Single-cell transcriptomics reveals colonic immune perturbations during amyloid-ß driven Alzheimer's disease in mice.

The "gut-brain axis" is emerging as an important target in Alzheimer's disease (AD). However, immunological mechanisms underlying this axis remain poorly understood. Using single-cell RNA sequencing of the colon immune compartment in the 5XFAD amyloid-ß (Aß) mouse model, we uncovered AD-associated changes in ribosomal activity, oxidative stress, and BCR/plasma cell activity. Strikingly, levels of colon CXCR4 + antibody secreting cells (ASCs) were significantly reduced. This corresponded with accumulating CXCR4 + B cells and gut-specific IgA + cells in the brain and dura mater, respectively. Consistently, a chemokine ligand for CXCR4, CXCL12, was expressed at higher levels in 5XFAD glial cells and in in silico analyzed human brain studies, supporting altered neuroimmune trafficking. An inulin prebiotic fiber diet attenuated AD markers including Aß plaques and overall frailty. These changes corresponded to an expansion of gut IgA + cells and rescued peripheral T regs levels. Our study points to a key glia-gut axis and potential targets against AD. Study Highlights: AD is associated with altered immune parameters in the gut of 5XFAD mice. 5 XFAD colon has reduced ASCs, including CXCR4 + cells with a migratory gene signature. 5XFAD brain gliosis includes increased CXCL12 expression. CXCR4 + B cells and gut-specific IgA + ASCs accumulate in the 5XFAD brain and/or dura mater. Inulin diet attenuates AD disease parameters while boosting IgA + cell and T reg levels.

Non-mosaic trisomy 22 and congenital heart surgery using the shared decision making model: a case report.

BACKGROUND: Liveborn infants with non-mosaic trisomy 22 are rarely described in the medical literature. Reported lifespan of these patients ranges from minutes to 3 years, with the absence of cardiac anomalies associated with longer-term survival. The landscape for offering cardiac surgery to patients with rare autosomal trisomies is currently evolving, as has been demonstrated recently in trisomies 13 and 18. However, limited available data on patients with rare autosomal trisomies provides a significant challenge in perinatal counseling, especially when there are options for surgical intervention. CASE PRESENTATION: In this case report, we describe an infant born at term with prenatally diagnosed apparently non-mosaic trisomy 22 and multiple cardiac anomalies, including a double outlet right ventricle, hypoplastic aortic valve and severe aortic arch hypoplasia, who underwent cardiac surgery. The decisions made by her family lending to her progress and survival to this day were made with a focus on the shared decision making model and support in the prenatal and perinatal period. We also review the published data on survival and quality of life after cardiac surgery in infants with rare trisomies. CONCLUSIONS: This patient is the only known case of apparently non-mosaic trisomy 22 in the literature who has undergone cardiac surgery with significant survival benefit. This case highlights the impact of using a shared decision making model when there is prognostic uncertainty.

The utility of delta troponin in diagnosing significant coronary artery disease in patients with symptomatic atrial fibrillation.

BACKGROUND: Troponin I (cTnI) elevation is common in patients with atrial fibrillation (AF) but does not reliably indicate underlying coronary ischemia. We investigated whether dynamic changes in cTnI value (delta troponin) are useful in revealing significant coronary artery disease (sCAD) in patients presenting with symptomatic AF. METHODS: We conducted a retrospective case-control study analyzing serial cTnI values in 231 patients presenting with symptomatic AF who had an objective assessment for underlying CAD within 6 months of the index admission. Diagnostic performance of an elevated cTnI (>0.04 µg/L) only, and elevated cTnI coupled with Youden Index derived cutoffs for absolute and relative changes in troponin, for distinguishing patients with sCAD, was evaluated. RESULTS: A total of 107 patients had an elevated cTnI on serial measurements. In this group, the area under the receiver operating characteristic curve was 0.69 [95% confidence interval (CI), 0.56-0.81] for relative delta troponin and 0.71 (95% CI, 0.59-0.83) for absolute delta troponin. The optimal diagnostic cutoff for relative delta troponin was > -0.42, and > -0.055 µg/L for absolute delta troponin. The specificity of elevated troponin to diagnose sCAD increased from 56 to 77% when relative delta troponin was added, and to 88% with absolute delta troponin. Although the sensitivity of cTnI elevation (57.1%) decreased to 50% for relative and 35.7% for absolute delta troponin, the negative predictive values were high and similar at 86%. CONCLUSION: When added to the troponin peak, delta troponin is a promising test for the diagnosis of significant coronary artery disease in patients presenting with symptomatic AF with elevated cTnI. This result requires prospective validation in a larger cohort of patients.

