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José Luis Rosales-Alexander,1 Jerónimo Balsalobre Aznar,1 César Magro-Checa2 1Rheumatology Department, Hospiten Ramblas, Santa Cruz de Tenerife, 2Rheumatology Department, San Cecilio University Hospital, Granada, Spain Abstract: Calcium pyrophosphate dihydrate crystal deposition disease (CPPD) is an inflammatory arthritis produced by the deposition of calcium pyrophosphate (CPP) crystals in the synovium and periarticular soft tissues. It is the third most common inflammatory arthritis. Diagnosis is suspected on the basis of the clinical picture and radiographic/laboratory findings. The reference standard for the diagnosis of CPPD is based on the identification of CPP crystals in synovial fluid by light microscopy, compensated polarized light microscopy, or phase contrast microscopy. Most treatment approaches for CPPD are based upon clinical experience and not upon controlled trials. They range – depending on the subtype and the characteristics of symptoms – from no treatment to interleukin-1 blockade antibodies or specific therapy for an underlying disease. This review summarizes all we know so far about the diagnosis and management of CPPD. Keywords: calcium pyrophosphate dihydrate deposition disease, CPPD, chondrocalcinosis, crystal-induced arthritides

Agus MSD, Alexander JL, Wolfsdorf JI. Utility of immediate hemoglobin A1c in children with type I diabetes mellitus. Objective: Immediate feedback (IFB) of hemoglobin A1c (HbA1c) results to adults with type 1 and 2 diabetes allows more appropriate care decisions at the clinic visit and may improve glycemic control. Our objective is to determine whether IFB of HbA1c results to children with type 1 diabetes will improve patient care and glycemic control. Methods: In this prospective randomized controlled trial, children under 18 years of age were randomly assigned to receive HbA1c results during their diabetes clinic visit by point-of-care fingerstick testing (immediate) or several days after by venipuncture and laboratory assessment (conventional). HbA1c levels, therapy changes, and painfulness of testing were recorded at baseline and every follow-up appointment for a year. Results: The 215 patients studied had similar baseline characteristics including initial HbA1c (7.90 ± 1.24% vs. 7.81 ± 1.13%, p = 0.25). IFB improved HbA1c at 3 months (−0.20 ± 0.66%, p = 0.005) with a return to baseline for the remainder of the study. Subjects receiving conventional feedback had increased HbA1c results at 12 months (+0.27 ± 1.05%, p = 0.048). Less frequent patient-clinician communication between visits was reported with IFB (0.29 ± 0.48 vs. 0.38 ± 0.49 contacts/visit, p = 0.043). Subjects rated fingersticks as less painful than conventional venipuncture (0.30 ± 0.66 vs. 3.9 ± 2.6, p < 0.001). Conclusions: IFB of HbA1c is a more acceptable method of HbA1c determination in children with type 1 diabetes mellitus. Although sustained improvements in glycemic control did not result from this intervention alone, IFB testing resulted in more efficient patient-clinician communication and was less painful. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate the cardiovascular effects of anabolic androgenic steroid (AAS) use, specifically the hemodynamic response, during maximal treadmill exercise testing by comparing the exercise response between users of AAS (U-AAS) and non-AAS users (N-AAS). Twenty-four men (n=12; 29+/-3.4 years and n=12; 29.5+/-8.2 years for the U-AAS and N-AAS groups, respectively) with regular participation in both resistance (mean=6 d.wk) and aerobic exercise (mean=2 d.wk) volunteered for the study. Both groups of subjects completed a ramp-protocol maximal treadmill exercise test to volitional fatigue. Several hemodynamic and metabolic measures were obtained before, during, and after testing. The results demonstrate for the first time that chronic administration of high doses of AAS (355.4+/-59.47 mg.wk) lead to hemodynamic and metabolic response impairment. In conclusion, the chronotropic significant incompetence in the current study was reflected by an exaggerated hemodynamic response to exercise. Furthermore, the findings suggest that nonusers of AAS showed increases in VO2max when compared to the AAS group. Therefore, this study provides a contraindication to AAS use, especially in those at increased risk of cardiovascular events. [ABSTRACT FROM AUTHOR]

Mourning a suicide can be a difficult, complicated experience for family and friends. A therapist's bereavement can be even more complex. The multitude of feelings is often unspoken and/or unattended by colleagues, loved ones, and themselves. This article explores some defenses, both helpful and unhelpful, that one clinician used to process the event. [ABSTRACT FROM AUTHOR]

PURPOSE: To provide outpatient asthma education for children and families along the southwest border of the U.S. and to study the effectiveness of a southwest border hospital's in-house asthma educational program. DATA SOURCES: (1) 'Increasing the Knowledge Base of Asthmatics and Their Families through Asthma Clubs along the Southwest Border.' (2) American Lung Association. (3) National Institutes of Health, National Heart, Lung and Blood Institute. (4) Referrals from a southwest border hospital. CONCLUSIONS: Only two of 23 patients referred for asthma follow-up were readmitted to hospital and/or emergency care during the following year. Large group teaching pretest-posttest score means for 3,429 fourth and fifth grade students revealed a 23% increase in asthma knowledge. Small follow-up groups of students received in-depth asthma education. IMPLICATIONS FOR PRACTICE: Effectiveness of hospital inpatient asthma education combined with outpatient family follow-up was supported. An additional finding was that southwest border families are more receptive to visits arranged with a school nurse in their children's school than to home visits from primary care clinic nurses. [ABSTRACT FROM AUTHOR]

