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Timely colorectal cancer (CRC) screening has been shown to improve CRC-related morbidity and mortality rates. However, even with this preventative care tool, CRC screening rates remain below 70% among eligible United States (US) adults, with even lower rates among US immigrants. The aim of this scoping review is to describe the barriers to CRC screening faced by this unique and growing immigrant population and discuss possible interventions to improve screening.Four electronic databases were systematically searched for all original research articles related to CRC screening in US immigrants published after 2010. Following a full-text review of articles for inclusion in the final analysis, data extraction was conducted while coding descriptive themes. Thematic analysis led to the organization of this data into five themes.Of the 4637 articles initially identified, 55 met inclusion criteria. Thematic analysis of the barriers to CRC screening identified five unique themes: access, knowledge, culture, trust, health perception, and beliefs. The most cited barriers were in access (financial burden and limited primary care access) and knowledge (CRC/screening knowledge).US immigrants face several barriers to the receipt of CRC screening. When designing interventions to increase screening uptake among immigrants, gaps in physician and screening education, access to care, and trust need to be addressed through culturally sensitive supports. These interventions should be tailored to the specific immigrant group, since a one-size-fits approach fails to consider the heterogeneity within this population.

Protein arylation has attracted much attention for developing new classes of bioconjugates with improved properties. Here, we have systematically evaluated 2-sulfonylpyrimidines as covalent warheads for the mild, chemoselective and metal free cysteine S-arylation. 2-sulfonylpyrimidines react rapidly with cysteine, resulting in stable S-heteroarylated adducts at neutral pH. Fine tuning the heterocyclic core and exocyclic leaving group allowed predictable SNAr reactivity with model tripeptide glutathione in vitro, covering 9 orders of magnitude. We achieved extremely fast chemo- and regio- specific arylation of a mutant p53 protein, and confirmed arylation sites by protein X-ray crystallography. Hence, we report the first example of a protein site specifically S-arylated with iodo-aromatic motifs. Overall, this study provides the most comprehensive structure-reactivity relationship to date on heteroaryl sulfones, and highlights 2-sulfonylpyrimidine as a synthetically tractable and protein compatible covalent motif for targeting reactive cysteines, expanding the arsenal of tunable warheads for modern covalent ligand discovery.

OBJECTIVE To validate the performance of a natural language processing (NLP) model in characterizing the quality of feedback provided to surgical trainees. DESIGN Narrative surgical resident feedback transcripts were collected from a large academic institution and classified for quality by trained coders. 75% of classified transcripts were used to train a logistic regression NLP model and 25% were used for testing the model. The NLP model was trained by uploading classified transcripts and tested using unclassified transcripts. The model then classified those transcripts into dichotomized high- and low- quality ratings. Model performance was primarily assessed in terms of accuracy and secondary performance measures including sensitivity, specificity, and area under the receiver operating characteristic curve (AUROC). SETTING A surgical residency program based in a large academic medical center. PARTICIPANTS All surgical residents who received feedback via the Society for Improving Medical Professional Learning smartphone application (SIMPL, Boston, MA) in August 2019. RESULTS The model classified the quality (high vs. low) of 2,416 narrative feedback transcripts with an accuracy of 0.83 (95% confidence interval: 0.80, 0.86), sensitivity of 0.37 (0.33, 0.45), specificity of 0.97 (0.96, 0.98), and an area under the receiver operating characteristic curve of 0.86 (0.83, 0.87). CONCLUSIONS The NLP model classified the quality of operative performance feedback with high accuracy and specificity. NLP offers residency programs the opportunity to efficiently measure feedback quality. This information can be used for feedback improvement efforts and ultimately, the education of surgical trainees.

Polygenic adaptation is thought to be ubiquitous, yet remains poorly understood. Here, we model this process analytically, in the plausible setting of a highly polygenic, quantitative trait that experiences a sudden shift in the fitness optimum. We show how the mean phenotype changes over time, depending on the effect sizes of loci that contribute to variance in the trait, and characterize the allele dynamics at these loci. Notably, we describe the two phases of the allele dynamics: The first is a rapid phase, in which directional selection introduces small frequency differences between alleles whose effects are aligned with or opposed to the shift, ultimately leading to small differences in their probability of fixation during a second, longer phase, governed by stabilizing selection. As we discuss, key results should hold in more general settings and have important implications for efforts to identify the genetic basis of adaptation in humans and other species.