Cholinergic Nucleus 4 Degeneration and Cognitive Impairment in Isolated Rapid Eye Movement Sleep Behavior Disorder.

BACKGROUND: Cholinergic nucleus 4 (Ch4) degeneration is associated with cognitive impairment in Parkinson's disease and dementia with Lewy bodies, but it is unknown if Ch4 degeneration is also present in isolated rapid eye movement sleep behavior disorder (iRBD). OBJECTIVE: The aim was to determine if there is evidence of Ch4 degeneration in patients with iRBD and if it is associated with cognitive impairment. METHODS: We analyzed the clinical and neuropsychological data of 35 iRBD patients and 35 age- and sex-matched healthy controls. Regional gray matter density (GMD) was calculated for Ch4 using probabilistic maps applied to brain magnetic resonance imaging (MRI). RESULTS: Ch4 GMD was significantly lower in the iRBD group compared to controls (0.417 vs. 0.441, P = 0.02). Ch4 GMD was also found to be a significant predictor of letter number sequencing (ß-coefficient = 58.31, P = 0.026, 95% confidence interval [7.47, 109.15]), a measure of working memory. CONCLUSIONS: iRBD is associated with Ch4 degeneration, and Ch4 degeneration in iRBD is associated with impairment in working memory. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The Effect of Location of a Unicortical Defect on the Mechanical Properties of Rabbit Tibiae: A Model of the Distal Jig Pin Hole in Tibial Plateau Levelling Osteotomy.

OBJECTIVE: The aim of this study was to determine the effect of a unicortical defect at either the mid-diaphysis (MD) or distal metaphysis (DM) on the torsional properties of tibiae in an in vitro rabbit model, and to further examine optimal distal jig pin position for the canine tibial plateau levelling osteotomy (TPLO) procedure. STUDY DESIGN: Thirty-eight tibiae from 19 skeletally mature female New Zealand White rabbits were assigned to one of three groups; Group 1: intact, Group 2: MD defect and Group 3: DM defect. Defects were created using a 1.6 mm Ellis pin. Pure torsion was applied to each sample and peak torque and angular displacement recorded. RESULTS: All tibiae fractured in a spiral configuration. Fracture lines involved the defect in 33% of the MD samples and 0% of the DM samples. No differences were detected for peak torque and stiffness between groups. However, energy (mean ± standard deviation) was significantly reduced (p = 0.028) in the MD group (0.18 ± 0.07) relative to the intact tibia group (0.31 ± 0.14). Angle was also significantly reduced (p = 0.040) in the MD group (0.17 ± 0.05) compared with the intact group (0.23 ± 0.07). Placement of a DM defect had no significant effect on mechanical properties of the rabbit tibiae. CONCLUSION: Defects placed in the MD significantly reduced energy and angle in comparison to intact samples. No significant difference in peak torque or stiffness was observed between groups. If canine tibiae were similarly affected, our findings suggest jig pin placement in the DM to have a lesser effect on the torsional properties of the tibiae.

Hexameric Aggregation Nucleation Core Sequences and Diversity of Pathogenic Tau Strains.

