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Introduction and Objectives: Tralokinumab-a biological that specifically targets interleukin-13-is one of the newer advanced systemic treatments for patients with moderate-to-severe atopic dermatitis (AD). Although safety and efficacy have been shown in phase-III clinical trials, daily practice data are needed. Therefore, the aim of this study was to evaluate 28-week safety and effectiveness, serum proteins and total IgE levels in adult AD patients treated with tralokinumab in daily practice., Materials and Methods: Data of all adult AD patients who started treatment with tralokinumab and participated in the BioDay registry were collected at baseline, and after 4,16 and 28 weeks of treatment. Clinical efficacy was evaluated by clinical outcome measures, such as the Eczema Area and Severity Index (EASI) as well as patient-reported outcome measures, such as the numerical rating scale (NRS) for pruritus. Adverse events were evaluated. In a subgroup of patients, 18 proteins as well as total IgE levels were measured in serum., Results: A total of 84 patients were included, of whom 39 were dupilumab-naïve (D-naïve) and 45 were dupilumab non-naïve (D-non-naïve) patients. All primary outcomes significantly improved during 28 weeks of tralokinumab treatment and the probability of achieving EASI ≤ 7 and NRS-pruritis ≤ 4 was 75.8% (56.9-88.2) and 51.4% (28.0-74.2), respectively. The disease severity-associated proteins TARC/CCL17 and PARC/CCL18 decreased during treatment, and total IgE levels significantly decreased in the D-naïve patients. The most reported adverse events were eye disorders (n = 24, 28.6%). A total of 23 patients (27.4%) discontinued treatment due to adverse events and/or ineffectiveness, with hair loss being the most common adverse event leading to treatment discontinuation (n = 6)., Conclusion: Tralokinumab is an effective treatment for moderate-to-severe AD in adult patients, in both dupilumab-naïve patients and patients who previously failed on dupilumab treatment. The clinical effect is supported by the biological data., (© 2024 The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Bovine tuberculosis (bTB) is a chronic disease caused by members of the Mycobacterium tuberculosis complex (MTBC) that ultimately leads to the development of progressive granulomatous lesions. Although the disease is widespread, especially in crossbred cattle in Ethiopia, routine investigations and surveillance are lacking. Thus, the aim of this study was to determine the prevalence, associated risk factors, and species of mycobacteria causing bTB in slaughtered cattle at four slaughterhouses in Central Ethiopia., Methods: Postmortem examination of 7,640 cattle was conducted using a cross-sectional slaughterhouse survey. A total of 388 tuberculous-like lesions (TBLs) were collected from 173 animals and cultured. Six target genes were used to differentiate mycobacterial species using multiplex real-time PCR (mRT-PCR). Multivariate logistic regression analyses and related odds ratios (ORs) were used to gauge the strength of the associations between risk factors, TBL incidence and culture growth., Results: The prevalence of TBL was 2.3% (95% CI = 2.0-2.6). Logistic regression analysis indicated an increased risk of TBL in crossbred cattle (OR = 11.8, 95% CI: 6.4, 21.2, p < 0.001). Animals slaughtered at Adama (OR = 3.2, 95% CI: 1.2, 7.3, p = 0.009) or Burayu (OR = 5.8, 95% CI: 3.9, 8.9, p < 0.001) had a greater risk of TBL than those slaughtered at Sululta. There were significantly more TBL-positive lesions in the lungs and lymph nodes related to the lung (OR = 7.1; 95% CI: 2.7, 24.5, p < 0.001) and the head lymph node (OR = 5.6; 95% CI: 1.8, 21.7; p = 0.006) compared to gut associated lymph nodes. Among the 173 TBL-positive animals, 36% (95% CI = 28.8, 43.2), and among the 388 TBL-positive tissues, 24.2% (95% CI = 20, 29) were culture and mRT-PCR positive. All the culture-generated isolates were positive for M. bovis in mRT-PCR. Among them, two animals had mixed infections including one zebu cattle tested positive for both M. caprae and M. bovis, and a crossbred cow tested positive for both M. tuberculosis and M. bovis in mRT-PCR. This suggests persistent transmission within the cattle population, posing a substantial public health threat., Conclusion: This study revealed an eleven-fold greater risk of bTB-related lesions in crossbred cattle compared to local zebu cattle. This finding highlights the necessity for targeted interventions, continuous vigilance, and thorough carcass inspection to mitigate public health risks., (© 2024. The Author(s).)

Introduction: Health professions training programmes face increasing reports of professionalism lapses, which can delay, or end, trainee progression. How programmes respond to professionalism lapses to facilitate professional identity development has not been clarified. The objective of this study is to identify factors that facilitate and impair transformations around professionalism lapses in health professions training programmes., Methods: We conducted a qualitative study interviewing 5 faculty and 20 trainees with firsthand or secondhand experience with professionalism lapses from a range of health professions training programmes at McMaster University. Using reflexive thematic analysis, we coded verbatim transcripts informed by the lenses of social and transformative learning theories. We constructed themes through iterative and comparative analysis, seeking meaningful variation across professions and triangulating faculty and trainee perspectives., Results: Four themes were constructed. First, lapses are in the eye of the beholder with personal definitions intersecting with institutional and situation norms. Difficulties exist in recognising and convincing trainees to respond to lapses that are perceived to be minor or subject to interpretation. Second, responses to professionalism lapses occurred within power hierarchies, which impacted how trainees reacted to the remediation process, risked superficial trainee responses to concerns and led to concerns around inequitable treatment in how standards were applied. Third, fostering transformation involves building trainee confidence, agency, trust and engagement. Focused support and advocacy for trainees can empower and promote agency in tackling disorienting lapses. Fourth, perspective shifts involve deep engagement over time, including but not limited to self-reflection, structured discussion and seeking support., Discussion: Identifying and addressing professionalism lapses is complex and requires nuanced and contextual exploration of personal, institutional and situational dynamics at play. By fostering environments that promote genuine reflection and dialogue and focus on building trainee confidence, agency, trust and engagement, health professions training programmes can better support trainees in navigating these complex situations and contribute to the broader goal of socialising to a professional culture and practice., (© 2024 The Author(s). Medical Education published by Association for the Study of Medical Education and John Wiley & Sons Ltd.)

Sodium glucose cotransporter 2 inhibitors (SGLT2i) constitute the only medication class that consistently prevents or attenuates human heart failure (HF) independent of ejection fraction. We have suggested earlier that the protective mechanisms of the SGLT2i Empagliflozin (EMPA) are mediated through reductions in the sodium hydrogen exchanger 1 (NHE1)-nitric oxide (NO) pathway, independent of SGLT2. Here, we examined the role of SGLT2, NHE1 and NO in a murine TAC/DOCA model of HF. SGLT2 knockout mice only showed attenuated systolic dysfunction without having an effect on other signs of HF. EMPA protected against systolic and diastolic dysfunction, hypertrophy, fibrosis, increased Nppa/Nppb mRNA expression and lung/liver edema. In addition, EMPA prevented increases in oxidative stress, sodium calcium exchanger expression and calcium/calmodulin-dependent protein kinase II activation to an equal degree in WT and SGLT2 KO animals. In particular, while NHE1 activity was increased in isolated cardiomyocytes from untreated HF, EMPA treatment prevented this. Since SGLT2 is not required for the protective effects of EMPA, the pathway between NHE1 and NO was further explored in SGLT2 KO animals. In vivo treatment with the specific NHE1-inhibitor Cariporide mimicked the protection by EMPA, without additional protection by EMPA. On the other hand, in vivo inhibition of NOS with L-NAME deteriorated HF and prevented protection by EMPA. In conclusion, the data support that the beneficial effects of EMPA are mediated through the NHE1-NO pathway in TAC/DOCA-induced heart failure and not through SGLT2 inhibition., (© 2024. The Author(s).)