Background: To investigate the correlation and level of agreement between end-tidal carbon dioxide (EtCO2) and blood gas pCO2 in non-intubated children with moderate to severe respiratory distress.Methods: Retrospective study of patients admitted to an intermediate care unit (InCU) at a tertiary care center over a 20-month period with moderate to severe respiratory distress secondary to asthma, bronchiolitis, or pneumonia. Patients with venous pCO2 (vpCO2) and EtCO2 measurements within 10 minutes of each other were eligible for inclusion. Patients with cardiac disease, chronic pulmonary disease, poor tissue perfusion, or metabolic abnormalities were excluded.Results: Eighty EtCO2-vpCO2 paired values were available from 62 patients. The mean +/- SD for EtCO2 and vpCO2 was 35.7 +/- 10.1 mmHg and 39.4 +/- 10.9 mmHg respectively. EtCO2 and vpCO2 values were highly correlated (r = 0.90, p < 0.0001). The correlations for asthma, bronchiolitis and pneumonia were 0.74 (p < 0.0001), 0.83 (p = 0.0002) and 0.98 (p < 0.0001) respectively. The mean bias +/- SD between EtCO2 and vpCO2 was -3.68 +/- 4.70 mmHg. The 95% level of agreement ranged from -12.88 to +5.53 mmHg. EtCO2 was found to be more accurate when vpCO2 was 35 mmHg or lower.Conclusion: EtCO2 is correlated highly with vpCO2 in non-intubated pediatric patients with moderate to severe respiratory distress across respiratory illnesses. Although the level of agreement between the two methods precludes the overall replacement of blood gas evaluation, EtCO2 monitoring remains a useful, continuous, non-invasive measure in the management of non-intubated children with moderate to severe respiratory distress. [ABSTRACT FROM AUTHOR]

This study aimed to validate visual plate waste estimation against weighed waste as a method of dietary assessment of nursing home and hostel residents. Assessment of nutrient intake is integral to safeguarding minimal nutrition standards for aged residential care. A pilot study was conducted of residents from six institutions to validate a quick, reliable visual plate waste method. Comparing observed and weighed waste for 1368 food items, a difference of only 1.5 to 1.7% was found in assessed waste. Inter-observer difference in assessed waste was only 0.21°%. The method was equally valid for different institution types, diet textures and most food types. Estimation of nutrient intake from meals using weighed waste assessment indicated that those taking texture modified diets were at risk of lower energy, protein and fibre intakes. Therefore visual assessment of plate waste provides a valid means of assessing intake in groups of elderly persons in residential care, where dietary intake may be suboptimal. [ABSTRACT FROM AUTHOR]

Metabolomics aims to study the downstream effects of variables like diet, environment, or disease on a given biological system. However, inconsistencies in sample preparation, data acquisition/processing protocols lead to reproducibility and accuracy concerns. A systematic study was conducted to assess how sample preparation methods and data analysis platforms affect metabolite susceptibility. A targeted panel of 25 metabolites was evaluated in 69 clinical metabolomics samples prepared following three different protocols: intact, ultrafiltration, and protein precipitation. The resulting metabolic profiles were characterized by 1D 1 H nuclear magnetic resonance (NMR) spectroscopy and analyzed with Chenomx v8.3 and SMolESY software packages. Greater than 90% of the metabolites were extracted more efficiently using protein precipitation than filtration, which aligns with previously reported results. Additionally, analysis of data processing software suggests that metabolite concentrations were overestimated by Chenomx batch-fitting, which only appears reliable for determining relative fold changes rather than absolute quantification. However, an assisted-fit method provided sufficient guidance to achieve accurate results while avoiding a time-consuming fully manual-fitting approach. By combining our results with previous studies, we can now provide a list of 5 common metabolites [2-hydroxybutyrate (2-HB), choline, dimethylamine (DMA), glutamate, lactate] with a high degree of variability in reported fold changes and standard deviations that need careful consideration before being annotated as potential biomarkers. Our results show that sample preparation and data processing package critically impact clinical metabolomics study success. There is a clear need for an increased degree of standardization and harmonization of methods across the metabolomics community to ensure reliable outcomes.