Tau aggregation associates with multiple neurodegenerative diseases including Alzheimer's disease and rare tauopathies such as Pick's disease, progressive supranuclear palsy, and corticobasal degeneration. The molecular and structural basis of tau aggregation and related diverse misfolded tau strains are not fully understood. To further understand tau-protein aggregation mechanisms, we performed systematic truncation mutagenesis and mapped key segments of tau proteins that contribute to tau aggregation, where it was determined that microtubule binding domains R2 and R3 play critical roles. We validated that R2- or R3-related hexameric PHF6 and PHF6* peptide sequences are necessary sequences that render tau amyloidogenicity. We also determined that the consensus VQI peptide sequence is not sufficient for amyloidogenicity. We further proposed single- and dual-nucleation core-based strain classifications based on recent cryo-EM structures. We analyzed the structural environment of the hexameric peptide sequences in diverse tau strains in tauopathies that, in part, explains why the VQI consensus core sequence is not sufficient to induce tau aggregation. Our experimental work and complementary structural analysis highlighted the indispensible roles of the hexameric core sequences, and shed light on how the interaction environment of these core sequences contributes to diverse pathogenic tau-strains formation in various tauopathy brains.

Structure activity relationship of N-1 substituted 1,5-naphthyrid-2-one analogs of oxabicyclooctane-linked novel bacterial topoisomerase inhibitors as broad-spectrum antibacterial agents (Part-9).

Novel bacterial topoisomerase inhibitors (NBTIs) are the newest members of gyrase inhibitor broad-spectrum antibacterial agents, represented by the most advanced member, gepotidacin, a 4-amino-piperidine linked NBTI, which is undergoing phase III clinical trials for treatment of urinary tract infections (UTI). We have extensively reported studies on oxabicyclooctane linked NBTIs, including AM-8722. The present study summarizes structure activity relationship (SAR) of AM-8722 leading to identification of 7-fluoro-1-cyanomethyl-1,5-naphthyridin-2-one based NBTI (16, AM-8888) with improved potency and spectrum (MIC values of 0.016-4 µg/mL), with Pseudomonas aeruginosa being the least sensitive strain (MIC 4 µg/mL).

Knowledge, Attitudes, and Perceptions Toward Dementia Among Middle-Aged Singapore Residents.

BACKGROUND: Dementia is the decline in cognitive function sufficient to impair one's accustomed functioning. Countries with aging populations, such as Singapore, face rising rates of dementia. Dementia patients and their caregivers endure great financial and emotional stress. With the broad aim of minimizing these stresses, this study provides a cross-sectional view of the knowledge, attitudes, and perceptions (KAP) towards dementia in middle-aged Singaporean residents. OBJECTIVE: We aim to examine 1) the associations between demographic correlates and KAP; and 2) the effect of dementia knowledge on attitudes and perceptions towards dementia. METHODS: An online anonymous cross-sectional questionnaire was administered to Singaporeans and Permanent Residents aged 45 to 65 years old in English, Mandarin, and Malay. Knowledge was evaluated across three domains: symptoms, risk factors, and management. Total and domain scores were dichotomized as good or poor knowledge using median cut-offs. Attitudes/perceptions across six domains were evaluated on Likert scales, and responses to each question were dichotomized into positive or negative attitudes/perceptions. RESULTS: From 1,733 responses, 1,209 valid complete responses were accepted (mean age±SD 54.8±5.12 years old, females = 69.6%). Lower socioeconomic status was associated with poorer knowledge and greater barriers to risk-mitigating lifestyle modifications. Lack of personal experience with dementia and poor knowledge were also associated with erroneous attitudes/perceptions. CONCLUSION: Socioeconomic status and personal experience affect KAP towards dementia. Policy and education campaigns to address KAP towards dementia should account for baseline differences across demographics, for greater improvements in dementia incidence and support.

Leptin Enhances Hepatic Fibrosis and Inflammation in a Mouse Model of Cholestasis.

