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The association between knee injury and knee osteoarthritis (OA) is understudied relative to its importance, particularly in younger populations. This study examined the association of knee injury with radiographic features of knee OA in military officers, who have a physically-demanding profession and high rates of knee injury.Participants were recruited in 2015-2017 from an existing program that enrolled 6,452 military officers during 2004-2009. Officers with a history of knee ligament or meniscal injuries (n=117 via medical record review) were compared to officers with no history of knee injury (n=143). Bilateral posteroanterior knee radiographs were obtained using a standardized fixed-flexion positioning frame. All images were read for Kellgren-Lawrence grade (KLG), osteophyte (OST), and joint space narrowing (JSN) scores. Data were analyzed using linear-risk regression models with generalized estimating equations.Injured and non-injured participants were similar (mean age=28 years, mean body mass index=25 kg/mAt the midpoint of a projected 20-year military career, officers with a history of traumatic knee injury have a markedly increased prevalence of knee rOA compared to officers without injury. This article is protected by copyright. All rights reserved.

Isotopic information from 81 snowpits was collected over a 5-year period in a large, Colorado watershed. Data spans gradients in elevation, aspect, vegetation, and seasonal climate. They are combined with overlapping campaigns for water isotopes in precipitation and snowmelt, and a land-surface model for detailed estimates of snowfall and climate at sample locations. Snowfall isotopic inputs, describe the majority of δ18O snowpack variability. Aspect is a secondary control, with slightly more enriched conditions on east and north facing slopes. This is attributed to preservation of seasonally enriched snowfall and vapour loss in the early winter. Sublimation, expressed by decreases in snowpack d-excess in comparison to snowfall contributions, increases at low elevation and when seasonal temperature and solar radiation are high. At peak snow accumulation, post-depositional fractionation appears to occur in the top 25 ± 14% of the snowpack due to melt-freeze redistribution of lighter isotopes deeper into the snowpack and vapour loss to the atmosphere during intermittent periods of low relative humidity and high windspeed. Relative depth of fractionation increases when winter daytime temperatures are high and winter precipitation is low. Once isothermal, snowpack isotopic homogenization and enrichment was observed with initial snowmelt isotopically depleted in comparison to snowpack and enriching over time. The rate of δ18O increase (d-excess decrease) in snowmelt was 0.02‰ per day per 100-m elevation loss. Isotopic data suggests elevation dictates snowpack and snowmelt evolution by controlling early snow persistence (or absence), isotopic lapse rates in precipitation and the ratio of energy to snow availability. Hydrologic tracer studies using stable water isotopes in basins of large topographic relief will require adjustment for these elevational controls to properly constrain stream water sourcing from snowmelt.

Proper embryonic and postnatal skeletal development require coordination of myriad complex molecular mechanisms. Disruption of these processes, through genetic mutation, contributes to variation in skeletal development. We developed a high-throughput N-ethyl-N-nitrosourea (ENU)-induced saturation mutagenesis skeletal screening approach in mice to identify genes required for proper skeletal development. Here, we report initial results from live-animal X-ray and dual-energy X-ray absorptiometry (DXA) imaging of 27,607 G3 mice from 806 pedigrees, testing the effects of 32,198 coding/splicing mutations in 13,020 genes. A total of 39.7% of all autosomal genes were severely damaged or destroyed by mutations tested twice or more in the homozygous state. Results from our study demonstrate the feasibility of in vivo mutagenesis to identify mouse models of skeletal disease. Furthermore, our study demonstrates how ENU mutagenesis provides opportunities to create and characterize putative hypomorphic mutations in developmentally essential genes. Finally, we present a viable mouse model and case report of recessive skeletal disease caused by mutations in FAM20B. Results from this study, including engineered mouse models, are made publicly available via the online Mutagenetix database. © 2021 American Society for Bone and Mineral Research (ASBMR).

