments had a higher correlation between length and width, indicating that they were about the same size in two dimensions. In contrast, larger films and fragments showed low correlations of height with length and width. This demonstrates that larger particles show greater variability in shape and thus plastic fragmentation is associated with particle rounding. These results offer important opportunities for refinement of risk assessment and for modeling the fragmentation and distribution of plastic in the ocean. They further illustrate that GMM is a useful method to map ocean plastics, with advantages over approaches that use arbitrary categorizations and assume size independence or normal distributions.

The majority of women in the United States with children younger than 1 year are in the labor force. (1) In fact, a recent multisite, prospective study of approximately 1,200 [...]

In their commentary in CMAJ, Bielawska and Dube (1) criticize our recent guideline on colorectal cancer screening published in BMJ. (2) They reason that because screening is effective in reducing [...]

The present work aimed to study whether a high sugar diet can alter immune responses and the gut microbiome in green iguanas. Thirty-six iguanas were split into four treatment groups using a 2×2 design. Iguanas received either a sugar-supplemented diet or a control diet, and either a lipopolysaccharide (LPS) injection or a phosphate-buffered saline (PBS) injection. Iguanas were given their respective diet treatment through the entire study (∼3 months) and received a primary immune challenge 1 and 2 months into the experiment. Blood samples and cloacal swabs were taken at various points in the experiment and used to measure changes in the immune system (bacterial killing ability, lysis and agglutination scores, LPS-specific IgY concentrations), and alterations in the gut microbiome. We found that a sugar diet reduces bacterial killing ability following an LPS challenge, and sugar and the immune challenge temporarily alters gut microbiome composition while reducing alpha diversity. Although sugar did not directly reduce lysis and agglutination following the immune challenge, the change in these scores over a 24-h period following an immune challenge was more drastic (it decreased) relative to the control diet group. Moreover, sugar increased constitutive agglutination outside of the immune challenges (i.e. pre-challenge levels). In this study, we provide evidence that a high sugar diet affects the immune system of green iguanas (in a disruptive manner) and alters the gut microbiome.

There is continued uncertainty regarding the risks of hepato‐pancreato‐biliary cancers in patients with inflammatory bowel disease (IBD) with or without concomitant primary sclerosing cholangitis (PSC). To give updated estimates on risk of hepato‐pancreato‐biliary cancers in patients with IBD, including pancreatic cancer, hepatocellular carcinoma, gall bladder cancer, and intra – and extrahepatic cholangiocarcinoma. In a population‐based cohort study, we included all patients diagnosed with IBD in Norway and Sweden from 1987 to 2016. The cohort comprised of 141,960 patients, identified through hospital databases and the National Patient Register. Participants were followed through linkage to national cancer, cause of death, and population registries. We calculated absolute risk and standardized incidence ratios (SIRs) of hepato‐pancreato‐biliary cancers by PSC and other clinical characteristics. Of the 141,960 IBD patients, 3.2% were diagnosed with PSC. During a median follow‐up of 10.0 years, we identified 443 biliary tract cancers (SIR 5.2, 95% confidence interval [CI] 4.8–5.7), 161 hepatocellular carcinomas (SIR 2.4, 95% CI 2.0–2.7) and 282 pancreatic cancers (SIR 1.3, 95% CI 1.2–1.5). The relative risks were considerably higher in PSC‐IBD patients, with SIR of 140 (95% CI 123–159) for biliary tract, 38.6 (95% CI 29.2–50.0) for hepatocellular, and 9.0 (95% CI 6.3–12.6) for pancreatic cancer. The SIRs were still slightly increased in non‐PSC‐IBD patients, compared to the general population. For biliary tract cancer, the cumulative probability at 25 years was 15.6% in PSC‐IBD patients, and 0.4% in non‐PSC‐IBD patients. The dramatically increased risks of hepato‐pancreato‐biliary cancers in PSC‐IBD patients support periodic surveillance for these malignancies. While much lower, the excess relative risks in non‐PSC‐IBD patients were not trivial compared to non‐IBD related risk factors.