Purpose: The relationship between refractive error at age 1 and the risk of developing amblyopia or accommodative esotropia, and the protection offered by early glasses, is unknown. These are determined in the Early Glasses Study, a prospective, population-based, longitudinal, randomized controlled study. We report baseline findings., Methods: Healthy children aged 12-18 months were recruited at Children's Healthcare Centres (CHCs) and received an entry orthoptic examination followed by cycloplegic retinoscopy. Children with amblyopia, strabismus, ophthalmic disease or very high refractive error were excluded. Those exceeding the AAPOS 2003 Criteria (> + 3.5D spherical equivalent (SE), > 1.5D astigmatism, > 1.5D anisometropia) were randomized into wearing glasses or not, and are followed-up by research orthoptists. Other children are followed-up by regular vision screening at CHCs and visual acuity is measured in all children at age 4., Results: Parents of 865 children were called, 123 were excluded. Of 742 children enrolled, 601 underwent the entry orthoptic examination at age 14.5 ± 1.7 months. Mean SE was + 1.73 ± 1.18D, astigmatism -0.70 ± 0.44D, anisometropia 0.21D (IQR: 0-0.25). Of 62 (10.3%) children exceeding the Criteria, 52 were randomized into wearing glasses or not. Of 539 other children, 522 are followed up at CHCs. In total, 31 were excluded: 2 had strabismus and amblyopia, 7 strabismus, 2 amblyopia suspect, 1 strabismus suspect, 1 squinting during sinusitis, 4 excessive refractive error, 9 myopia, 2 ptosis, 1 oculomotor apraxia, 1 Duane syndrome, 1 congenital nystagmus., Conclusion: Prevalence of strabismus (10/601) was as expected, but prevalence of amblyopia (2/601) was low, suggesting that common amblyopia develops later than generally thought., Key Messages: What is known High refractive errors cause amblyopia, but no study has determined the exact relationship between the kind and size of refractive error at age 1 and the risk to develop amblyopia, and assessed the protective effect of glasses in a controlled, population-based, longitudinal study. What is new At baseline, 601 children received a full orthoptic examination followed by retinoscopy in cycloplegia at the age of 14.5 ± 1.7 months; 10.3% had high refractive error exceeding spherical equivalent > + 3.5D, > 1.5D astigmatism, > 1D oblique astigmatism or > 1.5D anisometropia. The prevalence of amblyopia was lower (0.3%) than expected, suggesting that most amblyopia develops after the first year of life. The prevalence of anisometropia, associated with amblyopia in older children, was low (0.8%)., Competing Interests: Declarations. Ethics approval: The study was approved by the Medical Ethics Review Committee (MERC) of the Erasmus University Medical Center on April 30th, 2021, and was carried out in accordance with the ethical conduct and juridical laws laid down in the Declaration of Helsinki, version 2013. Consent to participate: All parents of enrolled children were required to provide written consent by both parents or legal representative or guardian prior to the Entry Orthoptic Examination. Consent for publication: Not applicable, all data is presented anonymously. Conflict of interest: The authors have no relevant financial or non-financial interest to disclose., (© 2024. The Author(s).)

People are influenced by members of high-status groups and members of their ingroup. These principles of "status orientation" and "ingroup orientation" can imply opposing forces for people of lower status. Are lower-status individuals more influenced by members of higher-status outgroups or by members of their lower-status ingroup? Engaging status characteristics theory and self-categorization theory, we predict that status orientation is relatively stronger on questions about facts, which have an objectively correct answer, whereas ingroup orientation is stronger when it comes to 'opinion questions' that have no objectively correct answer. Results of an online survey experiment confirm that on factual questions, less-educated individuals are more strongly influenced by highly-educated outgroup individuals than by less-educated ingroup individuals. On opinion questions, we observe relatively weaker status orientation, with status orientation and ingroup orientation being about equally strong. These findings suggest that it is harder to reach societal consensus on opinion questions than on factual questions., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Chronic kidney disease (CKD) is a prevalent disease among felids; yet its origin is still poorly understood, and the disease often remains asymptomatic for years, underscoring the need for early diagnosis. This study aimed to investigate the diagnostic value of urinalysis in accurately staging CKD, particularly as routine health checks in large felids often overlook its significance. In this research, ultrasound-guided cystocentesis (UGC) was performed on 50 captive nondomestic felids during routine veterinary health checks under general anesthesia. Urinalysis included microscopic examination of the sediment, measurement of urine specific gravity (USG) and protein to creatinine ratio (UPC). Additional serum kidney markers, such as creatinine and symmetric dimethylarginine, were compared with USG and UPC to assess their diagnostic value as urinary biomarkers. The results demonstrated proteinuria (UPC > 0.4) or borderline proteinuria (UPC 0.2-0.4) in 49% of the animals. Among these cases, 62% were of renal origin, and 38% were postrenal causes. USG was significantly higher in felids with borderline proteinuria compared to those with proteinuria. A moderate, but significant negative correlation between serum parameters and USG was observed, emphasizing the importance of assessing both diagnostic parameters during kidney evaluations. Additionally, felids with CKD have an increased risk of urinary tract infections, necessitating microscopic urinalysis and bacterial culture analysis. Abnormalities, including hematuria, pyuria, crystalluria, and bacteriuria, were found in approximately 38% of cases through microscopical examination of urine. No complications associated with UGC were observed and abnormal findings were detected in 60% of the cases. Based on these results, the authors recommend the inclusion of UGC and urinalysis as standard diagnostic tools in general health checks for nondomestic felids. This approach provides valuable insights into the early detection and staging of CKD, supporting early intervention and supportive medical care to prolong renal health in these animals.

Severe uveitis is a rare complication of interleukin-4 receptor alpha blocking by dupilumab in topic dermatitis (AD) patients. The aim of this study was to describe five moderate-to-severe AD patients who developed uveitis during dupilumab treatment and to compare the proteomic profile of aqueous humor (AqH) of dupilumab-associated uveitis (n=3/5 available samples) with non-infectious uveitis (n=27) and cataract controls (n=11). Included patients were treated at the University Medical Center Utrecht (the Netherlands). Active dupilumab-associated uveitis complicated by serous detachment, cystoid macular edema, or secondary glaucoma developed within a median of 6.0 months (interquartile range 2.3-16.5 months) after starting dupilumab. Uveitis resolved after discontinuation of dupilumab and/or treatment with local or systemic corticosteroids. Proteomic profiling of AqH revealed that the molecular profile of dupilumab-associated uveitis resembled that of non-infectious uveitis. In conclusion, dupilumab-associated uveitis is a severe adverse event of dupilumab therapy, requiring urgent referral to an ophthalmologist.

In aged humans and mice, aggregates of hypobranched glycogen molecules called polyglucosan bodies (PGBs) accumulate in hippocampal astrocytes. PGBs are known to drive cognitive decline in neurological diseases but remain largely unstudied in the context of typical brain aging. Here, we show that PGBs arise in autophagy-dysregulated astrocytes of the aged C57BL/6J mouse hippocampus. To map the genetic cause of age-related PGB accumulation, we quantified PGB burden in 32 fully sequenced BXD-recombinant inbred mouse strains, which display a 400-fold variation in hippocampal PGB burden at 16-18 months of age. A major modifier locus was mapped to chromosome 1 at 72-75 Mb, which we defined as the Pgb1 locus. To evaluate candidate genes and downstream mechanisms by which Pgb1 controls the aggregation of glycogen, extensive hippocampal transcriptomic and proteomic datasets were produced for aged mice of the BXD family. We utilized these datasets to identify Smarcal1 and Usp37 as potential regulators of PGB accumulation. To assess the effect of PGB burden on age-related cognitive decline, we performed phenome-wide association scans, transcriptomic analyses as well as conditioned fear memory and Y-maze testing. Importantly, we did not find any evidence suggesting a negative impact of PGBs on cognition. Taken together, our study demonstrates that the Pgb1 locus controls glycogen aggregation in astrocytes of the aged hippocampus without affecting age-related cognitive decline.