As a contribution to the more general discussion on causes of language endangerment and death, we describe the language ecologies of four related languages (Bà Mambila [mzk]/[mcu], Sombә (Somyev or Kila) [kgt], Oumyari Wawa [www], Njanga (Kwanja) [knp]) of the Cameroon-Nigeria borderland to reach an understanding of the factors and circumstances that have brought two of these languages, Sombә and Njanga, to the brink of extinction; a third, Oumyari, is unstable/eroded, while Bà Mambila is stable. Other related languages of the area, also endangered and in one case extinct, fit into our discussion, though with less focus. We argue that an understanding of the language ecology of a region (or of a given language) leads to an understanding of the vitality of a language. Language ecology seen as a multilayered phenomenon can help explain why the four languages of our case studies have different degrees of vitality. This has implications for how language change is conceptualised: we see multilingualism and change (sometimes including extinction) as normative.

Aim To assess feasibility of a novel remotely-supervised exercise programme at a vascular hub during the COVID-19 lockdown. Methods Participants with arterial claudication (ABPI Results 12 participants were enrolled, of these 2 participants were unsuitable. Median age was 63 years and 2 (20%) were female. Baseline median ABPI was 0.7 (IQR 0.5-0.8), median baseline absolute walking distance was 75m (IQR 50-140) and median baseline QoL was 51/80 (IQR 15-79). 7 participants (70%) successfully completed the programme and were discharged. Their median daily longest walk was 2000m (IQR 200-4000) and QoL scores improved to 6/80 (IQR 2-20) (p = 0.02). Remaining 3 participants required revascularisation for disease progression. Reimbursement tariffs for the supervised exercise programme were £700 per patient, whereas for revascularisation were £2000 - £5000. Conclusion Remotely supervised exercise was feasible and improved walking distance and quality of life in 70% of participants. Approximately £3000 per patient was saved from a reduction in revascularisation procedures in our unit.

Genetic testing can provide definitive molecular diagnoses and guide clinical management decisions from preconception through adulthood. Innovative solutions for scaling clinical genomics services are necessary if they are to transition from a niche specialty to a routine part of patient care. The expertise of specialists, like genetic counselors and medical geneticists, has traditionally been relied upon to facilitate testing and follow-up, and while ideal, this approach is limited in its ability to integrate genetics into primary care. As individuals, payors, and providers increasingly realize the value of genetics in mainstream medicine, several implementation challenges need to be overcome. These include electronic health record integration, patient and provider education, tools to stay abreast of guidelines, and simplification of the test ordering process. Currently, no single platform offers a holistic view of genetic testing that streamlines the entire process across specialties that begins with identifying at-risk patients in mainstream care settings, providing pretest education, facilitating consent and test ordering, and following up as a "genetic companion" for ongoing management. We describe our vision for using software that includes clinical-grade chatbots and decision support tools, with direct access to genetic counselors and pharmacists within a modular, integrated, end-to-end testing journey.

Lymphatic filariasis (LF) and onchocerciasis are priority neglected tropical diseases targeted for elimination. The only safe drug treatment with substantial curative activity against the filarial nematodes responsible for LF (Brugia malayi, Wuchereria bancrofti) or onchocerciasis (Onchocerca volvulus) is doxycycline. The target of doxycycline is the essential endosymbiont, Wolbachia. Four to six weeks doxycycline therapy achieves >90% depletion of Wolbachia in worm tissues leading to blockade of embryogenesis, adult sterility and premature death 18–24 months post-treatment. Long treatment length and contraindications in children and pregnancy are obstacles to implementing doxycycline as a public health strategy. Here we determine, via preclinical infection models of Brugia malayi or Onchocerca ochengi that elevated exposures of orally-administered rifampicin can lead to Wolbachia depletions from filariae more rapidly than those achieved by doxycycline. Dose escalation of rifampicin achieves >90% Wolbachia depletion in time periods of 7 days in B. malayi and 14 days in O. ochengi. Using pharmacokinetic-pharmacodynamic modelling and mouse-human bridging analysis, we conclude that clinically relevant dose elevations of rifampicin, which have recently been determined as safe in humans, could be administered as short courses to filariasis target populations with potential to reduce anti-Wolbachia curative therapy times to between one and two weeks.