Objective: To compare anterior chamber depth (ACD) and lens thickness (LT) measurements by ultrasound biomicroscopy (UBM), A-scan cross vector (CV) overlay with UBM, and immersion A-scan technique in pediatric eyes., Methods: This prospective comparative cohort study comprised 43 eyes of 25 pediatric participants (mean age: 2.3±2.2 y). UBM and immersion A-scan biometry were performed prior to dilation and intraocular surgery. ACD and LT were measured by UBM image analysis, A-scan CV UBM overlay, and immersion A-scan technique., Results: ACD and LT measurements obtained using immersion A-scan were significantly greater than with UBM image analysis with mean differences of 0.52 mm and 0.62 mm, respectively (p < 0.001). Immersion A-scan and UBM measurements were moderately correlated (r = 0.70 and 0.64, p < 0.001). ACD and LT measurements obtained using CV overlay were not significantly different than UBM measurements and the values were strongly positively correlated (r = 0.95 and 0.93, p < 0.001)., Conclusion: Immersion A-scan may overestimate ACD and LT compared to UBM in pediatric patients due to oblique placement of the A-scan probe relative to the optical axis. Supplemental use of UBM and/or CV overlay is indicated to improve measurement accuracy in pediatric patients who cannot reliably fixate due to the ability to confirm proper alignment of the probe with the pupil by visualizing the anterior segment., Competing Interests: Conflict of interest The authors declare no competing interests., (Copyright © 2024 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Over half of women in the United States report urinary incontinence (UI). This condition can be treated conservatively, but many people do not seek treatment. The current correlational study assessed women's knowledge of UI. Specifically, we investigated the relationships between knowledge level about UI and quality of life (QoL), and between severity level of UI and QoL. A convenience cross-sectional sample of 39 older women was obtained from two YMCA locations. Data were analyzed using the Spearman rank-order correlation coefficient. A significant relationship was found between severity of UI and QoL, r s = -.73, p < .001; no relationship was found between knowledge level of UI and QoL, r s = .24, p = .13. Results suggested women's knowledge about the causes of UI and conservative therapy is limited. Occupational therapists need to address UI with their patients and educate them about treatment options and availability., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: The purpose of this study was to determine the association between lens thickness and cataract in participants aged 0 to 5 years., Design: This was a prospective, multicenter, case-control study., Participants: We enrolled 118 participants (171 eyes) aged 0 to 5 years, mean age 14.6 ± 17.0 months, range 0 to 60 months., Methods: Lens thickness was measured on 342 ultrasound biomicroscopy (UBM) images., Main Outcome Measures: Lens thickness; feasibility of lens thickness measurement from UBM images., Results: The mean lens thickness among noncataracts was 3.60 ± 0.17 mm, compared with 3.16 ± 0.61 mm among cataracts ( P < 0.0001). Lens thickness <3.5 mm was significantly associated with increased odds of cataract; adjusted odds ratio = 5.99 (95% confidence interval, 2.41-14.88; P < 0.0003) among participants age 0 to 7 months. Lens thickness was significantly associated with cataract laterality among participants age 0 to 7 months ( P < 0.0001)., Conclusions: Quantitative UBM can be used to evaluate lens thickness in infants and children with congenital cataracts. The lens in congenital cataract eyes was thinner than that of controls among infants. Abnormal lens thickness was significantly associated with cataract. Future longitudinal studies will examine the association between lens thickness and postcataract surgery outcomes., Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (© 2024 by the American Academy of Ophthalmology.)

Investigating the gut microbiome and metabolome frequently requires faecal samples, which can be difficult to obtain. Previous studies have shown that rectal swabs are comparable to faecal samples for analysing gut microbiota composition and key metabolites. In this study, 3D printed rectal swabs were compared with conventional flocked swabs and faecal samples, due to the potential advantages 3D printing as a technique offers for swab production and development. 16S rRNA gene sequencing, qPCR and metabolite profiling (using 1 H-NMR spectroscopy) were performed on swab and faecal samples from healthy participants. Faecal calprotectin and total protein analysis were performed on samples from inflammatory bowel disease (IBD) patients. There were no significant differences between both swab types and faecal samples when assessing key measures of alpha and beta diversity, and differences in the abundance of major phyla. There was a strong correlation between both swab types and faecal samples for all combined metabolites detected by NMR. In IBD patients, there was no significant difference in faecal calprotectin and total protein levels between both swab types and faecal samples. These data lead us to conclude that 3D printed swabs are equivalent to flocked swabs for the analysis of the gut microbiome, metabolome and inflammation., (© 2024. The Author(s).)