Background: Mitral annular flutter (MAF) is the most common left atrial macro-reentrant arrhythmia following catheter ablation of atrial fibrillation (AF). The best ablation approach for this arrhythmia remains unclear., Methods: This single-center, retrospective study sought to compare the acute and long-term outcomes of patients with MAF treated with an anterior mitral line (AML) versus a mitral isthmus line (MIL). Acute ablation success, complication rates, and long-term arrhythmia recurrence were compared between the two groups., Results: Between 2015 and 2021, a total of 81 patients underwent ablation of MAF (58 with an AML and 23 with a MIL). Acute procedural success defined as bidirectional block was achieved in 88% of the AML and 91% of the MIL patients respectively (p = 1.0). One year freedom from atrial arrhythmias was 49.5% versus 77.5% and at 4 years was 24% versus 59.6% for AML versus MIL, respectively (hazard ratio [HR]: 0.38, confidence interval [CI]: 0.17-0.82, p = .009). Fewer patients in the MIL group had recurrent atrial flutter when compared to the AML group (HR: 0.32, CI: 0.12-0.83, p = .009). The incidence of recurrent AF, on the other side, was not different between both groups (21.7% vs. 18.9%; p = .76). There were no serious adverse events in either group., Conclusion: In this retrospective study of patients with MAF, a MIL compared to AML was associated with a long-term reduction in recurrent atrial arrhythmias driven by a reduction in macroreentrant atrial flutters., (© 2024 Wiley Periodicals LLC.)

Bovine tuberculosis (bTB) is endemic and has a substantial impact on the livestock sector in Ethiopia and other low and middle-income countries (LMICs). With a national emphasis on dairy farm intensification to boost milk production and spur economic growth, the incidence of bTB is anticipated to rise. However, Ethiopia, like other LMICs, lacks a comprehensive national bTB control strategy due to the economic and social infeasibility of traditional test-and-cull (TC) approaches. To inform the development of such a strategy, we evaluated the effectiveness and feasibility of TC and test-and-segregation (TSg) strategies for bTB control on Ethiopian dairy farms. A TC approach was used at Farm A [N = 62; comparative cervical test (CCT) > 4 mm, starting prevalence 11.3%] while TSg was implemented at Farm B (N = 45; CCT > 4 mm, prevalence 22.2%), with testing intervals of 2-4 months. Both strategies achieved a reduction in bTB prevalence to 0%, requiring seven rounds of TC over 18 months at Farm A, and five rounds of TSg over 12 months at Farm B's negative herd. The results show that adopting more sensitive thresholds [CCT > 0 mm or single cervical test (SCT) > 2 mm] during later rounds was pivotal in identifying and managing previously undetected infections, emphasizing the critical need for optimized diagnostic thresholds. Cost analysis revealed that TC was approximately twice as expensive as TSg, primarily due to testing, labor, and cow losses in TC, versus construction of new facilities and additional labor for TSg. This underscores the economic and logistical challenges of bTB management in resource-limited settings. Taken together, our study highlights an urgent need for the exploration of alternative approaches including TSg and or vaccination to mitigate within herd transmission and enable implementation of bTB control in regions where TC is not feasible., (© 2024. The Author(s).)

Decreased nicotinamide adenine dinucleotide (NAD + ) levels contribute to various pathologies such as ageing, diabetes, heart failure and ischemia-reperfusion injury (IRI). Nicotinamide riboside (NR) has emerged as a promising therapeutic NAD + precursor due to efficient NAD + elevation and was recently shown to be the only agent able to reduce cardiac IRI in models employing clinically relevant anesthesia. However, through which metabolic pathway(s) NR mediates IRI protection remains unknown. Furthermore, the influence of insulin, a known modulator of cardioprotective efficacy, on the protective effects of NR has not been investigated. Here, we used the isolated mouse heart allowing cardiac metabolic control to investigate: (1) whether NR can protect the isolated heart against IRI, (2) the metabolic pathways underlying NR-mediated protection, and (3) whether insulin abrogates NR protection. NR protection against cardiac IRI and effects on metabolic pathways employing metabolomics for determination of changes in metabolic intermediates, and 13 C-glucose fluxomics for determination of metabolic pathway activities (glycolysis, pentose phosphate pathway (PPP) and mitochondrial/tricarboxylic acid cycle (TCA cycle) activities), were examined in isolated C57BL/6N mouse hearts perfused with either (a) glucose + fatty acids (FA) ("mild glycolysis group"), (b) lactate + pyruvate + FA ("no glycolysis group"), or (c) glucose + FA + insulin ("high glycolysis group"). NR increased cardiac NAD + in all three metabolic groups. In glucose + FA perfused hearts, NR reduced IR injury, increased glycolytic intermediate phosphoenolpyruvate (PEP), TCA intermediate succinate and PPP intermediates ribose-5P (R5P) / sedoheptulose-7P (S7P), and was associated with activated glycolysis, without changes in TCA cycle or PPP activities. In the "no glycolysis" hearts, NR protection was lost, whereas NR still increased S7P. In the insulin hearts, glycolysis was largely accelerated, and NR protection abrogated. NR still increased PPP intermediates, with now high 13 C-labeling of S7P, but NR was unable to increase metabolic pathway activities, including glycolysis. Protection by NR against IRI is only present in hearts with low glycolysis, and is associated with activation of glycolysis. When activation of glycolysis was prevented, through either examining "no glycolysis" hearts or "high glycolysis" hearts, NR protection was abolished. The data suggest that NR's acute cardioprotective effects are mediated through glycolysis activation and are lost in the presence of insulin because of already elevated glycolysis., (© 2024. The Author(s).)

The maldistribution of family physicians challenges equitable primary care access in Canada. The Theory of Social Attachment suggests that preferential selection and distributed training interventions have potential in influencing physician disposition. However, evaluations of these approaches have focused predominantly on rural underservedness, with little research considering physician disposition in other underserved communities. Accordingly, this study investigated the association between the locations from which medical graduates apply to medical school, their undergraduate preclerkship, clerkship, residency experiences, and practice as indexed across an array of markers of underservedness. We built association models concerning the practice location of 347 family physicians who graduated from McMaster University's MD Program between 2010 and 2015. Postal code data of medical graduates' residence during secondary school, pre-clerkship, clerkship, residency and eventual practice locations were coded according to five Statistics Canada indices related to primary care underservedness: relative rurality, employment rate, proportion of visible minorities, proportion of Indigenous peoples, and neighbourhood socioeconomic status. Univariate and multivariable logistic regression models were then developed for each dependent variable (i.e., practice location expressed in terms of each index). Residency training locations were significantly associated with practice locations across all indices. The place of secondary school education also yielded significant relationships to practice location when indexed by employment rate and relative rurality. Education interventions that leverage residency training locations may be particularly influential in promoting family physician practice location. The findings are interpreted with respect to how investment in education policies can promote physician practice in underserved communities., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Atopic dermatitis (AD) is a chronic inflammatory skin disease for which new targeted therapies are currently available. Due to the increased rates of ocular surface disease (OSD) reported during treatment with these new targeted treatments, more insight into the occurrence and pathomechanism of OSD in moderate-to-severe AD patients is needed. Therefore, this review's first part highlights that most patients with moderate-to-severe AD already have characteristics of OSD before starting targeted treatment. Remarkably, not all AD patients with OSD report ocular symptoms. OSD in AD is associated with less conjunctival goblet cells (GC) compared to healthy controls. In addition, OSD severity in AD patients is associated with high AD activity, the presence of eyelid and/or facial eczema, and high levels of AD-related severity biomarkers in tear fluid. The second part of this review highlights that pre-existing ocular pathology (e.g. in combination with the use of ophthalmic medication or eyelid eczema) may be associated with the development of dupilumab-associated ocular surface disease (DAOSD). During dupilumab treatment, DAOSD (which can be new-onset OSD or worsening of pre-existing OSD) is observed in approximately one-third of the dupilumab-treated AD patients. Anti-inflammatory ophthalmic treatment improves DAOSD, and dose reduction of dupilumab may also be an effective treatment option. The pathomechanism of DAOSD is still not fully elucidated. In a prospective study low, but stable conjunctival GC numbers were observed in moderate-to-severe AD patients, before and during dupilumab treatment. However, the Mucin 5 AC (MUC5AC) expression of GCs decreased during dupilumab treatment, suggesting an impairment of the GC function by dupilumab treatment. In addition, higher dupilumab tear fluid levels were found in dupilumab-treated AD patients with moderate-to-severe OSD compared to patients with no or mild OSD, whereas the dupilumab serum levels are similar. Clinicians should be aware of the frequent occurrence of OSD in moderate-to-severe AD patients, and a low-threshold referral to an ophthalmologist is recommended., (© 2024 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)

Bacillus Calmette-Guérin (BCG) is a routinely used vaccine for protecting children against Mycobacterium tuberculosis that comprises attenuated Mycobacterium bovis . BCG can also be used to protect livestock against M. bovis ; however, its effectiveness has not been quantified for this use. We performed a natural transmission experiment to directly estimate the rate of transmission to and from vaccinated and unvaccinated calves over a 1-year exposure period. The results show a higher indirect efficacy of BCG to reduce transmission from vaccinated animals that subsequently become infected [74%; 95% credible interval (CrI): 46 to 98%] compared with direct protection against infection (58%; 95% CrI: 34 to 73%) and an estimated total efficacy of 89% (95% CrI: 74 to 96%). A mechanistic transmission model of bovine tuberculosis (bTB) spread within the Ethiopian dairy sector was developed and showed how the prospects for elimination may be enabled by routine BCG vaccination of cattle.