Leptin is an adipokine with roles in food intake and energy metabolism through its actions on neurons in the hypothalamus. The role of leptin in obesity and cardiovascular disorders is well documented. However, its influence on liver conditions such as cholestasis is poorly understood. The effects of exogenous leptin and leptin-neutralizing antibody on biliary hyperplasia, hepatic fibrosis, and inflammation in the multidrug resistance protein 2 knockout (Mdr2KO) mouse model of cholestasis were assessed by quantifying markers specific for cholangiocytes, activated hepatic stellate cells (HSCs), and cytokines. Serum and hepatic leptin were increased in Mdr2KO mice compared with FVB/NJ (FVBN) controls, and exogenous leptin enhanced biliary hyperplasia and liver fibrosis in Mdr2KO and FVBN mice. Leptin administration increased hepatic expression of C-C motif chemokine ligand 2 and IL-6 in Mdr2KO mice. In contrast, leptin-neutralizing antibody reduced intrahepatic bile duct mass and decreased HSC activation in Mdr2KO mice compared with FVBN controls. Sex-related differences were noted, with female Mdr2KO mice having more leptin than males. In cholangiocytes and LX2 cells in vitro, leptin increased phosphorylated Akt and stimulated cell proliferation. Leptin receptor siRNA and inhibitors of Akt phosphorylation impaired leptin-induced cell proliferation and proinflammatory cytokines. The current data suggest that leptin is abnormally increased in cholestatic mice, and excess leptin increases ductular reaction, hepatic fibrosis, and inflammation via leptin receptor-mediated phosphorylation of Akt in cholangiocytes and HSCs.

Knowledge and Interdisciplinary Communication of Gastroenterologists and Dentists in the Netherlands About Gastrointestinal Diseases With Oral Manifestations.

Background: Gastrointestinal diseases can have oral manifestations. The aim of this study was to investigate the knowledge of gastroenterologists and dentists about gastrointestinal diseases with oral manifestations and to assess the frequency, extent and content of communication between gastroenterologists and oral healthcare professionals. Methods: Separate questionnaires were developed and sent to all 523 gastroenterologists and a random selection of 500 dentists in the Netherlands. Both questionnaires contained questions about demographic characteristics of the participants, 10 statements about gastrointestinal diseases with possible oral manifestations and questions about the communication between gastroenterologists and oral healthcare professionals. Additionally, the questionnaire for gastroenterologists contained 9 statements about general dentistry and the questionnaire for dentist had 9 questions about gastrointestinal diseases. Results: Gastroenterologists answered 47.6% ± 31.9% of the questions correct about gastrointestinal diseases with possible oral manifestations and 57.5% ± 27.9% of the questions correct about general dentistry. Dentists answered 26.6% ± 20.5% of the questions correct about possible oral manifestations of gastrointestinal diseases and 50.3% ± 18.7% of the questions correct about gastrointestinal diseases. Gastroenterologists and dentists valued interdisciplinary consultation as very useful with scores of 4.07 ± 0.70 and 4.67 ± 0.49 on a 5-point Likert scale, respectively, but the frequency of consultation was considered insufficiently with a mean score of 2.88 ± 1.01 and 2.24 ± 1.05 on a 5-point Likert scale, respectively. Conclusions: This study suggests that the knowledge of gastroenterologists and dentists about gastrointestinal diseases with oral manifestations could be improved. Interdisciplinary consultation was considered valuable for the optimal treatment of their patients but was assessed as insufficient.

Prediction of in-hospital mortality of Clostriodiodes difficile infection using critical care database: a big data-driven, machine learning approach.

