Activity behaviors and relative changes in activity patterns recorded by precision technology were associated with diarrhea status in individually housed calves.

The objective of this case-control study was to quantify any association of daily activity behaviors and relative changes in activity patterns (lying time, lying bouts, step count, activity index) with diarrhea status in preweaning dairy calves. Individually housed calves sourced from auction were health-scored daily for signs of diarrhea (fecal consistency loose or watery for 2 consecutive days) for the 28 d after arrival. Calves with diarrhea were pair-matched with healthy controls (n = 13, matched by arrival date, arrival weight, and diagnosis days to diarrheic calves). Mixed linear regression models were used to evaluate the association of diarrhea status, and the diarrhea status by day interaction with activity behaviors (d -3 to d 4) and relative changes in activity patterns (d -3 to d 4) relative to diagnosis of a diarrhea bout. The serum Brix percentage at arrival and daily temperature-humidity index from the calf barn were explored as quantitative covariates, with day as a repeated measure. The baseline for relative changes in activity patterns was set at 100% on d 0. Diarrheic calves were less active; they averaged fewer steps (119.1 ± 18.81 steps/d) than healthy calves (227.4 ± 18.81 steps/d, LSM ± SEM). Diarrheic calves also averaged lower activity indices (827.34 ± 93.092 daily index) than healthy calves (1,396.32 ± 93.092 daily index). We also found also a diarrhea status by day interaction for lying time on d -3, with diarrheic calves spending more time lying (20.80 ± 0.300 h/d) than healthy calves (19.25 ± 0.300 h/d). For relative changes in activity patterns, a diarrhea status by day interaction was detectable on d -2, where diarrheic calves had greater relative changes in step counts (diarrhea 634.85 ± 87.581% vs. healthy 216.51 ± 87.581%) and activity index (diarrhea 316.83 ± 35.692% vs. healthy 150.68 ± 35.692%). Lying bouts were not associated with diarrhea status. These results show that diarrheic calves were more lethargic, and they had relative changes in activity patterns 2 d before clinical signs of diarrhea. Future research should explore the potential of an activity alert that positively indicates an individually housed calf at risk for a diarrhea bout using deviations from relative changes in individual calf activity patterns.

Implication of chromosomal microarray analysis prior to in-utero repair of fetal open neural tube defect.

OBJECTIVE: In-utero repair of open neural tube defects (ONTD) is an accepted treatment option with demonstrated superior outcome for eligible patients. While current guidelines recommend genetic testing by chromosomal microarray analysis (CMA) when a major congenital anomaly is detected prenatally, the requirement for an in-utero repair, based on the Management of Myelomeningocele Study (MOMS) criteria, is a normal karyotype. In this study, we aimed to evaluate if CMA should be recommended as a prerequisite for in-utero ONTD repair. METHODS: This was a retrospective cohort study of pregnancies complicated by ONTD that underwent laparotomy-assisted fetoscopic repair or open-hysterotomy fetal surgery at a single tertiary center between September 2011 and July 2021. All patients met the MOMS eligibility criteria and had a normal karyotype. In a subset of the pregnancies (n = 77), CMA testing was also conducted. We reviewed the CMA results and divided the cohort into two groups according to whether clinically reportable copy-number variants (CNV) were detected (reportable-CNV group) or not (normal-CMA group). Surgical characteristics, complications, and maternal and early neonatal outcomes were compared between the two groups. The primary outcomes were fetal or neonatal death, hydrocephalus, motor function at 12 months of age and walking status at 30 months of age. Standard parametric and non-parametric statistical tests were employed as appropriate. RESULTS: During the study period, 146 fetuses with ONTD were eligible for and underwent in-utero repair. CMA results were available for 77 (52.7%) patients. Of those, 65 (84%) had a normal CMA and 12 (16%) had a reportable CNV, two of which were classified as pathogenic. The first case with a pathogenic CNV was diagnosed with a 749-kb central 22q11.21 deletion spanning low-copy-repeat regions B-D of chromosome 22; the second case was diagnosed with a 1.3-Mb interstitial deletion at 1q21.1q21.2. Maternal demographics, clinical characteristics, operative data and postoperative complications were similar between those with normal CMA results and those with reportable CNVs. There were no significant differences in gestational age at delivery or any obstetric and early neonatal outcome between the study groups. Motor function at birth and at 12 months of age, and walking status at 30 months of age, were similar between the two groups. CONCLUSIONS: Standard diagnostic testing with CMA should be offered when an ONTD is detected prenatally, as this approach has implications for counseling regarding prognosis and recurrence risk. Our results indicate that the presence of a clinically reportable CNV should not a priori affect eligibility for in-utero repair, as overall pregnancy outcome is similar in these cases to that of cases with normal CMA. Nevertheless, significant CMA results will require a case-by-case multidisciplinary discussion to evaluate eligibility. To generalize the conclusion of this single-center series, a larger, multicenter long-term study should be considered. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Comparison of the marine soundscape before and during the COVID-19 pandemic in dolphin habitat in Sarasota Bay, FL.