Background Atopy, the overall tendency to become sensitized to an allergen, is heritable but seldom ascribed to mutations within specific genes. Atopic individuals develop abnormally elevated IgE responses to immunization with potential allergens. To gain insight into the genetic causes of atopy, we carried out a forward genetic screen for atopy in mice. Methods We screened mice carrying homozygous and heterozygous N-ethyl-N-nitrosourea (ENU)-induced germline mutations for aberrant antigen-specific IgE and IgG1 production in response to immunization with the model allergen papain. Candidate genes were validated by independent gene mutation. Results Of 31 candidate genes selected for investigation, the effects of mutations in 23 genes on papain-specific IgE or IgG1 were verified. Among the 20 verified genes influencing the IgE response, eight were necessary for the response, while 12 repressed IgE. Nine genes were not previously implicated in the IgE response. Fifteen genes encoded proteins contributing to IgE class switch recombination or B-cell receptor signaling. The precise roles of the five remaining genes (Flcn, Map1lc3b, Me2, Prkd2, and Scarb2) remain to be determined. Loss-of-function mutations in nine of the 12 genes limiting the IgE response were dominant or semi-dominant for the IgE phenotype but did not cause immunodeficiency in the heterozygous state. Using damaging allele frequencies for the corresponding human genes and in silico simulations (Monte Carlo) of undiscovered atopy mutations, we estimated the percentage of humans with heterozygous atopy risk mutations. Conclusions Up to 37% of individuals may be heterozygous carriers for at least one dominant atopy risk mutation.

Background and objectives Conflicting evidence indicates that both race and geographic setting may influence the management of malignancies such as gastric adenocarcinoma (GAC). Methods We designed a retrospective cohort study utilizing data from the Surveillance, Epidemiology, and End Results program to identify patients with resectable GAC (N = 15 991). Exposures of interest were race and geographic region of diagnosis (West [WE], Midwest [MW], South [SO], or Northeast [NE]). Endpoints included: (1) recommendation against surgery and (2) gastric adenocarcinoma-specific survival (GACSS). Multivariable logistic and Cox regression models were used to identify pertinent associations. Results A total of 15 991 patients were included (2007-2015). In adjusted analysis, African American individuals more frequently received a recommendation against surgical resection than White (adjusted odds ratio [aOR] = 0.86; 95% confidence interval [CI], 0.76-0.98), Asian American (aOR = 0.55; 95% CI, 0.46-0.65), and American Indian (aOR = 0.50; 95% CI, 0.31-0.82) individuals. In addition to race-based discrepancies, there was a significant association between geography and management: individuals diagnosed with GAC in the SO were more likely to receive a recommendation against surgery (odds ratio = 1.35; 95% CI, 1.23-1.49) and exhibited poorer GACSS as compared with those in the WE, MW, or NE regions. Conclusions Race and geographic region of diagnosis affect treatment recommendations and GACSS among individuals with resectable tumors. African Americans with resectable cancers are more likely to receive a recommendation against surgery than individuals of other racial groups.

OBJECTIVE The aim of this study was to investigate the characteristics of bacteremia caused by professional mechanical plaque removal (PMPR) in two groups of patients with generalized moderate chronic periodontitis. MATERIALS AND METHODS Venous blood samples were taken at multiple time points for one hour following PMPR in fifty patients with generalized moderate chronic periodontitis. Subjects consisted of two groups, one group was receiving supportive periodontal therapy (SPT, n = 25) and the other group was receiving initial periodontal therapy (IPT, n = 25). Blood samples were processed and analyzed for cultivable microflora. Pertinent clinical parameters were recorded for each patient in both groups. RESULTS Bacteremia was detected in 10 of 25 SPT and 8 of 25 IPT patients (p = 0.796). In both groups, the prevalence of bacteremia was dependent on the time of blood sampling and varied in magnitude between

Resistance and its extreme variation, reactance, are uniformly observed across varieties of psychotherapy. Social psychologists note that reactant individuals prove to be less so when offered a receptive and nondirective environment. We provide definitions of reactance, review its frequent measures, and offer a clinical example. A meta-analysis of 13 controlled studies (1,208 patients) examined the degree to which treatment outcomes are enhanced when therapists offer less directive treatments to high-reactance patients. The results revealed a large effect size (d = .79), confirming that highly reactant individuals did better in psychotherapy when the therapist assumed a reflective and nondirective stance than a directive and authoritative one. To a lesser degree, the opposite was also true. Limitations of the research and diversity considerations are noted. Practice recommendations are provided to minimize a patient's reactant behavior.