RESEARCH OBJECTIVES: Clostriodiodes difficile infection (CDI) is a major cause of healthcare-associated diarrhoea with high mortality. There is a lack of validated predictors for severe outcomes in CDI. The aim of this study is to derive and validate a clinical prediction tool for CDI in-hospital mortality using a large critical care database. METHODOLOGY: The demographics, clinical parameters, laboratory results and mortality of CDI were extracted from the Medical Information Mart for Intensive Care-III (MIMIC-III) database. We subsequently trained three machine learning models: logistic regression (LR), random forest (RF) and gradient boosting machine (GBM) to predict in-hospital mortality. The individual performances of the models were compared against current severity scores (Clostridiodes difficile Associated Risk of Death Score (CARDS) and ATLAS (Age, Treatment with systemic antibiotics, leukocyte count, Albumin and Serum creatinine as a measure of renal function) by calculating area under receiver operating curve (AUROC). We identified factors associated with higher mortality risk in each model. SUMMARY OF RESULTS: From 61 532 intensive care unit stays in the MIMIC-III database, there were 1315 CDI cases. The mortality rate for CDI in the study cohort was 18.33%. AUROC was 0.69 (95% CI, 0.60 to 0.76) for LR, 0.71 (95% CI, 0.62 to 0.77) for RF and 0.72 (95% CI, 0.64 to 0.78) for GBM, while previously AUROC was 0.57 (95% CI, 0.51 to 0.65) for CARDS and 0.63 (95% CI, 0.54 to 0.70) for ATLAS. Albumin, lactate and bicarbonate were significant mortality factors for all the models. Free calcium, potassium, white blood cell, urea, platelet and mean blood pressure were present in at least two of the three models. CONCLUSION: Our machine learning derived CDI in-hospital mortality prediction model identified pertinent factors that can assist critical care clinicians in identifying patients at high risk of dying from CDI.

Effect of ultraviolet-C light on the environmental bacterial bioburden in various veterinary facilities.

OBJECTIVE: To determine the effect of a mobile UV-C disinfection device on the environmental bacterial bioburden in veterinary facilities. SAMPLES: 40 swab samples of surfaces from the operating theaters of 3 veterinary hospitals and 1 necropsy laboratory. PROCEDURES: Various surfaces were swabbed, and collected material was eluted from the swabs in PBSS. Then, an aliquot of the sample fluid was processed with a bacteria-specific rapid metabolic assay to quantify bacterial bioburden. Each site was then treated with UV-C light with an automated disinfection device for approximately 45 minutes. The same surfaces were swabbed following UV-C treatment, and bioburden was quantified. The bioburden at additional time points, including after a second UV-C treatment, was determined for the small animal operating theater. RESULTS: All surfaces at all sites had a persistent viable bacterial population following manual cleaning. Disinfection with UV-C achieved a mean bioburden reduction of 94% (SD, 5.2%; range, 91% to 95%) for all surfaces, compared with manual disinfection alone. Repeated UV-C treatment of the small animal operating theater reduced mean bioburden by 99% (SD, 0.8%), including no detectable bacteria on 4 of 10 surfaces. CONCLUSIONS AND CLINICAL RELEVANCE: Disinfection with UV-C light may be a beneficial adjunct method for terminal disinfection of veterinary operating theaters to reduce environmental bioburden. (Am J Vet Res 2021;82:582-588).

SMA Identified: Clinical and Molecular Findings From a Sponsored Testing Program for Spinal Muscular Atrophy in More Than 2,000 Individuals.

Background: Spinal muscular atrophy (SMA) linked to chromosome 5q is an inherited progressive neuromuscular disorder with a narrow therapeutic window for optimal treatment. Although genetic testing provides a definitive molecular diagnosis that can facilitate access to effective treatments, limited awareness and other barriers may prohibit widespread testing. In this study, the clinical and molecular findings of SMA Identified-a no-charge sponsored next-generation sequencing (NGS)-based genetic testing program for SMA diagnosis-are reported. Methods: Between March 2018 and March 2020, unrelated individuals who had a confirmed or suspected SMA diagnosis or had a family history of SMA were eligible. All individuals underwent diagnostic genetic testing for SMA at clinician discretion. In total, 2,459 individuals were tested and included in this analysis. An NGS-based approach interrogated sequence and copy number of SMN1 and SMN2. Variants were confirmed by multiplex ligation-dependent probe amplification sequencing. Individuals were categorized according to genetic test results: diagnostic (two pathogenic SMN1 variants), nearly diagnostic (SMN1 exon-7 deletion with a variant of uncertain significance [VUS] in SMN1 or SMN2), indeterminate VUS (one VUS in SMN1 or SMN2), carrier (heterozygous SMN1 deletion only), or negative (no pathogenic variants or VUS in SMN1 or SMN2). Diagnostic yield was calculated. Genetic test results were analyzed based on clinician-reported clinical features and genetic modifiers (SMN2 copy number and SMN2 c.859G>C). Results: In total, 2,459 unrelated individuals (mean age 24.3 ± 23.0 years) underwent diagnostic testing. The diagnostic yield for diagnostic plus nearly diagnostic results was 31.3% (n = 771/2,459). Age of onset and clinical presentation varied considerably for individuals and was dependent on SMN2 copy number. Homozygous deletions represented the most common genetic etiology (96.2%), with sequence variants also observed in probands with clinical diagnoses of SMA. Conclusions: Using a high-yield panel test in a no-charge sponsored program early in the diagnostic odyssey may open the door for medical interventions in a substantial number of individuals with SMA. These findings have potential implications for clinical management of probands and their families.