ABSTRACTBackgroundQuinolones comprise a class of antibiotics that are globally preferred for treating a wide range of bacterial infections due to their potency, broad coverage, favorable pharmacologic profile, and mostly mild to moderate adverse reactions. Spontaneous reports on adverse drug events (ADE) and data from some pharmacoepidemiologic studies have raised concerns regarding quinolones and risk of retinal detachment (RD). This study examined ADE reports submitted to FDA adverse event reporting system (FAERS) for evidence on quinolone-associated RD risk.Research design and methodsWe identified all RD reports in FAERS between 2010–2019. We compared ADE signals between quinolones and selected medications that were previously associated with RD, and with reference medications not known to cause RD. For signal detection, we used two techniques: the proportional reporting ratio (PRR) and multi-item gamma Poisson shrinker (MGPS), which are known for their higher sensitivity and specificity for ADE signal detection, respectively.ResultsMoxifloxacin showed a positive and significant PRR signal for RD [PRR: 2.54 (1.60, 4.04)], and a marginally significant EBGM signal [EBGM: 2.21 (1.41, 3.02)].ConclusionMoxifloxacin is the only quinolone showing a positive disproportionality signal for RD. Further epidemiologic research is needed to clarify the association between moxifloxacin and RD risk.

•Acute neuropathic pain after SCI can be present at- and below-level.•Multiple sources of pain challenge the diagnosis in the acute phase after injury.•Distinct neuropathic pain phenotypes develop as a function of time since injury.

Study design: Observational study. Objectives: To examine the feasibility of meeting the current clinical guidelines for the hemodynamic management of acute spinal cord injury (SCI) which recommend maintaining mean arterial pressure (MAP) at 85–90 mmHg in the days following injury. Methods: This study examined data collected minute-by-minute to describe the pressure profile in the first 5 days following SCI in 16 patients admitted to the Intensive Care Unit at Vancouver General Hospital (40 ± 19 years, 13 M/3 F, C4-T11). MAP and intrathecal pressure (ITP) were monitored at 100 Hz by arterial and lumbar intrathecal catheters, respectively, and reported as the average of each minute. Spinal cord perfusion pressure was calculated as the difference between MAP and ITP. The minute-to-minute difference (MMdiff) of each pressure variable was calculated as the absolute difference between consecutive minutes. Results: Only 24 ± 7% of MAP recordings were between 85 and 90 mmHg. Average MAP MMdiff was ~3 mmHg. The percentage of MAP recordings within target range was negatively correlated with the degree of variability (i.e. MMdiff; r= −0.64, p< 0.008) whereas higher mean MAP was correlated with greater variability (r= 0.57, p= 0.021). Conclusions: Our findings point to the ‘real life’ challenges in maintaining MAP in acute SCI patients. Given MAP fluctuated ~3 mmHg minute-to-minute, maintaining MAP within a 5 mmHg range with conventional volume replacement and vasopressors presents an almost impossible task for clinicians and warrants reconsideration of current management guidelines.

Depression is becoming recognized as a prime factor affecting older adults' functional abilities and disability. However there is a scarcity of data on depression in older adult American Indians and [...]

Anthropogenic pressure, such as urbanization and habitat loss, can wield many effects on wildlife that radiate through ecosystems. Large carnivores tend to experience these effects more severely than other species, diminishing their viability and altering ecosystem function by suppressing their role as an apex predator. Yet opportunistic carnivores that rely on an omnivorous diet can sometimes take advantage of anthropogenic food and improve their fitness prospects. We quantified the effect of phenotypic and ecological factors on female body mass of the American black bear (Ursus americanus) in New Jersey, USA. Habitat and reliable mast crops in New Jersey keep adult female black bear body mass and reproduction higher than many parts of the United States, and historically, female black bears in the mid‐Atlantic states tend to be larger than in other parts of their range. We used data collected from den surveys (n= 317) in northern New Jersey from 1984 to 2019 to examine the shared roles of climate, anthropogenic pressure (human food subsidies, harvest), habitat composition and configuration, natural food availability (hard mast production), and bear characteristics (age, history of human–black bear conflict) on female black bear body mass using generalized linear mixed models. Adult female body mass was heaviest with increased availability of cultivated crop and within low‐intensity developed land covers, suggesting anthropogenic food subsidies found in these 2 land cover types are contributing to female overall body mass. A history of conflict with humans explained heavier females, and a quadratic effect of age on body mass supported a senescent decline in adult female body mass later in life. Our results suggest that access to specific land cover types (i.e., crops, low‐intensity developments) that provide a diversity of food (e.g., corn, soft and hard mast) and support low human densities, explains female black bear body mass in a fragmented landscape. We quantified the effect of phenotypic, ecological, and anthropogenic factors on American black bear female body mass using data collected from den surveys in northern New Jersey over 35 years. We examine the shared roles of bear characteristics (age, history of human‐black bear conflict), population factors (density, harvest), habitat composition and configuration, and natural food production on female body mass. Our results suggest that age, a past history of conflict behavior, and access to anthropogenic foods within land cover types with low human density support heavier females.