Over the course of 60 years of research, several personality traits have emerged as potential predictors of differential change in psychotherapy. Among them is the patient's coping style (CS), commonly distinguished between those who deal with change by looking inwardly (internalization) and those who deal with it outwardly (externalization). This study provides definitions of CSs, clinical examples, and frequent measures. We update a 2011 meta-analytic review that revealed a consistent interaction between CSs and treatment focus-symptom focus versus insight focus. The current meta-analysis of 18 studies revealed a medium to large effect (d = 0.60) and suggested that a symptom focus proves more effective for externalizing patient whereas an insight focus is generally more effective for internalizers. The article concludes with limitations of the research, diversity considerations, and therapeutic practices based on the meta-analytic results.

Background and purpose The diterpene ester tonantzitlolone (TZL) is a natural product, which displays cytotoxicity towards certain types of cancer cell such as renal cell carcinoma cells. The effect is similar to that of (-)-englerin A, and so, although it is chemically distinct, we investigated whether TZL also targets transient receptor potential canonical (TRPC) channels of the 1, 4 and 5 type (TRPC1/4/5 channels). Experimental approach The effects of TZL on renal cell carcinoma A498 cells natively expressing TRPC1 and TRPC4, modified HEK293 cells overexpressing TRPC4, TRPC5, TRPC4-TRPC1 or TRPC5-TRPC1 concatemer, TRPC3 or TRPM2, or CHO cells overexpressing TRPV4 were studied by determining changes in intracellular Ca2+ , or whole-cell or excised membrane patch-clamp electrophysiology. Key results TZL induced an elevation of intracellular Ca2+ in A498 cells, similar to that evoked by englerin A. TZL activated overexpressed channels with EC50 values of 123 nM (TRPC4), 83 nM (TRPC5), 140 nM (TRPC4-TRPC1) and 61 nM (TRPC5-TRPC1). These effects of TZL were reversible on wash-out and potently inhibited by the TRPC1/4/5 inhibitor Pico145. TZL activated TRPC5 channels when bath-applied to excised outside-out but not inside-out patches. TZL failed to activate endogenous store-operated Ca2+ entry or overexpressed TRPC3, TRPV4 or TRPM2 channels in HEK 293 cells. Conclusions and implications TZL is a novel potent agonist for TRPC1/4/5 channels, which should be useful for testing the functionality of this type of ion channel and understanding how TRPC1/4/5 agonists achieve selective cytotoxicity against certain types of cancer cell.

Groundwater Visibility: The Missing Link published within Column Theme: Groundwater Management Directions—Stewardship to Sustain Our Water Resources, edited by Vicki Kretsinger Grabert and Dawn Samara Kaback.

BACKGROUND With increasing demand for umbilical cord blood units (CBUs) with total nucleated cell (TNC) counts of more than 150 × 10(7) , preshipping assessment is mandatory. Umbilical cord blood processing requires aseptic techniques and laboratories with specific air quality and cleanliness. Our aim was to establish a fast and efficient method for determining TNC counts at the obstetric ward without exposing the CBU to the environment. STUDY DESIGN AND METHODS Data from a total of 151 cord blood donations at a single procurement site were included in this prospective study. We measured TNC counts in cord blood aliquots taken from the umbilical cord (TNCCord ), from placenta (TNCPlac ), and from a tubing segment of the sterile collection system (TNCTS ). TNC counts were compared to reference TNC counts in the CBU which were ascertained at the cord blood bank (TNCCBU ). RESULTS TNCTS counts (173 ± 33 × 10(7) cells; calculated for 1 unit) correlated fully with the TNCCBU reference counts (166 ± 33 × 10(7) cells, Pearson's r = 0.97, p