Single level posterolateral lumbar fusion in a New Zealand White rabbit (Oryctolagus cuniculus) model: Surgical anatomy, operative technique, autograft fusion rates, and perioperative care.

INTRODUCTION: The posterolateral lumbar fusion (PLF) New Zealand White (NZW) (Oryctolagus cuniculus) rabbit model is a long-standing surgical technique for the preclinical evaluation of materials for spinal fusion. A detailed understanding of lumbar spine anatomy and perioperative care requirements of rabbits is imperative for correct execution of the model both scientifically and ethically. This study describes the preoperative procedures and surgical techniques used in single level PLF in a NZW rabbit model as it pertains to the animal husbandry, lumbar spine anatomy, anesthesia, surgical approach, and perioperative care of rabbits in a research setting. MATERIALS AND METHODS: We describe the surgical technique and perioperative patient care for single level PLF in a NZW rabbit model. Medical records from a single research facility were retrospectively reviewed for adult NZW rabbits that underwent single level PLF (L4-L5) between January 2016 and December 2019. The number of lumbar vertebrae per rabbit, fusion rates at 12 weeks using iliac crest autograft and complications are reported. Skeletal maturity was confirmed by preoperative fluoroscopic and radiographic documented closure of hindlimb physes. RESULTS: The PLF rabbit surgical model and perioperative patient care is described. PLF was performed in 868 adult female entire NZW rabbits. The majority of rabbits had seven lumbar vertebrae (620/868; 71.4%), followed by six (221/868; 25.5%), and eight (27/868; 3.1%). Fusion rates at 12 weeks for PLF using iliac crest autograft as assessed by manual palpation and radiographic assessment was 76.9% and 70.0%, respectively. Postoperative complications included occasional partial autograft site wound dehiscence due to self-trauma. CONCLUSIONS: For PLF rabbit models, a detailed understanding of the surgical technique, rabbit lumbar anatomy including number of lumbar vertebrae, and dietary and husbandry requirements of rabbits, is essential for execution of the model and animal welfare.

Effectiveness of Clinical Decision Tools in Predicting Pulmonary Embolism.

OBJECTIVE: The Wells criteria and revised Geneva score are two commonly used clinical decision tools (CDTs) developed to assist physicians in determining when computed tomographic angiograms (CTAs) should be performed to evaluate the high index of suspicion for pulmonary embolism (PE). Studies have shown varied accuracy in these CDTs in identifying PE, and we sought to determine their accuracy within our patient population. METHODS: Patients admitted to the Emergency Department (ED) who received a CTA for suspected PE from 2019 Jun 1 to 2019 Aug 31 were identified. Two CDTSs, the Wells criteria and revised Geneva score, were calculated based on data available prior to CTA and using the common D-Dimer cutoff of >500 µg/L. We determined the association between confirmed PE and CDT values and determined the association between the D-Dimer result and PE. RESULTS: 392 CTAs were identified with 48 (12.1%) positive PE cases. The Wells criteria and revised Geneva score were significantly associated with PE but failed to identify 12.5% and 70.4% of positive PE cases, respectively. Within our cohort, a D-Dimer cutoff of >300 µg/L was significantly associated with PE and captured 95.2% of PE cases. CONCLUSIONS: Both CDTs were significantly associated with PE but failed to identify PE in a significant number of cases, particularly the revised Geneva score. Alternative D-Dimer cutoffs may provide better accuracy in identifying PE cases.