Backgroundobjectives: To compare the structural anatomy of the anterior segment in pediatric Trisomy 21 (T21) subjects with and without cataracts to age-matched controls., Design: Prospective case-control study., Participants: 40 subjects (57 eyes) age 0-25 years old (9.1 ± 10.6 years)., Methods: This prospective case-control study evaluated anterior segment measurements from ultrasound biomicroscopy (UBM) imaging on 342 images., Results: Among persons with T21 cataract, the iris was significantly thinner than T21 individuals without cataract (0.28 vs 0.32 mm, p = 0.0181). T21/cataract subjects also had significantly thinner lenses than subjects without cataract, regardless of whether they have T21 or are controls (3.1 mm vs 3.5 mm, p = 0.0074).Thinner lens (<3.5 mm) was insignificantly associated with increased odds of cataract (OR = 9.5 [0.872,104], p = 0.065). Thinner iris (<0.32 mm) was associated with increased odds of cataract (OR = 8.4 [1.188, 59.273], p = 0.033)., Conclusions: These findings support the hypothesis that subtle quantitative anatomic variants are present in the anterior eye of individuals with T21. Specific anatomic variants are unique to the presence of cataract among subjects with T21., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Objective: To investigate the relationship between corneal diameter and internal corneal span determined from angle-to-angle distance using ultrasound biomicroscopy (UBM) in an observational cross-sectional patient population comprised of 54 eyes (28 healthy control eyes, ages 0.1 to 11.3 years; 26 eyes with primary congenital glaucoma, ages 0.1 to 3.5 years) from 41 pediatric participants ages 0.1 to 11.3 years (mean age: 3±3 years, median age: 2 years)., Methods: Forty cornea photographs with reference ruler and 110 UBM images were obtained. Three observers measured horizontal and vertical corneal diameter and angle-to-angle distance in each cornea photo and UBM image using ImageJ and the average values were used. Main outcome measures were Pearson correlation coefficient, linear regression, mean difference between corneal diameter and angle-to-angle distance, and intra-class correlation coefficients among measurements from all three observers for each parameter., Results: Corneal diameter and angle-to-angle distance had a strong positive correlation horizontally (Pearson r = 0.89, p<0.001) and vertically (r = 0.93, p<0.001). Correlation was consistent regardless of presence of primary congenital glaucoma and participant age. Regression analysis demonstrated a linear relationship between the parameters for horizontal (CD = 0.99*AA+0.28, R2 = 0.81, p<0.001) and vertical (CD = 0.91 *AA+1.32, R2 = 0.85, p<0.001) dimensions. Overall, reliability was good-excellent, ranging from an ICC of 0.76 for vertical corneal diameter to 0.90 for horizontal angle-to-angle distance., Conclusions: Based on the strong positive correlation found between corneal diameter and angle-to-angle distance in our study population, UBM image analysis can be used to accurately estimate corneal diameter from angle-to-angle distance in children with healthy eyes and primary congenital glaucoma. UBM may provide a useful intraocular alternative for estimating corneal diameter and monitoring diseases that affect the cornea in infants and children, such as congenital glaucoma., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Kolosky et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

This prospective study evaluated the relationship between laser speckle contrast imaging (LSCI) ocular blood flow velocity (BFV) and five birth parameters: gestational age (GA), postmenstrual age (PMA) and chronological age (CA) at the time of measurement, birth weight (BW), and current weight (CW) in preterm neonates at risk for retinopathy of prematurity (ROP). 38 Neonates with BW < 2 kg, GA < 32 weeks, and PMA between 27 and 47 weeks underwent 91 LSCI sessions. Correlation tests and regression analysis were performed to quantify relationships between birth parameters and ocular BFV. Mean ocular BFV index in this cohort was 8.8 +/- 4.0 IU. BFV positively correlated with PMA (r = 0.3, p = 0.01), CA (r = 0.3, p = 0.005), and CW (r = 0.3, p = 0.02). BFV did not correlate with GA nor BW (r = - 0.2 and r = - 0.05, p > 0.05). Regression analysis with mixed models demonstrated that BFV increased by 1.2 for every kilogram of CW, by 0.34 for every week of CA, and by 0.36 for every week of PMA (p = 0.03, 0.004, 0.007, respectively). Our findings indicate that increased age and weight are associated with increased ocular BFV measured using LSCI in premature infants. Future studies investigating the associations between ocular BFV and ROP clinical severity must control for age and/or weight of the infant., (© 2024. The Author(s).)

Purpose of Review: Vitamin B 12 (B12, cobalamin) deficiency has been associated with neuropsychiatric symptoms, suggesting a role for B12 supplementation both as a treatment for psychiatric symptoms due to B12 deficiency and as an augmentation strategy for pharmacological treatments of psychiatric disorders. This critical review discusses the major causes of B12 deficiency, the range of psychiatric and non-psychiatric manifestations of B12 deficiency, the indications for testing B12 levels, and the evidence for B12 supplementation for major psychiatric disorders., Recent Findings: We find that high-quality evidence shows no benefit to routine B12 supplementation for mild depressive symptoms or to prevent depression. There is very limited evidence on the role of B12 supplementation to augment antidepressants. No high-quality evidence to date suggests a role for routine B12 supplementation in any other major psychiatric disorder. No formal guidelines indicate when clinicians should test B12 levels for common psychiatric symptoms, in the absence of major risk factors for deficiency or cardinal symptoms of deficiency. No robust evidence currently supports routine B12 supplementation for major psychiatric disorders. However, psychiatrists should be aware of the important risk factors for B12 deficiency and should be able to identify symptoms of B12 deficiency, which requires prompt testing, medical workup, and treatment. Testing for B12 deficiency should be considered for atypical or severe psychiatric presentations., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Pediatric allogeneic hematopoietic cell transplant (allo-HCT) recipients are at risk for morbidity and mortality from human adenovirus (HAdV). HAdV can be detected in an asymptomatic state, referred to as infection or with signs or symptoms of illness, referred to as disease. Standardized case definitions are needed to distinguish infection from disease and allow for consistent reporting in both observational cohort studies and therapeutic clinical trials., Methods: A working group of experts in virology, transplant infectious disease, and HCT was assembled to develop HAdV infection and disease definitions with the degree of certainty (i.e., possible, probable, and proven). Definitions were further refined through an iterative process and independently applied by two central review committees (CRCs) to 20 pediatric allo-HCT recipients with at least one HAdV-positive PCR., Results: Initial HAdV infection and disease definitions were developed and updated through an iterative process after reviewing clinical and virological details for 81 subjects with at least one positive HAdV PCR detected in a clinical specimen. Independent application of final definitions to 20 HAdV positive allo-HCT recipients by two CRCs yielded similar number of HAdV infection or disease events but with variation of degree of certainty for some events., Conclusions: Application of definitions by a CRC for a study of HAdV infection and disease is feasible and can provide consistency in the assignment of outcomes. Definitions need further refinement to improve reproducibility and to provide guidance on determining clinical improvement or worsening after initial diagnosis of HAdV infection or disease., (© 2024 The Authors. Pediatric Transplantation published by Wiley Periodicals LLC.)