It has been proposed that CD4 T-cell responses to Staphylococcus aureus (SA) can inadvertently enhance neoplastic progression in models of skin cancer and cutaneous T-cell lymphoma (CTCL). In this prospective study, we explored the effect of transient antibiotic treatment on tumor cells and disease activity in 8 patients with advanced-stage CTCL. All patients experienced significant decrease in clinical symptoms in response to aggressive, transient antibiotic treatment. In some patients, clinical improvements lasted for more than 8 months. In 6 of 8 patients, a malignant T-cell clone could be identified in lesional skin, and a significant decrease in the fraction of malignant T cells was observed following antibiotics but an otherwise unchanged treatment regimen. Immunohistochemistry, global messenger RNA expression, and cell-signaling pathway analysis indicated that transient aggressive antibiotic therapy was associated with decreased expression of interleukin-2 high-affinity receptors (CD25), STAT3 signaling, and cell proliferation in lesional skin. In conclusion, this study provides novel evidence suggesting that aggressive antibiotic treatment inhibits malignant T cells in lesional skin. Thus, we provide a novel rationale for treatment of SA in advanced CTCL.

Objective: The aim of this study was to determine the health system costs from hospitalizations, emergency department (ED) visits, and medications due to potentially inappropriate prescribing (PIP) in Ontario, Canada, at the population-level. Methods: A retrospective cohort of individuals ≥ 66 years of age and prescribed at least one medication from April 2002 to March 2015 was identified using linked population-level health administrative databases from Ontario, Canada. Patients were identified as having PIP or no PIP by applying a subset of the Screening Tool of Older Persons’ Potentially Inappropriate Prescribing/Screening Tool to Alert Doctors to Right Treatment (STOPP/START) criteria. The number of days spent in hospital, new medications prescribed, and ED visits in the 90 days following PIP or patient index date were captured, as well as the total costs from each of these health services. Count regression models were used to generate incidence rate ratios (IRRs) for each outcome given the presence of PIP versus no PIP and combined with the prevalence of PIP to generate population attributable fractions (PAFs). The PAF was then multiplied by the cost for each health service to obtain the costs attributable to PIP in the whole cohort, and by age and sex. Results: PIP was associated with an increased rate of hospitalization (IRR 2.77, 95% confidence interval [CI] 2.72–2.82), ED visits (IRR 1.87, 95% CI 1.82–1.92), and newly prescribed medications (IRR 1.13, 95% CI 1.13–1.14), resulting in PAFs of 55.7, 37.9, and 5.0% for each outcome, respectively. PIP was associated with 38.8% of the total spent on these healthcare services ($1.22 billion) in the 90 days after PIP. Costs attributable to PIP decreased with age despite increasing prevalence. Conclusions: PIP in older adults is a significant source of health system costs from healthcare service use beyond medication costs, with a significant portion of hospitalizations and ED visit costs attributable to PIP. Future work should focus on identifying strategies and priorities for intervention.

Mycosis fungoides (MF) is the most frequent form of cutaneous T-cell lymphoma. The disease often takes an indolent course, but in approximately one-third of the patients, the disease progresses to an aggressive malignancy with a poor prognosis. At the time of diagnosis, it is impossible to predict which patients develop severe disease and are in need of aggressive treatment. Accordingly, we investigated the prognostic potential of microRNAs (miRNAs) at the time of diagnosis in MF. Using a quantitative reverse transcription polymerase chain reaction platform, we analyzed miRNA expression in diagnostic skin biopsies from 154 Danish patients with early-stage MF. The patients were subdivided into a discovery cohort (n = 82) and an independent validation cohort (n = 72). The miRNA classifier was built using a LASSO (least absolute shrinkage and selection operator) Cox regression to predict progression-free survival (PFS). We developed a 3-miRNA classifier, based on miR-106b-5p, miR-148a-3p, and miR-338-3p, which successfully separated patients into high-risk and low-risk groups of disease progression. PFS was significantly different between these groups in both the discovery cohort and the validation cohort. The classifier was stronger than existing clinical prognostic factors and remained a strong independent prognostic tool after stratification and adjustment for these factors. Importantly, patients in the high-risk group had a significantly reduced overall survival. The 3-miRNA classifier is an effective tool to predict disease progression of early-stage MF at the time of diagnosis. The classifier adds significant prognostic value to existing clinical prognostic factors and may facilitate more individualized treatment of these patients.