Lymphatic filariasis and onchocerciasis are parasitic helminth diseases, which cause severe morbidities such as elephantiasis, skin disease and blindness, presenting a major public health burden in endemic communities. The anti-Wolbachia consortium (A·WOL: http://www.a-wol.com/) has identified a number of registered antibiotics that target the endosymbiotic bacterium, Wolbachia, delivering macrofilaricidal activity. Here we use pharmacokinetics/pharmacodynamics (PK/PD) analysis to rationally develop an anti-Wolbachia chemotherapy by linking drug exposure to pharmacological effect. We compare the pharmacokinetics and anti-Wolbachia efficacy in a murine Brugia malayi model of minocycline versus doxycycline. Doxycycline exhibits superior PK in comparison to minocycline resulting in a 3-fold greater exposure in SCID mice. Monte-Carlo simulations confirmed that a bi-daily 25-40 mg/Kg regimen is bioequivalent to a clinically effective 100-200 mg/day dose for these tetracyclines. Pharmacodynamic studies showed that minocycline depletes Wolbachia more effectively than doxycycline (99.51% vs. 90.35%) after 28 day 25 mg/Kg bid regimens with a more potent block in microfilarial production. PK/PD analysis predicts that minocycline would be expected to be 1.7 fold more effective than doxycycline in man despite lower exposure in our infection models. Our findings warrant onward clinical investigations to examine the clinical efficacy of minocycline treatment regimens against lymphatic filariasis and onchocerciasis.

Significance Filarial nematode infections, caused by Wuchereria bancrofti , Brugia malayi (elephantiasis), and Onchocerca volvulus (river blindness) infect 150 million of the world’s poorest populations and cause profound disability. Standard treatments require repetitive, long-term, mass drug administrations and have failed to interrupted transmission in certain sub-Saharan African regions. A drug cure using doxycycline, which targets the essential filarial endosymbiont Wolbachia , is clinically effective but programmatically challenging to implement due to long treatment durations and contraindications. Here we provide proof-of-concept of a radical improvement of targeting Wolbachia via identification of drug synergy between the anthelmintic albendazole and antibiotics. This synergy enables the shortening of treatment duration of macrofilaricidal anti- Wolbachia based treatments from 4 wk to 7 d with registered drugs ready for clinical testing.

Lymphatic filariasis (LF) and onchocerciasis are priority neglected tropical diseases targeted for elimination. The only safe drug treatment with substantial curative activity against the filarial nematodes responsible for LF (Brugia malayi, Wuchereria bancrofti) or onchocerciasis (Onchocerca volvulus) is doxycycline. The target of doxycycline is the essential endosymbiont, Wolbachia. Four to six weeks doxycycline therapy achieves >90% depletion of Wolbachia in worm tissues leading to blockade of embryogenesis, adult sterility and premature death 18–24 months post-treatment. Long treatment length and contraindications in children and pregnancy are obstacles to implementing doxycycline as a public health strategy. Here we determine, via preclinical infection models of Brugia malayi or Onchocerca ochengi that elevated exposures of orally-administered rifampicin can lead to Wolbachia depletions from filariae more rapidly than those achieved by doxycycline. Dose escalation of rifampicin achieves >90% Wolbachia depletion in time periods of 7 days in B. malayi and 14 days in O. ochengi. Using pharmacokinetic-pharmacodynamic modelling and mouse-human bridging analysis, we conclude that clinically relevant dose elevations of rifampicin, which have recently been determined as safe in humans, could be administered as short courses to filariasis target populations with potential to reduce anti-Wolbachia curative therapy times to between one and two weeks.