During the COVID-19 pandemic, changes in vessel activity and associated noise have been reported globally. Sarasota Bay is home to a large and increasing number of recreational vessels as well as a long-term resident community of bottlenose dolphins, Tursiops truncatus. Data were analyzed from two hydrophones to compare the soundscape during the COVID-19 pandemic to previous years (March-May 2020 and 2018/2019). Hourly metrics were calculated: vessel passes, 95th percentile sound levels [125 Hz and 16 kHz third octave bands (TOBs), and two broader bands: 88-1122 Hz and 1781-17 959 Hz], and dolphin whistle detection to understand changes in vessel activity and the effect on wildlife. Vessel activity increased during COVID-19 restrictions by almost 80% at one site and remained the same at the other site. Of the four sound level measures, only the 125 Hz TOB and 88-1122 Hz band increased with vessel activity at both sites, suggesting that these may be appropriate measures of noise from rapid pass-bys of small vessels in very shallow (<10 m) habitats. Dolphin whistle detection decreased during COVID-19 restrictions at one site but remained the same at the site that experienced increased vessel activity. The results suggest that pandemic effects on wildlife should not be viewed as homogeneous globally.

"What needs to be seen": An exploration into the visual anticipation behaviour of different skill-level football referees while observing long passes on-field.

It is well established that elite football referees possess superior anticipatory skills in specific game scenarios such as when assessing foul situations. Referees might also have better anticipatory skills in other important scenarios such as when observing a long pass. In these often-occurring situations, a referee has to use visual information to anticipate the outcome of the pass, in particular to foresee any potential infringements that might occur when players battle for ball possession. However, little is known about if and how football referees might anticipate outcomes in these scenarios. The aim of the current study was therefore to analyse the visual anticipatory behaviour of football referees when long passes occur during actual football matches. Elite (N = 4) and sub-elite referees (N = 12) officiated an actual football match while wearing a mobile eye-tracker to analyse their gaze behaviour when long passes occurred (N = 196). The results revealed differences in the way that the elite and sub-elite referees tracked the ball and anticipated the outcome of the ball trajectories. The elite referees used a lower search rate (1.3 vs 1.8 fix/s; p < .05) and were more likely to direct their gaze towards the ball during the moment of kick (77 vs 52%; p < .05) and the early flight-phase of the pass (68 vs 45%; p < .05), and subsequently produced earlier anticipatory eye movements to the player(s) receiving the ball (at 50% vs 60% of the ball flight; p < .05). This earlier anticipation may help the elite referees to better pick-up relevant information about the receivers that could be vital in making adjudications about any potential infringement when the ball does arrive. Referee education programs can use the current study to highlight the importance of visual search behaviour and help referees to adapt a strategy that is beneficial for long-pass situations.

Identification of Health Systems Science in a Problem-Based Learning Clinical Reasoning Exercise.

The creation of developmentally appropriate and meaningfully complex clinical reasoning exercises in the pre-clerkship curriculum is a common challenge for many medical schools. We provide an overview of one component of the pre-clerkship clinical reasoning curriculum at Case Western Reserve University School of Medicine, and present evidence that inclusion of Health Systems Science in this exercise facilitates integrated thinking in a Problem-Based Learning curriculum.

Fetal heart rate mirrors maternal temperature during posterior fossa craniotomy: a case report.

While it is well known that maternal temperature affects fetal heart rate, the exact relationship is not well described. The circumstances accompanying most cases of maternal hypothermia and rewarming (e.g. a drowning event) have precluded a precise quantitative description of this relationship. We describe hypothermia and controlled rewarming during resection of a maternal brain stem tumor in the early third trimester. Continuous electronic fetal heart rate and core temperature monitoring demonstrated a near linear relationship during the development of hypothermia and rewarming. Recognition of the close relationship between maternal temperature and fetal heart rate can help safeguard maternal and fetal health, and prevent unnecessary delivery during non-obstetric surgery in pregnancy.

RNA sequencing reveals changes in the microRNAome of transdifferentiating hepatic stellate cells that are conserved between human and rat.