•Enterotoxins from S aureusbacteria induce drug resistance in primary malignant T cells in SS.•Targeting bacteria, their toxins, and downstream signaling pathways in malignant T cells abrogate the induction of drug resistance.

The three major gaps between HR practice and the scientific research in the area of employee attitudes in general and the most focal employee attitude toward job satisfaction are identified. The first one is the cause of employee attitudes, the second is the results of positive or negative job satisfaction and the final one how to measure and influence employee attitudes.

Summary points Results of epidemiological studies need to be expressed in understandable terms if they are to be of practical use to clinicians and policy makers Case-control studies are often [...]

Sézary syndrome (SS) is an aggressive leukemic variant of cutaneous T-cell lymphoma (CTCL) with a median life expectancy of less than 4 years. Although initial treatment responses are often good, the vast majority of patients with SS fail to respond to ongoing therapy. We hypothesize that malignant T cells are highly heterogeneous and harbor subpopulations of SS cells that are both sensitive and resistant to treatment. Here, we investigate the presence of single-cell heterogeneity and resistance to histone deacetylase inhibitors (HDACi) within primary malignant T cells from patients with SS. Using single-cell RNA sequencing and flow cytometry, we find that malignant T cells from all investigated patients with SS display a high degree of single-cell heterogeneity at both the mRNA and protein levels. We show that this heterogeneity divides the malignant cells into distinct subpopulations that can be isolated by their expression of different surface antigens. Finally, we show that treatment with HDACi (suberanilohydroxamic acid and romidepsin) selectively eliminates some subpopulations while leaving other subpopulations largely unaffected. In conclusion, we show that patients with SS display a high degree of single-cell heterogeneity within the malignant T-cell population, and that distinct subpopulations of malignant T cells carry HDACi resistance. Our data point to the importance of understanding the heterogeneous nature of malignant SS cells in each individual patient to design combinational and new therapies to counter drug resistance and treatment failure.

Deficient expression of SATB1 hampers thymocyte development and results in inept T-cell lineages. Recent data implicate dysregulated SATB1 expression in the pathogenesis of mycosis fungoides, the most frequent variant of cutaneous T-cell lymphoma. Here, we report on a disease stage-associated decrease of SATB1 expression and an inverse expression of STAT5 and SATB1 in situ. STAT5 inhibited SATB1 expression through induction of microRNA-155. Decreased SATB1 expression triggered enhanced expression of IL-5 and IL-9 (but not IL-6 and IL-32), whereas increased SATB1 expression had the opposite effect, indicating that the microRNA-155 target SATB1 is a repressor of IL-5 and IL-9 in malignant T cells. In accordance, inhibition of STAT5 and its upstream activator JAK3 triggered increased SATB1 expression and a concomitant suppression of IL-5 and IL-9 expression in malignant T cells. In conclusion, we provide a mechanistic link between the proto-oncogenic JAK3/STAT5/microRNA-155 pathway, SATB1, and cytokines linked to CTCL severity and progression, indicating that SATB1 dysregulation is involved in cutaneous T-cell lymphoma pathogenesis.

The lifetime risk of colorectal cancer (CRC) in the Western world is around 5%. CRC commonly develops from precursor lesions termed polyps, classified as adenomatous or serrated polyps according to growth pattern. Despite the well-known connection between polyps and cancer, most polyps will never develop into CRC. For those that do, the time until CRC development is generally thought of as >10 years. This gives opportunity for interventional strategies to prevent transformation into cancer. This article aims to provide an overview of the epidemiology of and risk factors for colorectal polyps in the average risk population, and will encompass the effect of age, gender, ethnicity, smoking, obesity, alcohol, physical activity, NSAIDs and dietary factors on colorectal polyps.