Background and Aims: We sought to determine whether six commonly used immunosuppressive regimens were associated with lower antibody responses after seasonal influenza vaccination in patients with inflammatory bowel disease [IBD]., Methods: We conducted a prospective study including 213 IBD patients and 53 healthy controls: 165 who had received seasonal influenza vaccine and 101 who had not. IBD medications included infliximab, thiopurines, infliximab and thiopurine combination therapy, ustekinumab, vedolizumab, or tofacitinib. The primary outcome was antibody responses against influenza/A H3N2 and A/H1N1, compared to controls, adjusting for age, prior vaccination, and interval between vaccination and sampling., Results: Lower antibody responses against influenza A/H3N2 were observed in patients on infliximab (geometric mean ratio 0.35 [95% confidence interval 0.20-0.60], p = 0.0002), combination of infliximab and thiopurine therapy (0.46 [0.27-0.79], p = 0.0050), and tofacitinib (0.28 [0.14-0.57], p = 0.0005) compared to controls. Lower antibody responses against A/H1N1 were observed in patients on infliximab (0.29 [0.15-0.56], p = 0.0003), combination of infliximab and thiopurine therapy (0.34 [0.17-0.66], p = 0.0016), thiopurine monotherapy (0.46 [0.24-0.87], p = 0.017), and tofacitinib (0.23 [0.10-0.56], p = 0.0013). Ustekinumab and vedolizumab were not associated with reduced antibody responses against A/H3N2 or A/H1N1. Vaccination in the previous year was associated with higher antibody responses to A/H3N2. Vaccine-induced anti-SARS-CoV-2 antibody concentration weakly correlated with antibodies against H3N2 [r = 0.27; p = 0.0004] and H1N1 [r = 0.33; p < 0.0001]., Conclusions: Vaccination in both the 2020-2021 and 2021-2022 seasons was associated with significantly higher antibody responses to influenza/A than no vaccination or vaccination in 2021-2022 alone. Infliximab and tofacitinib are associated with lower binding antibody responses to influenza/A, similar to COVID-19 vaccine-induced antibody responses., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Mismatch repair-deficient (MMRd) colorectal cancers (CRCs) have high mutation burdens, which make these tumours immunogenic and many respond to immune checkpoint inhibitors. The MMRd hypermutator phenotype may also promote intratumour heterogeneity (ITH) and cancer evolution. We applied multiregion sequencing and CD8 and programmed death ligand 1 (PD-L1) immunostaining to systematically investigate ITH and how genetic and immune landscapes coevolve. All cases had high truncal mutation burdens. Despite pervasive ITH, driver aberrations showed a clear hierarchy. Those in WNT/β-catenin, mitogen-activated protein kinase, and TGF-β receptor family genes were almost always truncal. Immune evasion (IE) drivers, such as inactivation of genes involved in antigen presentation or IFN-γ signalling, were predominantly subclonal and showed parallel evolution. These IE drivers have been implicated in immune checkpoint inhibitor resistance or sensitivity. Clonality assessments are therefore important for the development of predictive immunotherapy biomarkers in MMRd CRCs. Phylogenetic analysis identified three distinct patterns of IE driver evolution: pan-tumour evolution, subclonal evolution, and evolutionary stasis. These, but neither mutation burdens nor heterogeneity metrics, significantly correlated with T-cell densities, which were used as a surrogate marker of tumour immunogenicity. Furthermore, this revealed that genetic and T-cell infiltrates coevolve in MMRd CRCs. Low T-cell densities in the subgroup without any known IE drivers may indicate an, as yet unknown, IE mechanism. PD-L1 was expressed in the tumour microenvironment in most samples and correlated with T-cell densities. However, PD-L1 expression in cancer cells was independent of T-cell densities but strongly associated with loss of the intestinal homeobox transcription factor CDX2. This explains infrequent PD-L1 expression by cancer cells and may contribute to a higher recurrence risk of MMRd CRCs with impaired CDX2 expression. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)