MicroRNAs are small (~ 22nt long) noncoding RNAs (ncRNAs) that regulate gene expression at the post-transcriptional level. Over 2000 microRNAs have been described in humans and many are implicated in human pathologies including tissue fibrosis. Hepatic stellate cells (HSC) are the major cellular contributors to excess extracellular matrix deposition in the diseased liver and as such are important in the progression of liver fibrosis. We employed next generation sequencing to map alterations in the expression of microRNAs occurring across a detailed time course of culture-induced transdifferentiation of primary human HSC, this a key event in fibrogenesis. Furthermore, we compared profiling of human HSC microRNAs with that of rat HSC so as to identify those molecules that are conserved with respect to modulation of expression. Our analysis reveals that a total of 229 human microRNAs display altered expression as a consequence of HSC transdifferentiation and of these 104 were modulated early during the initiation phase. Typically modulated microRNAs were targeting kinases, transcription factors, chromatin factors, cell cycle regulators and growth factors. 162 microRNAs changed in expression during transdifferentiation of rat HSC, however only 17 underwent changes that were conserved in human HSC. Our study therefore identifies widespread changes in the expression of HSC microRNAs in fibrogenesis, but suggests a need for caution when translating data obtained from rodent HSC to events occurring in human cells.

Evaluating the utility of pre-operative airway assessment for intubation management in difficult airway patients.

OBJECTIVE: To assess intubation management in difficult airway patients by performing a multidisciplinary pre-operative examination of the airway using a flexible fibre-optic laryngoscope. METHODS: Patients with a known but stable difficult airway were evaluated prior to surgery in the pre-operative holding suite by both an ENT surgeon and an anaesthesiologist via a fibre-optic laryngeal examination. RESULTS: Performing a pre-operative fibre-optic examination of the difficult airway led to a change in intubation strategy in 6 out of 12 cases. Intubation 'first-pass' success occurred in 9 out of 12 (75 per cent) of our patients. CONCLUSION: By performing a multidisciplinary airway examination immediately prior to surgery, a safe plan to intubate on the initial attempt was developed. This resulted in improved first-pass success at intubation compared to historical data.

Microarray analysis of primary epithelial and fibroblast cells in chronic rhinosinusitis without nasal polyps.

BACKGROUND: Chronic rhinosinusitis is an inflammatory condition with an as yet unknown pathophysiology. We aimed to detect clusters of differentially regulated genes in the epithelial and fibroblast cells of patients with Chronic Rhinosinusitis without nasal polyposis (CRSsNP) and healthy controls. METHODOLOGY: Carefully phenotyped CRSsNP and healthy control participants were recruited. Primary cultures of isolated epithelial and fibroblast cells were established. Whole transcriptome analysis of the cells was performed using microarrays and replicated with quantitative RT-PCR and immunohistochemistry. RESULTS: Fibroblast cells from CRSsNP patients showed a significant upregulation (more than 2x) of the transcription factor NFE2L3 when compared to healthy controls by microarray with multiple hypothesis testing correction, qRT-PCR and immunohistochemistry. CONCLUSIONS: Here we have utilized microarray analysis to search for differentially expressed genes in isolated patient derived epithelial and fibroblast cells. The transcription factor NFE2L3 has been shown to be upregulated in fibroblast cells consistent with increasing evidence that fibroblasts play a key role in tissue specific inflammation within the paranasal sinuses.

Assessing manual wheelchair caster design for mobility in winter conditions.

Wheelchair users who live in cold climates are faced with daily difficulties related to personal independence and societal inclusion as their assistive devices are unable to overcome the physical barriers created by snow and ice. The purpose of the research was to evaluate four commercially available casters to determine which caster performed best on snow-covered surfaces. Performance measures included: travel time, force transfer through the palms of the hands, number of propulsive movements, static resistance to movement, kinetic resistance to movement, and caster penetration into the packed snow. On a snow-covered incline, the FreeWheel™ caster enabled travel time to be decreased by 10 s, requiring 3 fewer propulsive movements and 60% of the amount of force to propel the wheelchair compared with solid casters. Static and kinetic resistance tests did not differentiate the four caster types. Penetration into packed snow was reduced from 11.9 mm to approximately 1 mm by changing from solid casters to the FreeWheel™ or Wheelblades™ caster types on flat surfaces. Similar results were observed on a snow-covered incline for the Wheelblades™, however, the FreeWheel™ penetrated approximately 8 mm. Considering the entire body of evidence, the FreeWheel™ performed the best on snow-covered surfaces.

Question prompts to empower cancer patients: results of a randomized controlled trial.