The use of Deep Brain Stimulation (DBS) in treatment of various brain disorders is constantly growing; however, the number of studies of the reaction of the brain tissue toward implanted leads is still limited. Therefore, the aim of our study was to analyze the impact of DBS leads on brain tissue in a large animal model using minipigs. Twelve female animals, one control and eleven with bilaterally implanted DBS electrodes were used in our experiment. 3, 6, and 12 months after implantation the animals were sacrificed, perfused and the brains were removed. Tissue blocks containing the lead tracks were dissected, frozen, sectioned into 40 µm sections and stained using Nissl and Eosin, anti‐GFAPab or Isolectin. The tissue reaction was analyzed at five levels, following from the distal lead tip, to compare tissue response in stimulated and nonstimulated areas: four segments along each level of electrodes, and the fifth level lying outside the electrode area (control area). The sections were described both qualitatively and quantitatively. Quantitative assessment of the reaction to the implanted electrode was based on the measurement of the area covered by the staining and the thickness of the glial scar. Results and Conclusions:Tissue reaction was, on average, limited to distance of 500 μm from the lead track. The tissue response after 12 months was weaker than after 6 months confirming that it stabilizes over a time. There was no histological evidence that the stimulated part of the electrode triggered different tissue response than its nonstimulated part.

Background: Tofacitinib is a Janus Kinase (JAK) inhibitor used for the treatment of rheumatoid arthritis (RA) and psoriatic arthritis (PsA), dosed as 5 mg twice daily (BID). It is primarily metabolized by the cytochrome P-3A (CYP3A) enzyme, and therefore, the manufacturer recommends to halve the dose when using CYP3A-inhibiting co-medication. Combining half-dose tofacitinib with a registered CYP3A inhibitor (cobicistat) could reduce costs and improve patient experience.Objectives: Primary: bioequivalence of tofacitinib 5 mg combined with cobicistat once daily (QD; intervention) to tofacitinib 5 mg BID (control). Secondary: safety, patient preference (7-point Likert scale at study end) and predicted differences in disease activity (DAS28-CRP and probability of ACR20 response) using a validated exposure-response model.Design: Open-label, cross-over pharmacokinetic study.Methods: We included patients with RA or PsA, treated with tofacitinib 5 mg BID for ⩾14 days without co-medication affected by CYP3A inhibition. Pharmacokinetic sampling was performed at baseline and after 2–6 weeks of intervention treatment. Bioequivalence was defined as 90% CI of the average tofacitinib concentration (Cavg,ss; intervention to control) falling between 80% and 125%, assessed by non-linear mixed-effects modelling.Results: Between 16 September 2019 and 15 January 2021, 30 patients were included, of whom 25 completed both PK measurements. The tofacitinib Cavg,sswas 85% (90% CI: 75–96%). No serious adverse events occurred. Patient preference was 56% for intervention versus18% for control. No relevant differences in median predicted disease activity were found (DAS28-CRP: 0.03, 95% CI: −0.16 to 0.22; ACR20: −0.01, −0.07 to 0.05).Conclusion: Due to slightly lower tofacitinib concentrations during intervention treatment, pharmacokinetic bioequivalence could not formally be established. However, pharmacokinetic boosting may be an attractive strategy for cost reduction of tofacitinib because of its safety, similar predicted pharmacodynamics and patient preference.Registration: This study was registered on 29 May 2019 in the Netherlands Trial Register (register number: NL7766).

A 28-year-old man of Japanese descent presented to the ED with a 2-month history of dry cough, shortness of breath, and weakness. He did not complain of fever, chest pain, or abdominal symptoms, and had no history of smoking. The patient’s medical history was significant for an episode of ulcerative colitis 6 years previously after presenting with bloody diarrhea, stomach pain, fever, weight loss, and bilateral episcleritis. He had been treated consecutively with mesalazine, azathioprine, infliximab, golimumab, and adalimumab. Concomitant respiratory symptoms had been present during 2 flare-ups of severe ulcerative colitis disease activity and were successfully treated with a course of oral prednisone.