Introduction: Adenoma multiplicity is associated with increased colorectal cancer (CRC) risk. The utility of genetic testing in patients with multiple colorectal adenomas (MCRA) remains uncertain. We evaluated the diagnostic yield of mutations in polyposis- and CRC-associated genes in patients with MCRA., Methods: We performed a cross-sectional review of adult patients with 10-99 cumulative adenomas from the prospective database at the St Mark's Hospital Polyposis Registry and Family Cancer Clinic between 1999 and 2021. Genetic testing was performed for adenomatous polyposis-associated genes, hamartomatous polyposis-associated genes, and nonpolyposis colorectal cancer-associated genes. Clinicopathological outcomes were extracted for multiple logistic regression analysis., Results: Two hundred fifty-nine patients with MCRA (median age 61 [interquartile range 53-69] years) were identified. Sixty-six patients (25.5%) had a pathogenic variant or likely pathogenic variant, with APC and biallelic MUTYH mutations constituting the majority of identified pathogenic variant/likely pathogenic variants. Diagnostic yields were greater than 10% at any adenoma burden. In univariate analysis, higher adenoma burden and younger age were associated with higher yield (both P < 0.0001). In patients with MCRA with 10-19 adenomas without a relevant personal or family history of CRC, the diagnostic yield was nil. In multiple logistic regression analysis, higher adenoma burden, younger age, personal history of CRC, and first-degree familial history of CRC were associated with higher diagnostic yield., Discussion: Diagnostic yield of >10% at any adenoma burden supports current guidance for constitutional genetic testing in patients with MCRA, although the low yield in people older than 60 years with 10-19 adenomas suggests that a stratified approach might be appropriate., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Purpose: To determine the correlation between blood flow metrics measured by intravenous fluorescein angiography (IVFA) and the blood flow velocity index (BFVi) obtained by laser speckle contrast imaging (LSCI) in infants with retinopathy of prematurity (ROP)., Design: Prospective comparative pilot study., Subjects: Seven eyes from 7 subjects with ROP., Methods: Unilateral LSCI and IVFA data were obtained from each subject in the neonatal intensive care unit. Five LSCI-based metrics and 5 IVFA-based metrics were extracted from images to quantify blood flow patterns in the same region of interest. Correlation between LSCI-based and IVFA-based blood flow metrics was compared between 2 subgroups of ROP severity: moderate ROP (defined as stage ≤ 2 without Plus disease) and severe ROP (defined as stage ≥3 or Plus disease)., Main Outcome Measures: Pearson and Kendall rank correlation coefficients between IVFA and LSCI metrics; Student t test P values comparing LSCI metrics between "severe" and "moderate" ROP groups., Results: Pearson correlations between IVFA and LSCI included arterial-venous transit time (AVTT) and peak BFVi (pBFVi; r  = -0.917; P  = 0.004), AVTT and dip BFVi (dBFVi; r  = -0.920; P  = 0.003), AVTT and mean BFVi ( r  = -0.927- P  = 0.003), and AVTT and volumetric rise index ( r  = -0.779; P  = 0.039). Kendall rank correlation between AVTT and dBFVi was r  = -0.619 ( P  = 0.051). pBFVi was higher in severe ROP than in moderate ROP (8.4 ± 0.6 and 4.4 ± 1.8, respectively; P  = 0.0045 using the 2-sample t test with pooled variance and P  = 0.0952 using the Wilcoxon rank-sum test)., Conclusions: Correlation was found between blood flow metrics obtained by IVFA and noninvasive LSCI techniques. We demonstrate the feasibility of obtaining quantitative metrics using LSCI in infants with ROP in this pilot study; however, further investigation is needed to evaluate its potential use in clinical assessment of ROP severity., Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (© 2024 by the American Academy of Ophthalmology.)

Purpose: To assess the repeatability and reliability of semi-automated EyeMark Python program measurements compared to manual ImageJ image processing of anterior segment-optical coherence tomography (AS-OCT) structures in healthy and keratoconus eyes., Methods: Heidelberg AS-OCT was used to image 25 eyes from 14 healthy subjects and 25 eyes from 15 subjects with keratoconus between the ages of 20 and 80 years, collected prospectively, in this observational case-control study. Visual axis scan containing vertical fixation light beam was selected from the 15-line AS-OCT scan raster. Central corneal thickness (CCT), anterior corneal radius of curvature (ACRC), posterior corneal radius of curvature (PCRC), and truncated anterior vault (TAV) were measured using ImageJ software and the EyeMark Python program. MedCalc and R were used to calculate the intraclass correlation coefficient (ICC) and generate Bland-Altman plots (BAP)., Results: When comparing the measurements of CCT, ACRC, PCRC, and TAV between manual ImageJ analysis and the EyeMark Python program, ICC values were consistently greater than 0.9, indicating excellent agreement. BAPs comparing the ImageJ and Python measurements of anterior segment structures show no systematic proportional bias and the average differences were near zero and within 95% of the limits of agreement., Conclusions: Semi-automated tools may provide the necessary efficiency for point-of-care quantitative corneal analysis of raw AS-OCT images. The semi-automated EyeMark Python program offers a repeatable and reliable tool compared to manual ImageJ analysis for measuring anterior segment structures from AS-OCT images among individuals with keratoconus., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Immune checkpoint inhibitors (CPIs) are a relatively newly licenced cancer treatment, which make a once previously untreatable disease now amenable to a potential cure. Combination regimens of anti-CTLA4 and anti-PD-1 show enhanced efficacy but are prone to off-target immune-mediated tissue injury, particularly at the barrier surfaces. To probe the impact of immune checkpoints on intestinal homoeostasis, mice are challenged with anti-CTLA4 and anti-PD-1 immunotherapy and manipulation of the intestinal microbiota. The immune profile of the colon of these mice with CPI-colitis is analysed using bulk RNA sequencing, single-cell RNA sequencing and flow cytometry. CPI-colitis in mice is dependent on the composition of the intestinal microbiota and by the induction of lymphocytes expressing interferon-γ (IFNγ), cytotoxicity molecules and other pro-inflammatory cytokines/chemokines. This pre-clinical model of CPI-colitis could be attenuated following blockade of the IL23/IFNγ axis. Therapeutic targeting of IFNγ-producing lymphocytes or regulatory networks, may hold the key to reversing CPI-colitis., (© 2023. Springer Nature Limited.)