OBJECTIVE: In addition to question prompts for information transfer, we also used prompts to facilitate the expression of emotions. Our aim was to investigate how a question prompt list (QPL) is accepted by patients and whether it enhances interactional empowerment of the patients in the consultation with the radio-oncological treatment team before the beginning of radiotherapy. METHODOLOGY: Adult cancer patients before the beginning of radiotherapy were randomly assigned to the intervention group (IG) or control group (CG). The patients in the IG received a QPL with predefined subsets and subject areas. After the physician's consultation, both groups completed a self-developed, content validated questionnaire on interactional empowerment. The IG evaluated the QPL using a self-developed instrument. RESULT: A total of 279 adult cancer patients participated in the study (IG n = 139/CG n = 140). The participants of the IG reported a significantly higher interactional empowerment compared with those of the CG (t(277) = - 2.71, p = .007, 95% CI [- 1.61, - 0.26], d = 0.29). 60.4% of the IG agreed "rather" or "very" that they used the QPL in consultation with the medical team. CONCLUSION: The QPL used in the consultation improved the self-assessed competence for interaction with the medical team and strengthened the interactional empowerment. The QPL was well accepted by the patients and is to be introduced into a routine as a practicable and simple instrument in the future. The support of patients in addressing concerns and fears is an important innovation.

The role of lysosomes and autophagosomes in frontotemporal lobar degeneration.

INTRODUCTION: Cell biological and genetic evidence implicate failures in degrading aggregating proteins, such as tau and TDP-43, through the autophagy or lysosomal pathways in the pathogenesis of frontotemporal lobar degeneration (FTLD). METHODS: We investigated changes in the degradative pathways in 60 patients with different pathological or genetic forms of FTLD employing immunohistochemistry for marker proteins such as lysosomal-associated membrane proteins 1 (LAMP-1) and 2 (LAMP-2), cathepsin D (CTSD) and microtubule-associated protein 1 light chain 3 alpha (LC3A). Immunostained sections were qualitatively and semi-quantitatively assessed for the appearance, distribution and intensity of staining in neurones of the dentate gyrus (DG) and CA4 region of the hippocampus, and the temporal cortex (Tcx). RESULTS: Lower levels of neuronal LAMP-1 immunostaining were present in the DG and Tcx in FTLD-tau compared to FTLD-TDP. There was less LAMP-1 immunostaining in FTLD-tau with MAPT mutations, and FTLD-tau with Pick bodies, compared to FTLD-TDP types A and B, and less LAMP-1 immunostaining in FTLD-TDP type C than in FTLD-TDP types A and B. There was greater LAMP-1 immunostaining in GRN mutation which may reflect the underlying type A histology rather than mutation. There were no differences in neuronal LAMP-2, CTSD, EEA-1 or LC3A immunostaining between any of the five FTLD histological or four genetic groups, nor between FTLD-TDP and FTLD-tau. CONCLUSIONS: The underlying pathological mechanism in FTLD-tau may lie with a relative deficiency of lysosomes, or defective vesicular transport, whereas the failure to clear TDP-43 aggregates may lie with lysosomal dysfunction rather than a lack of available lysosomes or degradative enzymes.

CYP3A4 genotype is associated with sildenafil concentrations in patients with heart failure with preserved ejection fraction.

Despite its established inter-individual variability, sildenafil has been the subject of only a few pharmacogenetic investigations, with limited data regarding the genetic modulators of its pharmacokinetics. We conducted a pharmacogenetic sub-study of patients randomized to sildenafil (n=85) in the RELAX trial, which investigated the impact of high-dose sildenafil in patients with heart failure with preserved left ventricular ejection fraction (HFpEF). In the overall population, the CYP3A4 inferred phenotype appeared associated with the dose-adjusted peak concentrations of sildenafil at week 12 and week 24 (adjusted P=0.045 for repeated measures analysis), although this P-value did not meet our corrected significance threshold of 0.0167. In the more homogeneous Caucasian subgroup, this association was significant (adjusted P=0.0165 for repeated measures). Hence, CYP3A4 inferred phenotype is associated with peak sildenafil dose-adjusted concentrations in patients with HFpEF receiving high doses of sildenafil. The clinical impact of this association requires further investigation.

Inflammatory pathology markers (activated microglia and reactive astrocytes) in early and late onset Alzheimer disease: a post mortem study.