Cutaneous T-cell lymphoma (CTCL) is characterized by proliferation of malignant T cells in a chronic inflammatory environment. With disease progression, bacteria colonize the compromised skin barrier and half of CTCL patients die of infection rather than from direct organ involvement by the malignancy. Clinical data indicate that bacteria play a direct role in disease progression, but little is known about the mechanisms involved. Here, we demonstrate that bacterial isolates containing staphylococcal enterotoxin A (SEA) from the affected skin of CTCL patients, as well as recombinant SEA, stimulate activation of signal transducer and activator of transcription 3 (STAT3) and upregulation of interleukin (IL)-17 in immortalized and primary patient–derived malignant and nonmalignant T cells. Importantly, SEA induces STAT3 activation and IL-17 expression in malignant T cells when cocultured with nonmalignant T cells, indicating an indirect mode of action. In accordance, malignant T cells expressing an SEA-nonresponsive T-cell receptor variable region β chain are nonresponsive to SEA in monoculture but display strong STAT3 activation and IL-17 expression in cocultures with SEA-responsive nonmalignant T cells. The response is induced via IL-2 receptor common γ chain cytokines and a Janus kinase 3 (JAK3)-dependent pathway in malignant T cells, and blocked by tofacitinib, a clinical-grade JAK3 inhibitor. In conclusion, we demonstrate that SEA induces cell cross talk–dependent activation of STAT3 and expression of IL-17 in malignant T cells, suggesting a mechanism whereby SEA-producing bacteria promote activation of an established oncogenic pathway previously implicated in carcinogenesis.

Harvest indices are used by state wildlife management agencies to monitor population trends and set harvest quotas for furbearer species. Although harvest indices may be readily collected from hunters, the reliability of harvest indices for monitoring demography and abundance of the harvested species is rarely examined, particularly amongst large carnivores. The overall objective of this study was to assess whether cougar (Puma concolor) harvest statistics collected by wildlife managers were correlated with changes in cougar demography, mainly survival rates and abundance. We estimated key demographic parameters for 2 cougar populations in Utah over 17 years during which we monitored 235 radio-collared cougars. We then compared these demographic parameters to harvest statistics provided by the Utah Division of Wildlife Resources over the same time period for the Oquirrh-Stansbury (lightly harvested population) and Monroe (heavily harvested population) harvest management units. In the Oquirrh-Stansbury unit, the percent of harvested cougars >6 years old was positively correlated with annual survival, indicative of a population experiencing several years of high survival resulting in an older age structure. Percent of permits filled and cougar abundance were also significantly correlated, suggesting higher hunting success with increased density. In the Monroe management unit, the annual percent of permits filled was correlated with changes in overall annual survival and male and female annual survival. Of utmost importance, pursuit success (cougars treed/day) increased with the number of cougars on the unit suggesting that pursuit indices may be an informative metric for wildlife managers to determine cougar population trends. Because both management units were subjected to contrasting mortality regimes, results provided by this assessment could potentially be applied to additional management areas sharing similar ecological characteristics and harvest metrics. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.

Patients with cutaneous T-cell lymphoma (CTCL) are frequently colonized with Staphylococcus aureus (SA). Eradication of SA is, importantly, associated with significant clinical improvement, suggesting that SA promotes the disease activity, but the underlying mechanisms remain poorly characterized. Here, we show that SA isolates from involved skin express staphylococcal enterotoxins (SEs) that induce crosstalk between malignant and benign T cells leading to Stat3-mediated interleukin-10 (IL-10) production by the malignant T cells. The SEs did not stimulate the malignant T cells directly. Instead, SEs triggered a cascade of events involving cell-cell and asymmetric cytokine interactions between malignant and benign T cells, which stimulated the malignant T cells to express high levels of IL-10. Much evidence supports that malignant activation of the Stat3/IL-10 axis plays a key role in driving the immune dysregulation and severe immunodeficiency that characteristically develops in CTCL patients. The present findings thereby establish a novel link between SEs and immune dysregulation in CTCL, strengthening the rationale for antibiotic treatment of colonized patients with severe or progressive disease.

Snowshoe hares (Lepus americanus) are a primary prey species for Canada lynx (Lynx canadensis) in western North America. Lynx management plans require knowledge of potential prey distribution and abundance in the western United States. Whether even-aged regenerating forests or multi-storied forests contain more snowshoe hares is currently unknown. During 2006–2008, we estimated snowshoe hare density in 3 classes of 30–70-year-old lodgepole pine (Pinus contorta) and 4 classes of late seral multi-storied forest with a spruce (Picea engelmannii)-fir (Abies lasiocarpa) component in the Bridger-Teton National Forest, Wyoming. We recorded physiographic variables and forest structure characteristics to understand how these factors influence abundance of snowshoe hares. In many instances, snowshoe hares were more abundant in late seral multi-storied forests than regenerating even-aged forests. Forest attributes predicting hare abundance were often more prevalent in multi-storied forests. Late seral multi-storied forests with a spruce–fir component and dense horizontal cover, as well as 30–70-year-old lodgepole pine with high stem density, were disproportionately influential in explaining snowshoe hare densities in western Wyoming. In order to promote improved habitat conditions for snowshoe hares in this region, management agencies should consider shifting their focus towards maintaining, enhancing, and promoting multi-storied forests with dense horizontal cover, as well as developing 30–70-year-old lodgepole pine stands with high stem density that structurally mimic multi-storied forests. © 2012 The Wildlife Society.