Paclitaxel‐induced peripheral neuropathy (PIPN) cannot be predicted from clinical parameters and might have a pharmacogenomic basis. Previous studies identified single nucleotide variants (SNV) associated with PIPN. However, only a subset of findings has been confirmed to date in more than one study, suggesting a need for further re‐testing and validation in additional clinical cohorts. Candidate PIPN‐associated SNVs were identified from the literature. SNVs were retested in 119 patients selected by extreme phenotyping from 269 in NCCTG N08C1 (Alliance) as previously reported. SNV genotyping was performed by a combination of short‐read sequencing analysis and Taqman PCR. These 22 candidate PIPN SNVs were genotyped. Two of these, rs7349683 in the EPHA5 and rs3213619 in ABCB1 were found to be significantly associated with PIPN with an Odds ratios OR = 2.07 (P = 0.02) and OR = 0.12 (P = 0.03), respectively. In addition, three SNVs showed a trend toward a risk‐ or protective effect that was consistent with previous reports. The rs10509681 and rs11572080 in the gene CYP2C8*3 showed risk effect with an OR = 1.49 and rs1056836 in CYP1B1 showed a protective effect with an OR = 0.66. None of the other results supported the previously reported associations, including some SNVs displaying an opposite direction of effect from previous reports, including rs1058930 in CYP2C8, rs17222723 and rs8187710 in ABCC2, rs10771973 in FGD4, rs16916932 in CACNB2 and rs16948748 in PITPNA. Alliance N08C1 validated or supported a minority of previously reported SNV‐PIPN associations. Associations previously reported by multiple studies appeared to have a higher likelihood to be validated by Alliance N08C1.

BACKGROUND AND PURPOSE The diterpene ester tonantzitlonone (TZL) is a natural product which displays cytotoxicity towards certain types of cancer cell such as renal cell carcinoma cells. The effect is similar to that of (‐)‐Englerin A (EA) and so, although it is chemically distinct, we investigated whether TZL also targets transient receptor potential canonical (TRPC) channels of the TRPC1, TRPC4 and TRPC5 type (TRPC1/4/5 channels). EXPERIMENTAL APPROACH Renal cell carcinoma A498 cells natively expressing TRPC1 and TRPC4, modified HEK 293 cells over expressing TRPC4, TRPC5, TRPC4‐TRPC1 or TRPC5‐TRPC1 concatemer, TRPC3 or TRPM2 or CHO cells over expressing TRPV4 were studied by intracellular Ca2+ measurement or whole‐cell or excised membrane patch‐clamp electrophysiology. KEY RESULTS TZL evoked intracellular Ca2+ elevation in A498 cells, similar to that evoked by EA. TZL activated overexpressed channels with concentration for 50% activation (EC50) at 123 nM (TRPC4), 83 nM (TRPC5), 140 nM (TRPC4‐TRPC1) and 61 nM (TRPC5‐TRPC1). Effects of TZL were reversible on wash‐out and potently inhibited by the TRPC1/4/5 inhibitor Pico145. TZL activated TRPC5 channels when bath‐applied to excised outside‐out but not inside‐out patches. TZL failed to activate endogenous store‐operated Ca2+ entry in HEK 293 cells or overexpressed TRPC3, TRPV4 or TRPM2 channels. CONCLUSIONS AND IMPLICATIONS TZL is a novel potent agonist for TRPC1/4/5 channels which should be useful for testing the functionality of this type of ion channel and understanding how TRPC1/4/5 agonists achieve selective cytotoxicity against certain types of cancer cell.

Ernest Beutler was one of the preeminent haematologists of the last half of the 20th and the early 21st century. In a career that spanned six decades, his research interests included such diverse areas as red cell metabolism, blood preservation, glycolipid storage diseases, leukaemias and iron metabolism. Indeed, he was quite different from most of his contemporaries in that his knowledge encompassed not only haematology and not only the medical sciences, but the biological sciences as a whole. He was among the first to describe X chromosome inactivation, and he established the critical link between glucose-6-phosphate dehydrogenase deficiency and drug-induced haemolysis. He was a skilled and innovative clinician, and an early advocate of bone marrow transplantation for the treatment of acute leukaemia. He was a prolific author, with over 800 publications; a long time member of the Editorial Board of Blood; founder of the journal Blood Cells Molecules and Diseases; and an editor of Williams Haematology from the time of its inception. He bequeathed $1 million to the American Society of Haematology to recognise and reward outstanding basic research and its clinical application: a pursuit to which he had committed his life. Indeed, he became an extraordinary exemplar of the bench-to-bedside ethos, which holds that even today, an MD researcher, working with limited means and independent of pharmaceutical companies, can have a great impact on the practice of medicine.