Objective: We investigated the presence of latent transition profiles in a sample of users of a cognitive-behavioral mental health app for the general population. Users' baseline characteristics were used as predictors of the profiles. The role of engagement with the app in the transition profiles was examined., Method: A total of 541 users completed the Patient Health Questionnaire-9 and the General Anxiety Disorder-7 when started using the app and 30 days after. Random-Intercept Latent Transition Analysis was implemented to identify users' profiles and transition patterns as classes. The age of the users and the Emotional Self-Awareness Scale-Revised (ESAS-R) were used as predictors of class membership at baseline. The Homework Rating Scale-Mobile Application (HRS-MA; as a measure of engagement) was used as a predictor of class membership at 30 days of app use., Results: A 3-class solution was obtained according to the severity of symptoms (from mild to moderately severe). Age and ESAS-R predicted class membership initially; the higher the age and ESAS-R, the higher the probability of starting using the app with lower distress levels. The HRS-MA predicted class membership at 30 days of app use; the higher the engagement for more symptomatic and younger users, the higher the probability of improvement. However, older users tended to engage less., Conclusion: Our findings underpin the relevance of easily accessible digital interventions for young adults with mild to moderate mental health problems. Further studies and developments are required to enhance these apps for older cohorts., (Copyright © 2023 Association for Behavioral and Cognitive Therapies. Published by Elsevier Ltd. All rights reserved.)

Background: Bovine tuberculosis (bTB) is a chronic disease that results from infection with any member of the Mycobacterium tuberculosis complex. Infected animals are typically diagnosed with tuberculin-based intradermal skin tests according to World Organization of Animal Health which are presently in use. However, tuberculin is not suitable for use in BCG-vaccinated animals due to a high rate of false-positive reactions. Peptide-based defined skin test (DST) antigens have been identified using antigens (ESAT-6, CFP-10 and Rv3615c) which are absent from BCG, but their performance in buffaloes remains unknown. To assess the comparative performance of DST with the tuberculin-based single intradermal test (SIT) and the single intradermal comparative cervical test (SICCT), we screened 543 female buffaloes from 49 organized dairy farms in two districts of Haryana state in India., Results: We found that 37 (7%), 4 (1%) and 18 (3%) buffaloes were reactors with the SIT, SICCT and DST tests, respectively. Of the 37 SIT reactors, four were positive with SICCT and 12 were positive with the DST. The results show that none of the animals tested positive with all three tests, and 6 DST positive animals were SIT negative. Together, a total of 43 animals were reactors with SIT, DST, or both, and the two assays showed moderate agreement (Cohen's Kappa 0.41; 95% Confidence Interval (CI): 0.23, 0.59). In contrast, only slight agreement (Cohen's Kappa 0.18; 95% CI: 0.02, 0.34) was observed between SIT and SICCT. Using a Bayesian latent class model, we estimated test specificities of 96.5% (95% CI, 92-99%), 99.7% (95% CI: 98-100%) and 99.0% (95% CI: 97-100%) for SIT, SICCT and DST, respectively, but considerably lower sensitivities of 58% (95% CI: 35-87%), 9% (95% CI: 3-21%), and 34% (95% CI: 18-55%) albeit with broad and overlapping credible intervals., Conclusion: Taken together, our investigation suggests that DST has a test specificity comparable with SICCT, and sensitivity intermediate between SIT and SICCT for the identification of buffaloes suspected of tuberculosis. Our study highlights an urgent need for future well-powered trials with detailed necropsy, with immunological and microbiological profiling of reactor and non-reactor animals to better define the underlying factors for the large observed discrepancies in assay performance, particularly between SIT and SICCT., (© 2024. The Author(s).)

Rationale: Primary care access challenges are experienced by many communities. In several jurisdictions, including Canada, family physicians (FP) have the professional autonomy to organize their practice in alignment with professional and personal interests. Although system-level interventions are tremendously important, investment in upstream interventions associated with the medical education of graduating FPs is a promising strategy for ameliorating primary healthcare access challenges., Aims and Objectives: This study investigates the medical education experiences that influence FP's decisions about practice locations in Canada., Methods: We conducted semistructured interviews with FPs who completed undergraduate and postgraduate medical training in Canada and now have a practice in Ontario, Canada. Interview data were coded and analysed using an unconstrained descriptive approach., Results: FPs preferred practice locations are intimately tied to their desired practice scope. Practice preferences were shaped through training experiences with patient populations, heightened clinical responsibilities, practice models and locations, professional mentorships and networks. Proximity to family, partner and lifestyle preferences, cultural connections and the available practice opportunities also shaped practice location decisions., Conclusion: Medical education influences the identification and refinement of professional family practice preferences. Health workforce policies and interventions should leverage medical education to promote more equitable primary healthcare access., (© 2023 The Authors. Journal of Evaluation in Clinical Practice published by John Wiley & Sons Ltd.)

Instability of the distal radioulnar joint and scapholunate dissociation may cause pain, functional impairment and subsequent arthrosis. There is no consensus about whether these injuries should be treated acutely in patients undergoing surgery for distal radial fractures. We conducted a prospective cohort study to determine whether concomitant distal radioulnar joint instability or scapholunate dissociation negatively influence patient-related outcomes in these patients. The primary outcome was the patient-reported wrist/hand evaluation at 6 and 12 months after surgery. Out of 62 patients, 58% and 27% had intraoperative distal radioulnar joint instability and scapholunate dissociation, respectively. No significant differences were found in patient-reported scores at follow-up between patients with stable and unstable distal radioulnar joints, nor between patients with and without scapholunate dissociation. Sixty-three per cent of patients with an unstable distal radioulnar joint during surgery were stable on retesting after 6 months. Our study suggests that a wait-and-see policy in these patients therefore seems reasonable. Level of evidence: III., Competing Interests: Declaration of conflicting interestsThe authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Non-melanoma skin cancers (NMSCs) occur frequently in the Caucasian population and are considered a burden for health care. Risk factors include ultraviolet (UV) radiation, ethnicity and immunosuppression. The incidence of NMSC is significantly higher in solid organ transplant recipients (SOTRs) than in immunocompetent individuals, due to immunosuppressive medication use by SOTRs. While the immunosuppressive agents, calcineurin inhibitors and purine analogues increase the incidence of NMSC in transplant recipients, mTOR inhibitors do not. This is most likely due to the different immunological pathways that are inhibited by each class of drug. This review will focus on what is currently known about the immune response against cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC), two of the main types of NMSC. Furthermore, we will describe the different classes of immunosuppressants given to SOTRs, which part of the immune system they target and how they can contribute to NMSC development. The risk of developing NMSC in SOTRs is the result of a combination of inhibiting immunological pathways involved in immunosurveillance against NMSC and the direct (pro/anti) tumor effects of immunosuppressants.