Over the years, employee opinion surveys have evolved in their use and how they are conducted. A major advancement has been the use of linkage analyses, whereby employee attitudes at a unit level are statistically related to other important organizational outcomes. A more recent development has been linkage analyses at the individual level and over time. In order to carry out these types of analyses, “identified surveys” must be used—surveys that retain identifying informationon each survey respondent in order to link with other individual‐level variables over time. The purpose of this article is to open up a discussion on identified surveys, describe under what circumstances they may be uniquely beneficial, and highlight potential concerns with them. We close with proposed guidelines for professional practice and recommend that our profession have a point of view on identified surveys for ourselves and to advise others.

The goal of our focal article was to open up a discussion within our profession on a new trend called identified surveys. We feel that we have achieved this goal with the varied and interesting commentaries. At the same time, we do not feel discussion is enough. We as a profession need to better understand the implications and use of identified surveys. We have an obligation to inform others and to have a point of view on how they should be used, taking into account not just an organizational perspective but the point of view of employees as well.

Cutaneous T-cell lymphomas (CTCLs) are the most frequent primary skin lymphomas. Nevertheless, diagnosis of early disease has proven difficult because of a clinical and histologic resemblance to benign inflammatory skin diseases. To address whether microRNA (miRNA) profiling can discriminate CTCL from benign inflammation, we studied miRNA expression levels in 198 patients with CTCL, peripheral T-cell lymphoma (PTL), and benign skin diseases (psoriasis and dermatitis). Using microarrays, we show that the most induced (miR-326, miR-663b, and miR-711) and repressed (miR-203 and miR-205) miRNAs distinguish CTCL from benign skin diseases with > 90% accuracy in a training set of 90 samples and a test set of 58 blinded samples. These miRNAs also distinguish malignant and benign lesions in an independent set of 50 patients with PTL and skin inflammation and in experimental human xenograft mouse models of psoriasis and CTCL. Quantitative (q)RT-PCR analysis of 103 patients with CTCL and benign skin disorders validates differential expression of 4 of the 5 miRNAs and confirms previous reports on miR-155 in CTCL. A qRT-PCR–based classifier consisting of miR-155, miR-203, and miR-205 distinguishes CTCL from benign disorders with high specificity and sensitivity, and with a classification accuracy of 95%, indicating that miRNAs have a high diagnostic potential in CTCL.

The short story "Mummy (Baby)" by Lise M. Quintana is presented.

ABSTRACTThe levels of regulatory T cells (Treg cells), analyzed by Foxp3 mRNA expression, were determined in lesions from patients with acute cutaneous leishmaniasis (ACL) and chronic cutaneous leishmaniasis (CCL). We demonstrated that Treg cells preferentially accumulate in lesions from ACL patients during the early phase of infection (lesion duration of less than 1 month). In addition, levels of Foxp3 mRNA transcripts were significantly higher in specimens from patients with CCL than in those from patients with ACL, suggesting a critical role of intralesional Treg cells in CCL. Intralesional Treg cells from both ACL and CCL patients were shown to have suppressive functions in vitro, since they inhibited the gamma interferon (IFN-γ) produced by CD4+CD25−T cells purified from peripheral blood mononuclear cells from the same patient in response to Leishmania guyanensisstimulation. Intralesional 2,3-indoleamine dioxygenase (IDO) mRNA expression was associated with that of Foxp3, suggesting a role for IDO in the suppressive activity of intralesional Treg cells. In addition, a role, albeit minor, of interleukin-10 (IL-10) was also demonstrated, since neutralization of IL-10 produced by intralesional T cells increased IFN-γ production by effector cells in an in vitro suppressive assay. These results confirm the role of intralesional Treg cells in the immunopathogenesis of human Leishmaniainfection, particularly in CCL patients.

To determine the population-level impact of COVID-19 pandemic–related obstetric practice changes on maternal and newborn outcomes.