Lymphatic filariasis and onchocerciasis are parasitic helminth diseases, which cause severe morbidities such as elephantiasis, skin disease and blindness, presenting a major public health burden in endemic communities. The anti-Wolbachia consortium (A·WOL: http://www.a-wol.com/) has identified a number of registered antibiotics that target the endosymbiotic bacterium, Wolbachia, delivering macrofilaricidal activity. Here we use pharmacokinetics/pharmacodynamics (PK/PD) analysis to rationally develop an anti-Wolbachia chemotherapy by linking drug exposure to pharmacological effect. We compare the pharmacokinetics and anti-Wolbachia efficacy in a murine Brugia malayi model of minocycline versus doxycycline. Doxycycline exhibits superior PK in comparison to minocycline resulting in a 3-fold greater exposure in SCID mice. Monte-Carlo simulations confirmed that a bi-daily 25–40 mg/Kg regimen is bioequivalent to a clinically effective 100–200 mg/day dose for these tetracyclines. Pharmacodynamic studies showed that minocycline depletes Wolbachia more effectively than doxycycline (99.51% vs. 90.35%) after 28 day 25 mg/Kg bid regimens with a more potent block in microfilarial production. PK/PD analysis predicts that minocycline would be expected to be 1.7 fold more effective than doxycycline in man despite lower exposure in our infection models. Our findings warrant onward clinical investigations to examine the clinical efficacy of minocycline treatment regimens against lymphatic filariasis and onchocerciasis.

Inappropriate sexual behaviour (ISB) within older adult populations is arguably overlooked within the literature in comparison to other challenging behaviour such as aggression, yet the impact on service users and staff is equally disruptive and demanding. Additionally, there can be stigma attached to ISB. Inconsistencies in terminology and lack of measurement tools for ISB limit the degree to which such behaviour can be identified, reported and managed and as a result prevalence rates vary considerably.The St Andrew’s Sexual Behaviour Assessment (SASBA: Knight et al., 2008), based on the Overt Aggression Scale – Modified for Neurorehabilitation (OAS-MNR: Alderman et al., 1997), was conceived to increase knowledge and understanding about ISB, provide clinical information to inform treatment, and make available a means of enabling appropriate, open discussion about the subject. The scale allows continuous observations of four categories of ISB, each with four levels of severity, which were developed with reference to relevant literature.Information captured using the SASBA has been demonstrated to meaningfully contribute to a formulation about ISB, which can underpin the design of an appropriate intervention, and to measure outcome. Field data using SASBA has led to further insight about the nature of ISB within older adult populations. Clinical uses of the scale are outlined and the associated benefits and limitations are discussed.

This paper reflects on the development of community groups in partnership with service users and voluntary organisations. Issues of power and the need to deconstruct clinical psychology practice are explored.

This article investigates the impact of the introduction of a child-focused cognitive behaviour therapy clinic in the child and adolescent mental health service based at Peterborough. Information was gathered over a 12-month period, focusing on service user experience in addition to therapy outcomes.

The present study used archival clinical data to analyze the delivery and effectiveness of prolonged exposure (PE) and ancillary services for posttraumatic stress disorder (PTSD) among Operation Enduring Freedom, Operation Iraqi Freedom, and Operation New Dawn veterans (N = 69) with histories of mild to severe traumatic brain injury (TBI). Data from standard clinical assessments of veterans and active duty personnel treated in both inpatient and outpatient programs at 2 Department of Veteran Affairs medical centers were examined. Symptoms were assessed with self-report measures of PTSD (PTSD Checklist) and depression (Beck Depression Inventory-II) before and throughout therapy. Mixed linear models were utilized to determine the slope of reported symptoms throughout treatment, and the effects associated with fixed factors such as site, treatment setting (residential vs. outpatient), and TBI severity were examined. Results demonstrated significant decreases in PTSD, B = -3.00, 95% CI [-3.22, -2.78]; t(210) = -13.5; p.001, and in depressive symptoms, B = -1.46, 95% CI [-1.64, -1.28]; t(192) = -8.32; p.001. The effects of PE treatment did not differ by clinical setting and participants with moderate to severe injuries reported more rapid gains than those with a history of mild TBI. The results provide evidence that PE may well be effective for veterans with PTSD and TBI.

(2007). Given that there is much poverty on planet Earth, should nations be investing in the exploration of space? Transactions of the Royal Society of South Africa: Vol. 62, No. 1, pp. 37-38.