Background: Cavotricuspid isthmus (CTI) ablation requires permanent bidirectional block to prevent recurrence of typical atrial flutter (AFL). Catheter irrigation with half-normal saline (HNS) produces larger and deeper lesions in experimental models compared with normal saline (NS). This study was performed to compare the clinical efficacy and safety of HNS vs NS irrigation for typical AFL ablation., Methods: Sixty patients undergoing catheter ablation of typical AFL were randomized 1:1 to NS or HNS irrigation. Endpoints included time to CTI block, acute reconnection, incidence of steam pops, and recurrence of AFL during follow-up., Results: Baseline characteristics were comparable between both arms. The mean age of the patients was 68.5 ± 8.2 years, 20% were female, and 32% had atrial fibrillation before being enrolled. Bidirectional CTI block was obtained in all patients with no difference in time to CTI block between groups (6.4 ± 4.4 minutes vs 7.6 ± 4.5 minutes, respectively; P  = 0.15). There was a trend to less acute reconnection in the HNS group compared with NS (13.3% vs 26.6%; P  = 0.46). Steam pops occurred in 4 patients using HNS vs none in the NS group, but no major complications were observed. During the follow-up, rate of AFL recurrence was similar between groups (6.7% with HNS vs 10% with NS; P  = 0.5). There was no difference in time to recurrence (7.6 ± 6.9 vs 4.9 ± 4.5 months; P  = 0.6)., Conclusions: In this small pilot randomized controlled trial, there was no significant difference between HNS and NS for CTI ablation; however, HNS may increase the incidence of steam pops., (© 2023 The Authors.)

Background: Dupilumab-associated ocular surface disease (DAOSD) is frequently reported as side effect in atopic dermatitis (AD) patients. Therefore, the aim of this study was to investigate the frequency and severity of DAOSD, ophthalmic treatment response and to learn more about the effect of dupilumab on conjunctival goblet cells (GC)., Methods: This prospective study included dupilumab-treated AD patients between February 2020 and June 2022 from the University Medical Centre Utrecht. Patients were examined by an ophthalmologist and a dermatologist before start (baseline), and after 4 and 28 weeks of dupilumab treatment. Ophthalmological examination was assessed by the Utrecht Ophthalmic Inflammatory and Allergic disease (UTOPIA) score. DAOSD was defined as an increase in UTOPIA score of ≥3 points from baseline. To quantify conjunctival GCs and to investigate the percentage of Cytokeratin 19 (CK19)-CD45-Mucin 5 AC (MUC5AC)+ cells, conjunctival impression cytology samples were analysed., Results: Ocular surface disease (OSD) was present in 91.3% (n = 63/69) patients at baseline. DAOSD was observed in 28.9% (n = 20/69) patients, in whom GC numbers remained stable and the percentage of CK19-CD45-MUC5AC+ cells decreased at onset of DAOSD compared with baseline. After 28 weeks of dupilumab treatment, DAOSD was seen in 14.5% (n = 10/69) patients. Of the 85.5% (n = 59/69) patients without DAOSD or with controlled DAOSD at Week 28, 40.7% (n = 24/59) patients received anti-inflammatory ophthalmic drugs., Conclusions: Ocular surface disease is common in moderate-to-severe AD patients before starting dupilumab. During treatment with dupilumab DAOSD severity improves with early ophthalmic treatment. The decrease in percentage of CK19-CD45-MUC5AC+ cells during dupilumab treatment suggests an impairment of the GC function due to dupilumab treatment., (© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Introduction: The risk of typical atrial flutter (AFL) is increased proportionately to right atrial (RA) size or right atrial scarring that results in reduced conduction velocity. These characteristics result in propagation of a flutter wave by ensuring the macro re-entrant wave front does not meet its refractory tail. The time taken to traverse the circuit would take account of both of these characteristics and may provide a novel marker of propensity to develop AFL. Our goal was to investigate right atrial collision time (RACT) as a marker of existing typical AFL., Methods: This single-centre, prospective study recruited consecutive typical AFL ablation patients that were in sinus rhythm. Controls were consecutive electrophysiology study patients >18 years of age. While pacing the coronary sinus (CS) ostium at 600 ms, a local activation time map was created to locate the latest collision point on the anterolateral right atrial wall. This RACT is a measure of conduction velocity and distance from CS to a collision point on the lateral right atrial wall., Results: Ninety-eight patients were included in the analysis, 41 with atrial flutter and 57 controls. Patients with atrial flutter were older, 64.7 ± 9.7 versus 52.4 ± 16.8 years (<.001), and more often male (34/41 vs. 31/57 [.003]). The AFL group mean RACT (132.6 ± 17.3 ms) was significantly longer than that of controls (99.1 ± 11.6 ms) (p < .001). A RACT cut-off of 115.5 ms had a sensitivity and specificity of 92.7% and 93.0%, respectively for diagnosis of atrial flutter. A ROC curve indicated an AUC of 0.96 (95% CI: 0.93-1.0, p < .01)., Conclusion: RACT is a novel and promising marker of propensity for typical AFL. This data will inform larger prospective studies., (© 2023 The Authors. Journal of Cardiovascular Electrophysiology published by Wiley Periodicals LLC.)

Introduction: Pulmonary involvement in Osteogenesis Imperfecta (OI) can be severe but may be overlooked in milder cases. The Care4BrittleBones Foundation initiated this project to develop a set of global outcome measures focusing on respiratory-related issues in patients with OI. The objective was to reach an international consensus for a standardized set of outcomes and associated measuring instruments for the pulmonary care of individuals with OI. Based on the initial tests and questionnaires, we suggest parameters for when pulmonologists should seek guidance from the growing literature on OI pulmonary care and/or recognized experts in the field., Study Design and Methods: The project team consisted of a multidisciplinary mix of 12 people from six countries, including an OI patient representative, and facilitated by the Care4BrittleBones Foundation director. The International Consortium for Health Outcomes Measurement (ICHOM) process was followed, which includes the Delphi method, used to collect the opinions of the expert team. Patient input was present in each meeting due to the inclusion of a patient representative. In addition, online focus groups were held. They consisted of adults with OI from different countries, and they determined which questions matter the most to the OI community worldwide., Results: After three Delphi rounds, the expert team reached a consensus on the final set of measuring instruments, which included pulmonary function testing and patient self-reporting of symptoms related to breathing and sleep. Two questionnaires were decided upon: St. George's Respiratory Questionnaire (shortened version) and four questions regarding sleep. Patients should be screened for a history of pneumonia. Advanced testing for select patients by a pulmonologist would include further pulmonary function tests and a chest radiograph., Conclusions: A standardized set of outcome measures related to pulmonary care of individuals with OI was determined based on what is important to both experts and patients. This included patient-reported outcome measures and basic pulmonary function testing. Using these outcome measures, it can be determined which patients are at high risk for pulmonary complications., (Copyright © 2023 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Atopic dermatitis (AD) is a complex and highly heterogeneous inflammatory skin disease. Given the highly heterogeneous character of AD, it is unlikely that every patient will respond equally to a particular treatment. The recent introduction of novel targeted therapies for AD has driven the need for patient stratification based on immunologic biomarkers. We have reviewed the use of different types of biomarkers as potential tools in the movement toward personalized medicine in AD, comprising different ways of endotyping patients with AD based on immunologic profiles and predictive biomarkers. The application of biomarkers will result in better characterization and stratification of patients and allow better comparison of current and new treatments. The ultimate goal will be to switch from the current generalized "one-drug-fits-all" management to more personalized "patient endotype-specific" management., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Just as a single polypeptide strand can self-fold into a complex 3D structure, a single strand of DNA can self-fold into DNA origami. Most DNA origami structures (i.e., the scaffold-staple and DNA tiling systems) utilize hundreds of short single-stranded DNA. As such, these structures come with challenges inherent to intermolecular construction. Many assembly challenges involving intermolecular interactions can be resolved if the origami structure is constructed from one DNA strand, where folding is not concentration dependent, the folded structure is more resistant to nuclease degradation, and the synthesis can be achieved at an industrial scale at a thousandth of the cost. This review discusses the design principles and considerations employed in single-stranded DNA origami and its potential benefits and drawbacks., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Yang, Bakker, Raghu and Li.)

Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Background: The patho-mechanism of ocular surface disease (OSD) in dupilumab-treated atopic dermatitis (AD) patients remains unclear. The aim of this study is to measure dupilumab levels in tear fluid and serum, and relate these findings to the severity of OSD during dupilumab treatment in AD patients., Methods: This prospective study included dupilumab-treated moderate-to-severe AD patients who were seen by a dermatologist and an ophthalmologist before the start of dupilumab (baseline), and after 4 and 28 weeks of dupilumab treatment. Dupilumab levels in tear fluid and serum were measured by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Additionally, a pilot study was conducted to measure dupilumab on conjunctival epithelial cells using flow cytometry and LC-MS/MS., Results: At baseline, 89.6% (n = 43/48) of the patients had OSD, with 50.0% having moderate-to-severe OSD. After 28 weeks of dupilumab treatment, the median dupilumab tear fluid levels were 0.55 mg/L (IQR 0.35-1.31) and 0.29 mg/L (IQR 0.16-0.60) in patients with moderate-to-severe OSD and patients with no or mild OSD, respectively (p = 0.02). Dupilumab levels could be detected on conjunctival epithelial cells of 5 AD patients treated with dupilumab for 4 weeks., Conclusion: Patients with moderate-to-severe OSD had higher dupilumab tear fluid levels compared to patients with no or mild OSD, indicating that dupilumab reaches the ocular surface. Dupilumab was also detected in conjunctival cell suspensions and was found to directly bind CD45-conjunctival epithelial cells. This suggests that AD-induced changes of the conjunctival epithelium may play a role in the development of OSD as well as increased local drug availability., (© 2023 The Authors. Clinical and Translational Allergy published by John Wiley & Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology.)

Ocean acidification (OA) is expected to modify the structure and function of coral reef ecosystems by reducing calcification, increasing bioerosion, and altering the physiology of many marine organisms. Much of our understanding of these relationships is based on experiments with static OA treatments, although evidence suggests that the magnitude of diurnal fluctuations in carbonate chemistry may modulate the calcification response to OA. These light-mediated swings in seawater pH are projected to become more extreme with OA, yet their impact on bioerosion remains unknown. We evaluated the influence of diurnal carbonate chemistry variability on the bioerosion rates of two Caribbean sponges: the zooxanthellate Cliona varians and azooxanthellate Cliothosa delitrix. Replicate fragments from multiple colonies of each species were exposed to four precisely controlled pH treatments: contemporary static (8.05 ± 0.00; mean pH ± diurnal pH oscillation), contemporary variable (8.05 ± 0.10), future OA static (7.80 ± 0.00), and future OA variable (7.80 ± 0.10). Significantly enhanced bioerosion rates, determined using buoyant weight measurements, were observed under more variable conditions in both the contemporary and future OA scenarios for C. varians, whereas the same effect was only apparent under contemporary pH conditions for C. delitrix. These results indicate that variable carbonate chemistry has a stimulating influence on sponge bioerosion, and we hypothesize that bioerosion rates evolve non-linearly as a function of pCO 2 resulting in different magnitudes and directions of rate enhancement/reduction between day and night, even with an equal fluctuation around the mean. This response appeared to be intensified by photosymbionts, evident by the consistently higher percent increase in bioerosion rates for photosynthetic C. varians across all treatments. These findings further suggest that more variable natural ecosystems may presently experience elevated sponge bioerosion rates and that the heightened impact of OA enhanced bioerosion on reef habitat could occur sooner than prior predictions., (© 2022 John Wiley & Sons Ltd.)

Importance: The registered dose of dupilumab for adult patients with atopic dermatitis (AD) is 300 mg every other week. At present, it is unknown whether serum dupilumab levels are associated with treatment response or adverse effects., Objectives: To evaluate serum dupilumab levels at 16 weeks of treatment and to explore the association of serum dupilumab levels with treatment response and adverse effects in patients with AD., Design, Setting, and Participants: This clinical, prospective, observational cohort study used data from the prospective BioDay Registry including adult patients with AD who started dupilumab treatment and for whom a serum sample was available at 16 weeks of treatment. All patients were treated according to the BioDay protocol in the University Medical Center Utrecht in the Netherlands. Patients received a loading dose of dupilumab 600 mg subcutaneously, followed by 300 mg every other week. Patients who had a dose adjustment or discontinued treatment before 16 weeks of treatment were excluded. Data analyses were performed from January to June 2022., Main Outcomes and Measures: Disease severity of AD was assessed at baseline and at weeks 16 and 52 using the Eczema Area and Severity Index (EASI). Treatment response was defined as the percent reduction in EASI score vs the baseline score (eg, EASI 90 indicated a 90% reduction) and as an absolute EASI cutoff score of 7 or lower (controlled AD). Adverse effects were recorded during the first year. At 16 weeks, dupilumab serum levels and treatment responses were measured and analyzed. Multivariate logistic regression modeling was used to determine the prediction of response (EASI 90; EASI ≤7) and adverse effects at 52 weeks, with serum dupilumab levels at 16 weeks in the presence of the covariates age and sex., Results: Among the total of 295 patients with AD (mean [SD] age, 41.5 [15.9] years; 170 [57.6%] men), the median (IQR [range]) drug level was 86.6 μg/mL (64.6-110.0 μg/mL [10.1-382.0 μg/mL]) at 16 weeks of treatment. No significant differences were found in serum dupilumab levels between responder statuses (EASI, <50, 50, 75, or 90) at week 16. Multivariate logistic regression analysis showed nonsignificant odds ratios (ORs) for serum dupilumab levels at 16 weeks regarding prediction of long-term response (EASI ≥90: OR, 0.96 [95% CI, 0.90-1.04; P = .34] and EASI ≤7: OR, 1.03 [95% CI, 0.93-1.14; P = .55]) and adverse effects (OR, 1.01 [95% CI, 0.95-1.07; P = .83])., Conclusion and Relevance: This prospective clinical cohort study found a broad range of serum dupilumab levels at 16 weeks of treatment and no association with treatment response and adverse effects during first year of treatment. Response may be dependent on target availability of the interleukin-4 receptor subunit α, with an interpatient variability producing heterogeneity in response.

Background: At present, no real-world studies are available on different dupilumab dosing regimens in controlled atopic dermatitis (AD). The aim of this study was to clinically evaluate a patient-centered dupilumab dosing regimen in patients with controlled AD and to relate this to serum drug levels and serum biomarkers., Methods: Ninety adult AD patients from the prospective BioDay registry were included based on their dupilumab administration interval according to a predefined patient-centered dosing regimen. Group A (n = 30) did not fulfill the criteria for interval prolongation and continued using the standard dupilumab dosage (300 mg/2 weeks), group B (n = 30) prolonged dupilumab interval with 50% (300 mg/4 weeks), and group C (n = 30) prolonged dupilumab interval with 66%-75% (300 mg/6-8 weeks). AD severity score, patient-reported outcomes, serum dupilumab levels, and serum biomarkers were analyzed over time., Results: Disease severity scores did not significantly change over time during the tapering period in any of the groups. In groups B and C, the Numeric Rating Scale (NRS)-pruritus temporarily significantly increased after interval prolongation but remained low (median NRS-pruritus≤4). Median dupilumab levels remained stable in group A (standard dosage), but significantly decreased in groups B and C (24.1 mg/L (IQR = 17.1-45.6); 12.5 mg/L (IQR = 1.7-22.3)) compared with the levels during the standard dosage (88.2 mg/L [IQR = 67.1-123.0, p < .001]). Disease severity biomarker levels (CCL17/CCL18) remained low in all study groups during the whole observation period., Conclusions: This study showed that dose reduction was successful in a subgroup of patients with controlled AD by using a patient-centered dosing regimen. These patients showed stable low disease activity and low severity biomarkers over time., (© 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Purpose: If early active motion after 3-ligament tenodesis is safe, it may yield more patient comfort and an early return to activities. Therefore, the aim of this study was to investigate whether early active motion is noninferior to late active motion after 3-ligament tenodesis for scapholunate interosseous ligament injuries., Methods: This prospective, multicenter cohort study, using a noninferiority design with propensity score matching, compared a late active motion protocol (immobilization for 10-16 days, wrist therapy in weeks 5-6) with an early active motion protocol (immobilization for 3-5 days, wrist therapy during week 2). Patients who were older than 18 years, had complete baseline information on demographics, and underwent 3-ligament tenodesis were included. The outcome measures were postoperative Patient-Reported Wrist/Hand Evaluation scores, pain, complications, return to work, range of motion, grip strength, and satisfaction with treatment results at 3 months of follow-up., Results: After propensity matching, a total of 108 patients were included. Patient-Reported Wrist/Hand Evaluation and pain scores during physical load following an early active motion protocol were noninferior compared with scores following a late active motion protocol. Furthermore, early active motion did not lead to an increase of complications, differences in range of motion or grip strength, or less satisfaction with the treatment result. An earlier return to work was not observed., Conclusions: Early active motion leads to noninferior results without more complications as compared with late active motion. Based on these findings, early active motion can be considered safe, and might be recommended due to its potential benefits compared with late active motion after 3-ligament tenodesis., Type of Study/level of Evidence: Therapeutic III., (Copyright © 2022. Published by Elsevier Inc.)