Dental and periodontal disease in patients with inflammatory bowel disease.

OBJECTIVES: Although bowel symptoms are often predominant, inflammatory bowel disease (IBD) patients can have several oral manifestations. The aim of this study was to investigate the prevalence of dental caries and periodontal disease in patients with Crohn's disease (CD) and ulcerative colitis (UC) compared to an age and gender-matched control group of patients without IBD. MATERIAL AND METHODS: The DMFT (Decayed, Missing, Filled Teeth) scores and the DPSI (Dutch Periodontal Screening Index) of 229 IBD patients were retrieved from the electronic health record patient database axiUm at the Academic Centre for Dentistry Amsterdam (ACTA) and were compared to the DMFT scores and DPSI from age and gender-matched non-IBD patients from the same database. RESULTS: The total DMFT index was significantly higher in the IBD group compared to the control group. When CD and UC were analyzed separately, a statistically significant increased DMFT index was observed in CD patients but not in UC patients. The DPSI did not differ significantly between the IBD and non-IBD groups for each of the sextants. However, in every sextant, IBD patients were more frequently edentulous compared to the control patients. CONCLUSION: CD patients have significantly more dental health problems compared to a control group. Periodontal disease did not differ significantly between IBD and non-IBD groups as determined by the DPSI. CLINICAL RELEVANCE: It is important that IBD patients and physicians are instructed about the correlation between their disease and oral health problems. Strict oral hygiene and preventive dental care such as more frequent checkups should be emphasized by dental clinicians.

Fatigue implications for bending orthopaedic plates.

OBJECTIVES: - We aimed to investigate how pre-bending affects the mechanical properties, specifically fatigue, of stainless-steel plates. METHODS: - 3.5mm LCP 10-hole plates were pre-bent in 1, 2 and 3 locations to the same overall degree and fatigue testing performed. Finite Element Analysis (FEA) was performed in Strand7 (version 2.4.6) to better understand the failure point of the plates in four-point bending. RESULTS: - Six different plate pre-bending conditions were tested for resistance to fatigue failure. Increasing the number of pre-bends improved the fatigue resistance with two pre-bends having a mean 509,304 cycles to failure and three pre-bends 491,378 cycles to failure. The region of highest stress and the point of fatigue failure were at the plate's minimum cross-sectional area, which was predicted by the FEA and confirmed with mechanical testing. For plates pre-bent in two locations, the fatigue failure always occurred in the screw hole not in between the positions of the two pre-bends. Non-linear FEA simulation confirmed that work hardening occurs around pre-bend locations, conferring increased fatigue resistance to the holes next to, or between, pre-bend locations. CONCLUSIONS: We found that contrary to orthopaedic folklore, pre-bending of plates is not detrimental to fatigue resistance of the stainless-steel plates we tested. Pre-bending plates in a single plane increased the fatigue properties of the 10-hole stainless-steel plate tested.

Kinematics of the Feline Antebrachiocarpal Joint from Supination to Pronation.

OBJECTIVE: Cats rely on their forelimb mobility for everyday activities including climbing and grooming. Supination and pronation of the forelimb in cats are considered to primarily involve the antebrachium, rather than the carpus. Therefore, our null hypothesis was that there would be no movement of the carpal bones (radial carpal bone, ulnar carpal bone and accessory carpal bone) relative to the ulna during supination and pronation. STUDY DESIGN: Eight feline cadaveric forelimbs were rotated from supination to pronation in a jig and computed tomography was performed in the neutral, supinated and pronated positions. The individual carpal bones were segmented from computed tomography images of the supinated and pronated scans in each of the eight specimens. A feline ulna coordinate system was established and used to quantify the translations and rotations between bones of the proximal carpal row and antebrachium. RESULTS: After the carpus was rotated from the initial supinated position into pronation, there was significant translation (x, y and z axes) and rotation (x and y axes) of the proximal row of carpal bones based on absolute magnitude values. Given the differences in translations and rotations of the proximal row of carpal bones, our null hypothesis was rejected. CONCLUSION: The proximal row of carpal bones translate and rotate independently from the ulna in the cat during pronation of the antebrachium. This may have future implications in the diagnosis and management of feline carpal injuries involving the antebrachiocarpal joint.