Background: Patients with inflammatory bowel disease (IBD) receiving anti-TNF and JAK-inhibitor therapy have attenuated responses to COVID-19 vaccination. We aimed to determine how IBD treatments affect neutralising antibody responses against the Omicron BA.4/5 variant., Methods: In this multicentre cohort study, we prospectively recruited 340 adults (69 healthy controls and 271 IBD) at nine UK hospitals between May 28, 2021 and March 29, 2022. The IBD study population was established (>12 weeks therapy) on either thiopurine (n = 63), infliximab (n = 45), thiopurine and infliximab combination therapy (n = 48), ustekinumab (n = 45), vedolizumab (n = 46) or tofacitinib (n = 24). Patients were excluded if they were being treated with any other immunosuppressive therapies. Participants had two doses of either ChAdOx1 nCoV-19 or BNT162b2 vaccines, followed by a third dose of either BNT162b2 or mRNA1273. Pseudo-neutralisation assays against SARS-CoV-2 wild-type and BA.4/5 were performed. The half maximal inhibitory concentration (NT50) of participant sera was calculated. The primary outcome was anti-SARS-CoV-2 neutralising response against wild-type virus and Omicron BA.4/5 variant after the second and third doses of anti-SARS-CoV-2 vaccine, stratified by immunosuppressive therapy, adjusting for prior infection, vaccine type, age, and interval between vaccination and blood collection. This study is registered with ISRCTN (No. 13495664)., Findings: Both heterologous (first two doses adenovirus vaccine, third dose mRNA vaccine) and homologous (three doses mRNA vaccine) vaccination strategies significantly increased neutralising titres against both wild-type SARS-CoV-2 virus and the Omicron BA.4/5 variant in healthy participants and patients with IBD. Antibody titres against BA.4/5 were significantly lower than antibodies against wild-type virus in both healthy participants and patients with IBD (p < 0.0001). Multivariable models demonstrated that neutralising antibodies against BA.4/5 after three doses of vaccine were significantly lower in patients with IBD on infliximab (Geometric Mean Ratio (GMR) 0.19 [0.10, 0.36], p < 0.0001), infliximab and thiopurine combination (GMR 0.25 [0.13, 0.49], p < 0.0001) or tofacitinib (GMR 0.43 [0.20, 0.91], p = 0.028), but not in patients on thiopurine monotherapy, ustekinumab, or vedolizumab. Breakthrough infection was associated with lower neutralising antibodies against wild-type (p = 0.037) and BA.4/5 (p = 0.045)., Interpretation: A third dose of a COVID-19 mRNA vaccine based on the wild-type spike glycoprotein significantly boosts neutralising antibody titres in patients with IBD. However, responses are lower against the Omicron variant BA.4/5, particularly in patients taking anti-TNF and JAK-inhibitor therapy. Breakthrough infections are associated with lower neutralising antibodies and immunosuppressed patients with IBD may receive additional benefit from bivalent vaccine boosters which target Omicron variants., Funding: Pfizer., Competing Interests: ALH reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie, Arena, Atlantic, Bristol Myers Squibb, Celltrion, Ferring, Dr Falk, Galapagos, Janssen, MSD, Napp, Pfizer, Pharmacosmos, Shire, and Takeda; participation on the Global Steering Committee for Genentech. AJK reports consulting fees from Janssen; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Pfizer and Takeda; support for attending meetings or travel from Janssen, Tillotts, and Norgine; and participation in a data safety monitoring board or advisory board for AbbVie. CWL received personal consulting fees from Galapagos, AbbVie, Takeda, Pfizer, Janssen and Iterative Scopes; institutional consulting fees from Trellus Health; and support for attending meetings from Galapagos, AbbVie, Takeda, Pfizer, Janssen, GSK, Gilead, Fresenius Kabi, Ferring, and Dr Falk. GRJ received speaker fees from Takeda, Ferring, Janssen, AbbVie and Fresenius Kabi. JLA received support for attending meetings from Takeda. JRG reports grants from Roche, Biogen, Celltrion Healthcare, Takeda and Galapagos. KVP received consulting fees from AbbVie, Janssen, Galapagos and Pfizer; reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie, Dr Falk, Janssen, Galapagos, Pfizer, Takeda, Tillotts and Ferring; support for attending meetings or travel from AbbVie, Dr Falk, Janssen, Galapagos, Pfizer, Takeda, Tillotts and Ferring; and participation