Purpose: This study compared the interobserver agreement of arthroscopic classification of suspected scapholunate interosseous ligament (SLIL) pathology with and without midcarpal arthroscopy to help inform diagnostic strategies. It also measured the association of midcarpal arthroscopy with recommendations for reconstructive surgery. The association of midcarpal arthroscopy with the type of surgery recommended was also studied., Methods: Fourteen consecutive videos of diagnostic radiocarpal and midcarpal wrist arthroscopy for suspected SLIL pathology were selected. An international survey-based experiment was conducted among upper extremity surgeons of the Science of Variation Group. Participants were randomized to view either radiocarpal arthroscopic videos or radiocarpal and midcarpal videos. Surgeons rated SLIL pathology according to the Geissler classification and recommended surgical or nonsurgical treatment. If surgical treatment was recommended, they indicated the type of procedure., Results: The interobserver agreement for the Geissler classification was slight/fair for observers who reviewed midcarpal and radiocarpal videos and for those who viewed radiocarpal videos only. Viewing midcarpal videos was associated with higher pathology grades, the recommendation for reconstructive surgery, and a preference for tenodesis over scapholunate ligament repair., Conclusions: Diagnostic wrist arthroscopy for a wrist with normal radiological alignment has poor interobserver agreement., Clinical Relevance: The pursuit of a pathology that accounts for wrist symptoms in a nonspecific interview and examination and normal radiographs is understandable; however, the low reliability of the scapholunate pathology of diagnostic arthroscopy might be associated with more potential harm than benefit., (Copyright © 2022. Published by Elsevier Inc.)

Etorphine is widely used in zoological medicine for the immobilization of large herbivores. All reported immobilization protocols for kulans use etorphine as the primary immobilizing agent. However, etorphine can trigger severe side effects and is highly toxic for humans, its availability is occasionally limited for use in wildlife medicine. Therefore, two different alpha-2 agonist-based protocols for the general anesthesia of kulans were investigated and compared with the standard etorphine immobilization. In total, 21 immobilizations were performed within the scope of routine husbandry management at the Serengeti-Park Hodenhagen. Kulans were darted using a ketamine-medetomidine-midazolam-butorphanol (KMMB) protocol ( n = 8, treatment group (TG) 1), a tiletamine-zolazepam-medetomidine-butorphanol (TZMB) protocol ( n = 7, treatment group (TG) 2), or an etorphine-acepromazine-detomidine-butorphanol (EADB) protocol ( n = 6, control group). Vital parameters included heart rate, respiratory rate, arterial blood pressure (invasive), end tidal CO 2 (etCO 2 ), electromyography and core body temperature, which were all assessed every 10 min. For blood gas analysis, arterial samples were collected 15, 30, 45 and 60 min after induction. Subjective measures of quality and efficacy included quality of induction, immobilization, and recovery. Time to recumbency was longer for TG 1 (9.00 ± 1.67 min) and TG 2 (10.43 ± 1.79 min) compared to the induction times in the control group (5.33 ± 1.93 min). Treatment group protocols resulted in excellent muscle relaxation, normoxemia and normocapnia. Lower pulse rates combined with systolic arterial hypertension were detected in the alpha-2 agonist-based protocols. However, only in TZMB-immobilized kulans, sustained severe systolic arterial hypertension was observed, with significantly higher values than in the TG 1 and the normotensive control group. At 60 min following induction, medetomidine and detomidine were antagonized with atipamezole IM (5 mg/mg medetomidine or 2 mg/mg detomidine), etorphine and butorphanol with naltrexone IV (2 mg/mg butorphanol or 50 mg/mg etorphine), and midazolam and zolazepam with flumazenil IV (0.3 mg per animal). All three combinations provided smooth and rapid recoveries. To conclude, the investigated treatment protocols (KMMB and TZMB) provided a safe and efficient general anesthesia in kulans with significantly better muscle relaxation, higher respiration rates and improved arterial oxygenation compared with the immobilizations of the control group. However, the control group (EADB) showed faster recoveries. Therefore, EADB is recommended for ultra-short immobilizations (e.g., microchipping and collaring), especially with free-ranging kulans where individual recovery is uncertain, whereas the investigated treatment protocols are recommended for prolonged medical procedures on captive kulans., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bohner, Painer, Bakker, Haw, Rauch, Greunz, Egner and Goeritz.)

Marine mammals, regarded as sentinels of aquatic ecosystem health, are exposed to different pathogens and parasites under natural conditions. We surveyed live South American fur seals Arctocephalus australis and South American sea lions Otaria flavescens in Uruguay for Leptospira spp., canine distemper virus (CDV), Mycobacterium spp., Toxoplasma gondii, and Neospora caninum. Samples were collected from 2007 to 2013. The seroprevalence of Leptospira spp. was 37.6% positive, 50.9% negative, and 11.5% suspect for A. australis (n = 61) while for O. flavescens (n = 12) it was 67% positive, 25% negative, and 8% suspect. CDV RNA was not detected in any of the analyzed samples. Most animals tested seropositive to tuberculosis antigens by WiZo ELISA (A. australis: 29/30; O. flavescens: 20/20); reactivity varied with a novel ELISA test (antigens MPB70, MPB83, ESAT6 and MPB59). Seroprevalence against N. caninum and T. gondii was 6.7 and 13.3% positive for O. flavescens and 0 and 2.2% positive for A. australis respectively. To evaluate possible sources of infection for pinnipeds, wild rats Rattus rattus and semi-feral cats Felis catus were also tested for Leptospira spp. and T. gondii respectively. Water samples tested for Leptospira revealed saprofitic L. bioflexa. Pathogenic Leptospira were detected in the kidneys of 2 rats, and cats tested positive for T. gondii (100%). These results represent a substantial contribution to the study of the health status of wild pinnipeds in Uruguay.

The Bacillus Calmette-Guérin (BCG) vaccination provides partial protection against, and reduces severity of pathological lesions associated with bovine tuberculosis (bTB) in cattle. Accumulating evidence also suggests that revaccination with BCG may be needed to enhance the duration of immune protection. Since BCG vaccine cross-reacts with traditional tuberculin-based diagnostic tests, a peptide-based defined antigen skin test (DST) comprising of ESAT-6, CFP-10, and Rv3615c to detect the infected among the BCG-vaccinated animals (DIVA) was recently described. The DST reliably identifies bTB-infected animals in experimental challenge models and in natural infection settings, and differentiated these from animals immunized with a single dose of BCG in both skin tests and interferon-gamma release assay (IGRA). The current investigation sought to assess the diagnostic specificity of DST in calves ( Bos taurus ssp. taurus × B. t . ssp. indicus ; n = 15) revaccinated with BCG 6 months after primary immunization. The results show that none of the 15 BCG-revaccinated calves exhibited a delayed hypersensitivity response when skin tested with DST 61 days post-revaccination, suggesting 100% diagnostic specificity (one-tailed lower 95% CI: 82). In contrast, 8 of 15 (diagnostic specificity = 47%; 95% CI: 21, 73) BCG-revaccinated calves were positive per the single cervical tuberculin (SCT) test using bovine tuberculin. Together, these results show that the DST retains its specificity even after revaccination with BCG and confirms the potential for implementation of BCG-based interventions in settings where test-and-slaughter are not economically or culturally feasible., Competing Interests: APHA (MV) and Penn State (SSr and VK) have filed a patent application for DST (U.S. Patent Application 17/602,628). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Subramanian, Srinivasan, Ramaiyan Selvaraju, Vinoli, Selladurai, Ramasamy, Kumaragurubaran, Bakker, Vordermeier, Kapur and Gopal.)