Cutaneous T-cell lymphoma (CTCL) is a devastating lymphoid malignancy characterized by the accumulation of malignant T cells in the dermis and epidermis. Skin lesions cause serious symptoms that hamper quality of life and are entry sites for bacterial infection, a major cause of morbidity and mortality in advanced diseases. The mechanism driving the pathological processes that compromise the skin barrier remains unknown. Here, we report increased transepidermal water loss and compromised expression of the skin barrier proteins filaggrin and filaggrin-2 in areas adjacent to TOX-positive T cells in CTCL skin lesions. Malignant T cells secrete mediators (including cytokines such as interleukin 13 [IL-13], IL-22, and oncostatin M) that activate STAT3 signaling and downregulate filaggrin and filaggrin-2 expression in human keratinocytes and reconstructed human epithelium. Consequently, the repression of filaggrins can be counteracted by a cocktail of antibodies targeting these cytokines/receptors, small interfering RNA–mediated knockdown of JAK1/STAT3, and JAK1 inhibitors. Notably, we show that treatment with a clinically approved JAK inhibitor, tofacitinib, increases filaggrin expression in lesional skin from patients with mycosis fungoides. Taken together, these findings indicate that malignant T cells secrete cytokines that induce skin barrier defects via a JAK1/STAT3-dependent mechanism. As clinical grade JAK inhibitors largely abrogate the negative effect of malignant T cells on skin barrier proteins, our findings suggest that such inhibitors provide novel treatment options for patients with CTCL with advanced disease and a compromised skin barrier.

Background:In patients who underwent radical resection for gastric cancer, we investigate the relative efficacy of combined 5-fluorouracil + adriamycin or epirubicin and methotrexate with leucovorin rescue (FAMTX or FEMTX) compared with a control arm.

We have recently shown that alpha fetoprotein (AFP) and squamous cell carcinoma antigen (SCCA), biomarkers associated with hepatocellular carcinoma, may be detected in patient sera as circulating immune complexes with IgM, and that assessment of serum levels of AFP-IgM and SCCA-IgM may be used for the detection of liver cancer. In this study we measured the levels of carcinoembryonic antigen (CEA) as free form (FCEA) and complexed to IgMs (CEA-IgM) in sera of patients affected by colorectal carcinoma (CRC) at different stages as well as in healthy subjects. FCEA levels were above the 5 ng/mL cutoff in 43% of CRC patients (31/72) and CEA-IgM levels were above the 200 AU/mL cutoff in 38% of CRC patients (27/72). Serum levels of CEA-IgM immune complexes (IC) and FCEA did not overlap and 64% of patients (46/72) were positive for at least one marker without compromising the detection specificity (94%). Early detection of CRC was significantly improved by CEA-IgM IC assay. CRC patients at an early stage (stage 1) had elevated CEA-IgM levels in 29% of cases (7/24), while FCEA levels were elevated in only 8% of cases (2/24). These results indicate that CEA-IgM is a complementary serological marker to FCEA which is much more sensitive for early stage CRC, and that the combination of these biomarkers may be useful in the early detection of colorectal cancer.

Objective:To learn more about the attitudes of German general practitioners (GPs) concerning euthanasia and the frequency of its performance in Germany.Methods:500 GPs from all parts of Germany were randomly selected from telephone listings, and were sent a postal questionnaire with anonymous return envelopes. Participants were asked to make decisions based on hypothetical scenarios involving terminally ill patients and were questioned about their attitudes towards active euthanasia or physician assisted suicide (PAS).Results:The questionnaire was returned by 48 of all 481 eligible GPs (mean age 51 years, 68 male). Although the option of performing euthanasia was rarely chosen in hypothetical scenarios, its performance was considered acceptable by 34 (active euthanasia) and 80 (PAS). Seventy-seven percent of respondents believed that a comparison between euthanasia today and the atrocities committed during the 3rd Reich was not appropriate. Sixty-two percent of respondents had received requests for active euthanasia and 73 for PAS. Thirteen percent and 38 of respondents seem to have performed euthanasia themselves in the past.Conclusions:The majority of German GPs reject active euthanasia and physician-assisted suicide (PAS). Nonetheless, requests for and performance of euthanasia do not seem to be a rare occurrence. Only a small proportion of respondents are willing to perform euthanasia at a patient's request under the current legislation which make these acts illegal in Germany. German history seems to play only a minor role in shaping respondents' attitudes towards active euthanasia or PAS. Eur J Gen Pract2005;11(3):94–100.