AIMS: The association between the pathological features of AD and dementia is stronger in younger old persons than in older old persons suggesting that additional factors are involved in the clinical expression of dementia in the oldest old. Cumulative data suggests that neuroinflammation plays a prominent role in Alzheimer's disease (AD) and different studies reported an age-associated dysregulation of the neuroimmune system. Consequently, we sought to characterize the pattern of microglial cell activation and astrogliosis in brain post mortem tissue of pathologically confirmed cases of early and late onset AD (EOAD and LOAD) and determine their relation to age. METHODS: Immunohistochemistry (CD68 and glial fibrillary acidic protein) with morphometric analysis of astroglial profiles in 36 cases of AD and 28 similarly aged controls. RESULTS: Both EOAD and LOAD groups had higher microglial scores in CA1, entorhinal and temporal cortices, and higher astroglial response in CA1, dentate gyrus, entorhinal and temporal cortices, compared to aged matched controls. Additionally, EOAD had higher microglial scores in subiculum, entorhinal and temporal subcortical white matter, and LOAD higher astrogliosis in CA2 region. CONCLUSIONS: Overall, we found that the neuroinflammatory pathological markers in late stage AD human tissue to have a similar pattern in both EOAD and LOAD, though the severity of the pathological markers in the younger group was higher. Understanding the age effect in AD will be important when testing modifying agents that act on the neuroinflammation.

A pharmacogenetic investigation of intravenous furosemide in decompensated heart failure: a meta-analysis of three clinical trials.

We conducted a meta-analysis of pharmacogenomic substudies of three randomized trials conducted in patients with decompensated heart failure (HF) that were led by National Heart Lung and Blood Institute (NHLBI)-funded HF Network to test the hypothesis that candidate genes modulate net fluid loss and weight change in patients with decompensated HF treated with a furosemide-based diuretic regimen. Although none of the genetic variants previously shown to modulate the effects of loop diuretics in healthy individuals were associated with net fluid loss after 72 h of treatment, a set of rare variants in the APOL1 gene, which codes for apolipoprotein L1 (P=0.0005 in the random effects model), was associated with this end point. Moreover, a common variant in the multidrug resistance protein-4 coding gene (ABCC4, rs17268282) was associated with weight loss with furosemide use (P=0.0001). Our results suggest that both common and rare genetic variants modulate the response to a furosemide-based diuretic regimen in patients with decompensated HF.

Early changes in extracellular matrix in Alzheimer's disease.

AIMS: Although changes in extracellular matrix (ECM) scaffold have been reported previously in Alzheimer's disease (AD) compared to normal ageing, it is not known how alterations in the numerous components of the perivascular ECM might occur at different stages of AD. This study therefore investigates potential changes in basement membrane-associated ECM molecules in relation to increasing Braak stages. METHODS: Thirty patients were divided into three groups (control subject, subclinical AD and AD patients). ECM levels of collagen IV, perlecan and fibronectin as well as human platelet endothelial cell adhesion molecule (hPECAM) were quantified by immunohistochemistry. Von Willebrand factor staining was measured to assess vessel density. Expression levels were correlated with the presence of amyloid plaques. RESULTS: Collagen IV, perlecan and fibronectin expression was increased in subclinical AD and AD patients when compared to controls, in frontal and temporal cortex, whilst no further increase was detected between subclinical AD and AD. These changes were not associated with an increase in vessel density, which was instead decreased in the temporal cortex of AD patients. In contrast, hPECAM levels remained unchanged. Finally, we found similar pattern in levels of amyloid deposition between the different Braak stages and showed that changes in ECM components correlated with amyloid deposition. CONCLUSION: Present data support the hypothesis that significant ECM changes occur during the early stages of AD. ECM changes affecting brain microvascular functions could therefore drive disease progression and provide potential new early investigational biomarkers in AD.

International consensus on the definition and classification of fibrosis of the knee joint.

AIMS: The aim of this consensus was to develop a definition of post-operative fibrosis of the knee. PATIENTS AND METHODS: An international panel of experts took part in a formal consensus process composed of a discussion phase and three Delphi rounds. RESULTS: Post-operative fibrosis of the knee was defined as a limited range of movement (ROM) in flexion and/or extension, that is not attributable to an osseous or prosthetic block to movement from malaligned, malpositioned or incorrectly sized components, metal hardware, ligament reconstruction, infection (septic arthritis), pain, chronic regional pain syndrome (CRPS) or other specific causes, but due to soft-tissue fibrosis that was not present pre-operatively. Limitation of movement was graded as mild, moderate or severe according to the range of flexion (90° to 100°, 70° to 89°, < 70°) or extension deficit (5° to 10°, 11° to 20°, > 20°). Recommended investigations to support the diagnosis and a strategy for its management were also agreed. CONCLUSION: The development of standardised, accepted criteria for the diagnosis, classification and grading of the severity of post-operative fibrosis of the knee will facilitate the identification of patients for inclusion in clinical trials, the development of clinical guidelines, and eventually help to inform the management of this difficult condition. Cite this article: Bone Joint J 2016;98-B:1479-88.