Background and Objective: Physician maldistribution is a global problem that hinders patients' abilities to access healthcare services. Medical education presents an opportunity to influence physicians towards meeting the healthcare needs of underserved communities when establishing their practice. Understanding the impact of educational interventions designed to offset physician maldistribution is crucial to informing health human resource strategies aimed at ensuring that the disposition of the physician workforce best serves the diverse needs of all patients and communities., Methods: A scoping review was conducted using a six-stage framework to help map current evidence on educational interventions designed to influence physicians' decisions or intention to establish practice in underserved areas. A search strategy was developed and used to conduct database searches. Data were synthesized according to the types of interventions and the location in the medical education professional development trajectory, that influence physician intention or decision for rural and underserved practice locations., Results: There were 130 articles included in the review, categorized according to four categories: preferential admissions criteria, undergraduate training in underserved areas, postgraduate training in underserved areas, and financial incentives. A fifth category was constructed to reflect initiatives comprised of various combinations of these four interventions. Most studies demonstrated a positive impact on practice location, suggesting that selecting students from underserved or rural areas, requiring them to attend rural campuses, and/or participate in rural clerkships or rotations are influential in distributing physicians in underserved or rural locations. However, these studies may be confounded by various factors including rural origin, pre-existing interest in rural practice, and lifestyle. Articles also had various limitations including self-selection bias, and a lack of standard definition for underservedness., Conclusions: Various educational interventions can influence physician practice location: preferential admissions criteria, rural experiences during undergraduate and postgraduate medical training, and financial incentives. Educators and policymakers should consider the social identity, preferences, and motivations of aspiring physicians as they have considerable impact on the effectiveness of education initiatives designed to influence physician distribution in underserved locations., (© 2022. The Author(s).)

This study identified risk factors for the development of dupilumab-associated ocular surface disease in patients with moderate-to-severe atopic dermatitis in a large prospective daily practice cohort. Data from the Dutch BioDay Registry were used to assess the risk of developing dupilumab-associated ocular surface disease, by performing univariate and multivariate logistic regression analyses. A total of 469 patients were included, of which 152/469 (32.4%) developed dupilumab-associated ocular surface disease. Multivariate analysis showed a statistically significant association of the development of dupilumab-associated ocular surface disease with a history of any eye disease (history of self-reported episodic acute allergic conjunctivitis excluded) combined with the use of ophthalmic medication at the start of dupilumab (odds ratio 5.16, 95% confidence interval 2.30-11.56, p < 0.001). In conclusion, a history of any eye disease (history of self-reported episodic acute allergic conjunctivitis excluded) combined with the use of ophthalmic medication at baseline was associated with the development of dupilumab-associated ocular surface disease in patients with atopic dermatitis.

Bovine tuberculosis (bTB) is one of the top three, high-priority, livestock diseases in Ethiopia and hence, the need for evaluation of potential control strategies is critical. Here, we applied the test-and-segregate followed by cull strategy for the control of bTB in the intensive Alage dairy farm in Ethiopia. All cattle reared on this farm were repeatedly skin tested using the Comparative Cervical Tuberculin (CCT) test for a total of five times between 2015 and 2021. During the first (October 2015) and second (March 2017) rounds of testing, all reactor animals (>4 mm) were culled, while those that were deemed as inconclusive (1-4 mm) were segregated and retested. At retest, animals with CCT >2 mm were removed from the herd. In the third (December 2017) and fourth (June 2018) rounds of tuberculin testing, a more stringent approach was taken wherein all reactors per the severe mode of CCT test interpretation (>2 mm) were culled. A final herd status check was performed in May 2021. In summary, the number of CCT positives (>4 mm) in the farm dropped from 23.1% (31/134) in October 2015 to 0% in December 2017 and remained 0% until May 2021. In contrast, the number of Single Cervical Tuberculin (SCT) test positives (≥4 mm) increased from 1.8 to 9.5% (from 2017 to 2021), indicating that CCT test might not be sufficient to effectively clear the herd of bTB. However, a more stringent approach would result in a drastic increase in the number of false positives. The total cost of the bTB control effort in this farm holding 134-200 cattle at any given time was conservatively estimated to be ~US$48,000. This, together with the need for culling an unacceptably high number of animals based on skin test status, makes the test-and-cull strategy impractical for nationwide implementation in Ethiopia and other low- and middle-income countries (LMICs) where the infection is endemic. Hence, there is an increased emphasis on the need to explore alternate, affordable measures such as vaccination alongside accurate diagnostics to help control bTB in endemic settings., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lakew, Srinivasan, Mesele, Olani, Koran, Tadesse, Mekonnen, Almaw, Sahlu, Seyoum, Beyecha, Gumi, Ameni, Ashenafi, Bakker, Kapur and Gebre.)

The aim of this study was to compare extra-articular radiographic parameters of distal radial fractures measured on plain radiographs and CT scans. Two researchers independently measured four extra-articular radiographic parameters (dorsal tilt, carpal alignment, radial inclination and ulnar variance) on both radiographs and CT scans in 85 patients. Inter-observer reliability for both techniques was assessed, along with the agreement between CT scans and radiographs using the intraclass correlation coefficient and Bland-Altman plots. The results showed that dorsal tilt, carpal alignment, radial inclination and ulnar variance can be measured reliably on both radiographs and CT scans. At a patient level, carpal alignment, radial inclination and ulnar variance CT scan measurements are an acceptable alternative to plain radiograph measurements in the vast majority of patients. In contrast, dorsal tilt CT scan measurements are not comparable with radiographs in 40% of the cases. Therefore, caution should be taken in measuring dorsal tilt on CT scans.

In this paper we present the first global assessments of COVID-19's impacts on food systems and their actors, focusing specifically on the food security and nutritional status of those affected in low and middle-income countries. The assessment covers 62 countries and is based on the analysis of 337 documents published in English, French, Spanish and Portuguese. The review confirms the magnitude and the severity of an unprecedented crisis that has spread worldwide and has spared only a few. The analysis shows that the dimension of food security that has been most affected is accessibility, with reasonably solid evidence suggesting that both financial and physical access to food have been disrupted. In contrast, there is no clear evidence that the availability of food has been affected. Overall, data suggests that food systems resisted and adapted to the disruption of the pandemic. This resilience came, however, at great costs, with the majority of the systems' actors having to cope with severe disruptions in their activities. In contrast, grocery stores and supermarkets made billions of dollars in profits in 2020., Competing Interests: We declare that we do not have any conflict of interest of any sort in publishing this manuscript., (© 2021 The Authors.)

Background: Despite increased research interest in smartphone mental health applications (MHapps), few studies have examined user engagement and its determinants. MoodMission is a MHapp that targets low mood and anxiety via evidence-based techniques including behavioural activation (BA)., Aims: The present study aimed to investigate (i) whether BA interventions delivered with visual psychoeducation had greater engagement than BA interventions delivered with solely written psychoeducation, (ii) whether BA interventions targeting mastery would have greater engagement than those targeting pleasure, and (iii) the relationship between level of engagement and MHapp benefit., Method: Participants downloaded MoodMission and completed activities and within-app evaluations over a 30-day period. Data from 238 MoodMission users were analysed via multi-level modelling and linear regression., Results: The average number of app-based activities completed was 5.46 and the average self-reported engagement level was in the low to moderate range. As hypothesized, higher levels of engagement significantly predicted more positive activity appraisal., Conclusions: The results suggest that BA technique beliefs are involved in MHapp engagement and future research examining user appraisals of techniques is warranted.