Oral health and salivary function in ulcerative colitis patients.

BACKGROUND: Although ulcerative colitis primarily involves the colon, extra-intestinal manifestations are common and oral and dental complaints are no exception. OBJECTIVE: This study aims at evaluating oral and dental health problems and salivary function and composition in ulcerative colitis patients and its correlation with disease activity. METHODS: Xerostomia Inventory score, (unstimulated/stimulated) salivary flow rates, salivary amylase and mucin/ Mucin 5B levels, self-reported oral and dental complaints, the oral health related quality of life, Simple Clinical Colitis Activity Index and inflammatory bowel disease-specific health related quality of life were determined. RESULTS: The cohort consisted of 51 ulcerative colitis patients. Hyposalivation was experienced by 16% of patients under resting conditions and 24% under chewing-stimulated conditions. Xerostomia was not correlated with salivary flow rates. Disease activity did not influence salivary amylase and Mucin 5B concentrations. The Xerostomia Inventory score was correlated with the Simple Clinical Colitis Activity Index (p = 0.042) and inflammatory bowel disease-specific health related quality of life (p = 0.001). Most reported oral health problems were halitosis (29%) and aphthae (28%). Frequently reported dental problems were cavities (35%) and gum problems (31%). Patients with active disease experienced significantly more oral and dental complaints. The number of oral problems was positively correlated with the Simple Clinical Colitis Activity Index (p = 0.045) and negatively correlated with the inflammatory bowel disease-specific health related quality of life (p = 0.005). CONCLUSION: The subjective feeling of a dry mouth (xerostomia) is related to disease activity and disease activity-associated quality of life in ulcerative colitis patients, whereas the objective saliva secretion rate is not. Oral and dental health problems are frequently observed in patients with ulcerative colitis, especially during active disease.

Novel heterozygous truncating titin variants affecting the A-band are associated with cardiomyopathy and myopathy/muscular dystrophy.

BACKGROUND: Variants in TTN are frequently identified in the genetic evaluation of skeletal myopathy or cardiomyopathy. However, due to the high frequency of TTN variants in the general population, incomplete penetrance, and limited understanding of the spectrum of disease, interpretation of TTN variants is often difficult for laboratories and clinicians. Currently, cardiomyopathy is associated with heterozygous A-band TTN variants, whereas skeletal myopathy is largely associated with homozygous or compound heterozygous TTN variants. Recent reports show pathogenic variants in TTN may result in a broader phenotypic spectrum than previously recognized. METHODS: Here we report the results of a multisite study that characterized the phenotypes of probands with variants in TTN. We investigated TTN genotype-phenotype correlations in probands with skeletal myopathy and/or cardiomyopathy. Probands with TTN truncating variants (TTNtv) or pathogenic missense variants were ascertained from two academic medical centers. Variants were identified via clinical genetic testing and reviewed according to the American College of Medical Genetics criteria. Clinical and family history data were documented via retrospective chart review. Family studies were performed for probands with atypical phenotypes. RESULTS: Forty-nine probands were identified with TTNtv or pathogenic missense variants. Probands were classified by clinical presentation: cardiac (n = 30), skeletal muscle (n = 12), or both (cardioskeletal, n = 7). Within the cardioskeletal group, 5/7 probands had heterozygous TTNtv predicted to affect the distal (3') end of the A-band. All cardioskeletal probands had onset of proximal-predominant muscle weakness before diagnosis of cardiovascular disease, five pedigrees support dominant transmission. CONCLUSION: Although heterozygous TTNtv in the A-band is known to cause dilated cardiomyopathy, we present evidence that these variants may in some cases cause a novel, dominant skeletal myopathy with a limb-girdle pattern of weakness. These findings emphasize the importance of multidisciplinary care for patients with A-band TTNtv who may be at risk for multisystem disease.