on a data safety monitoring board or advisory board for AbbVie, Galapagos, Pfizer and Janssen. SB received research grant from Bowel Research UK and support for attending conferences from Ferring and Dr Falk, outside the submitted work. KMP is a member of the data safety monitoring board for NCT05249829 and NCT05575492; has received a fee for speaking from Seqirus and Sanofi Pasteur, and has research funding from the Chan Zuckerberg Initiative, the MRC/UKRI, the Vaccine Task Force, and NIHR Imperial BRC outside the submitted work. KK reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Janssen and Ferring; support for attending meetings or travel from Janssen and Takeda; and participation on a data safety monitoring board or advisory board for Janssen and PredictImmune. MP received research grant from Pfizer and speaker fees from Janssen. NAK reports grants from AbbVie, Biogen, Celgene, Celltrion, Galapagos, MSD, Napp, Pfizer, Pharmacosmos, Roche, and Takeda; consulting fees from Amgen, Bristol Myers Squibb, Dr Falk, Janssen, Mylan, Pharmacosmos, Galapagos, Takeda, and Tillotts; personal fees from Allergan, Celltrion, Dr Falk, Ferring, Janssen, Pharmacosmos, Takeda, Tillotts, and Galapagos; and support for attending meetings from AbbVie, Dr Falk, Tillotts and Janssen, outside the submitted work. PMI reports grants from Celltrion, Takeda, MSD, Pfizer, and Galapagos; personal fees from Gilead, Pfizer, Galapagos, Takeda, AbbVie, Celltrion, Janssen, Bristol Myers Squibb, Lilly, and Arena; speaker fees from Pfizer, Galapagos, Takeda, AbbVie, Celltrion, Janssen, Bristol Myers Squibb, Lilly, and Arena, outside the submitted work. SS reports grants from Tillotts, Takeda, Janssen, Pfizer and AbbVie; received personal fees from AbbVie, Tillotts, Janssen, Takeda, Dr Falk, Lilly and Bristol Myers Squibb; received support for attending meetings from Janssen, AbbVie and Celltrion; and serves as a member of the data safety monitoring board for AbbVie, Janssen, Takeda, Celltrion, Lilly and Bristol Myers Squibb. TA reports grant funding from Pfizer to deliver this study; grants from Celltrion, Roche, Takeda, Biogen, and Galapagos; and honoraria for lectures from Takeda and Roche, outside the submitted work. NP is the principal investigator on the research grant from Pfizer that funded the VIP study; has received research grants from Bristol Myers Squibb, Roche, Biogen, Celltrion Healthcare, Takeda, Galapagos, CCUK, AstraZeneca, Helmsley Charitable Trust, outside the submitted work; reports personal fees from Takeda, Janssen, Pfizer, Galapagos, Bristol Myers Squibb, AbbVie, Roche, Lilly, Allergan, Celgene and AstraZeneca outside the submitted work; and has served as a speaker or advisory board member for AbbVie, Allergan, Bristol Myers Squibb, Celgene, Dr Falk, AstraZeneca, Galapagos and Vifor; and serves as a member of the data safety monitoring board for Bristol Myers Squibb and AstraZeneca. All other authors declare no competing interests., (© 2023 The Author(s).)

Stool sampling is a useful tool for diagnosing gastrointestinal disease in veterinary medicine. The sub-clinical disease burden of Salmonella spp. in cattle can become significant for farmers. However, current methods of faecal sampling in a rural setting for diagnosis are not consistently sufficient for the preservation of Salmonella spp. in faeces. This study evaluated the use of a commercial stool storage kit for bacterial preservation in cow faecal samples compared to unpreserved stools placed into refrigeration at different time-points. A stool sample was collected per-rectum from one apparently healthy Holstein-Freisen cow. The sample was weighed and aliquoted into two sterile Falcon tubes and into two commercial kit tubes. The aliquots were then placed into refrigeration at 4 °C at 0, 24, and 96 h after processing. One commercial kit tube was not aliquoted and remained at ambient temperature. After 2 weeks, DNA was extracted from the samples and analysed using endpoint PCR, revealing a sub-clinical infection with Salmonella spp. The bacterium was best preserved when the stool was stored in the commercial kit at ambient temperature and re-homogenised immediately prior to DNA extraction. The unpreserved stool did not maintain obvious levels of Salmonella spp. after 24 h at ambient temperature. This commercial kit should be considered for use in the diagnosis of salmonellosis in cattle.