Phenotypic manifestations of copy number variation in chromosome 16p13.11

The widespread clinical utilization of array comparative genome hybridization, has led to the unraveling of many new copy number variations (CNVs). Although some of these CNVs are clearly pathogenic, the phenotypic consequences of others, such as those in 16p13.11 remain unclear. Whereas deletions of 16p13.11 have been associated with multiple congenital anomalies, the relevance of duplications of the region is still being debated. We report detailed clinical and molecular characterization of 10 patients with duplication and 4 patients with deletion of 16p13.11. We found that patients with duplication of the region have varied clinical features including behavioral abnormalities, cognitive impairment, congenital heart defects and skeletal manifestations, such as hypermobility, craniosynostosis and polydactyly. These features were incompletely penetrant. Patients with deletion of the region presented with microcephaly, developmental delay and behavioral abnormalities as previously described. The CNVs were of varying sizes and were likely mediated by non-allelic homologous recombination between low copy repeats. Our findings expand the repertoire of clinical features observed in patients with CNV in 16p13.11 and strengthen the hypothesis that this is a dosage sensitive region with clinical relevance.     

Finite element analysis on the biomechanical stability of open porous titanium scaffolds for large segmental bone defects under physiological load conditions

Repairing large segmental defects in long bones caused by fracture, tumour or infection is still a challenging problem in orthopaedic surgery. Artificial materials, i.e. titanium and its alloys performed well in clinical applications, are plenary available, and can be manufactured in a wide range of scaffold designs. Although the mechanical properties are determined, studies about the biomechanical behaviour under physiological loading conditions are rare. The goal of our numerical study was to determine the suitability of open-porous titanium scaffolds to act as bone scaffolds. Hence, the mechanical stability of fourteen different scaffold designs was characterized under both axial compression and biomechanical loading within a large segmental distal femoral defect of 30 mm. This defect was stabilized with an osteosynthesis plate and physiological hip reaction forces as well as additional muscle forces were implemented to the femoral bone. Material properties of titanium scaffolds were evaluated from experimental testing. Scaffold porosity was varied between 64 and 80%. Furthermore, the amount of material was reduced up to 50%. Uniaxial compression testing revealed a structural modulus for the scaffolds between 3.5 GPa and 19.1 GPa depending on porosity and material consumption. The biomechanical testing showed defect gap alterations between 0.03 mm and 0.22 mm for the applied scaffolds and 0.09 mm for the intact bone. Our results revealed that minimizing the amount of material of the inner core has a smaller influence than increasing the porosity when the scaffolds are loaded under biomechanical loading. Furthermore, an advanced scaffold design was found acting similar as the intact bone.     

Personal protective equipment related skin reactions in healthcare professionals during COVID‐19

Since the outbreak of COVID‐19 pandemic, clinicians have had to use personal protective equipment (PPE) for prolonged periods. This has been associated with detrimental effects, especially in relation to the skin health. The present study describes a comprehensive survey of healthcare workers (HCWs) to describe their experiences using PPE in managing COVID‐19 patients, with a particular focus on adverse skin reactions. A 24‐hour prevalence study and multi‐centre prospective survey were designed to capture the impact of PPE on skin health of hospital staff. Questionnaires incorporated demographics of participants, PPE type, usage time, and removal frequency. Participants reported the nature and location of any corresponding adverse skin reactions. The prevalence study included all staff in intensive care from a single centre, while the prospective study used a convenience sample of staff from three acute care providers in the United Kingdom. A total of 108 staff were recruited into the prevalence study, while 307 HCWs from a variety of professional backgrounds and demographics participated in the prospective study. Various skin adverse reactions were reported for the prevalence study, with the bridge of the nose (69%) and ears (30%) being the most affected. Of the six adverse skin reactions recorded for the prospective study, the most common were redness blanching (33%), itchiness (22%), and pressure damage (12%). These occurred predominantly at the bridge of the nose and the ears. There were significant associations (P < .05) between the adverse skin reactions with both the average daily time of PPE usage and the frequency of PPE relief. The comprehensive study revealed that the use of PPE leads to an array of skin reactions at various facial locations of HCWs. Improvements in guidelines are required for PPE usage to protect skin health. In addition, modifications to PPE designs are required to accommodate a range of face shapes and appropriate materials to improve device safety.     

Effects of TIPS on liver perfusion measured by dynamic CT

OBJECTIVE: Our aim was to measure the arterial, portal venous, and total perfusion of the liver parenchyma with dynamic, single-section CT in patients with liver cirrhosis before and after transjugular intrahepatic portosystemic shunt (TIPS) placement and to compare the results with normal values. SUBJECTS AND METHODS: Perfusion of the liver parenchyma was measured in 24 healthy volunteers and 41 patients with liver cirrhosis using dynamic single-section CT. Seventeen patients underwent TIPS placement, and CT measurements were repeated within 7 days. CT scans were obtained at a single level comprising the liver, spleen, aorta, and portal vein. Scans were obtained over a period of 88 sec (one baseline scan followed by 16 scans every 2 sec and eight scans every 7 sec) beginning with the injection of a contrast agent bolus (40 mL at 10 mL/sec). Parenchymal and vascular contrast enhancement was measured with regions of interest, and time-density curves were obtained. These data were processed with a pharmaco-dynamic fitting program (TopFit), and the arterial and portal venous component and the total perfusion of the hepatic parenchyma were calculated (milliliters of perfusion per minute per 100 mL of tissue). RESULTS: Mean normal values for hepatic arterial, portal venous, and total perfusion were 20, 102, and 122 mL/min per 100 mL, respectively. In patients with cirrhosis before TIPS, mean hepatic arterial, portal venous, and total perfusion was 28, 63, and 91 mL/min per 100 mL, respectively, which was statistically significant for all values (p <0.05). After TIPS, hepatic perfusion increased to a mean value of 48, 65, 113 mL/min per 100 mL for arterial (p <0.01), portal venous, and total (p=0.011) perfusion, respectively. CONCLUSION: In patients with cirrhosis, the hepatic arterial perfusion increased, whereas portal venous and total perfusion decreased compared with that of healthy volunteers. TIPS placement caused a statistically significant increase of the hepatic arterial and total hepatic perfusion. The portal venous parenchymal perfusion remained unchanged.     

Evaluation of the ‘Prostate Interdisciplinary Communication and Mapping Algorithm for Biopsy and Pathology’ (PIC-MABP)

Introduction

Experience from interdisciplinary cooperation revealed the need for a prostate mapping scheme to communicate multiparametric MRI (mpMRI) findings between radiologists, urologists, and pathologists, which should be detailed, yet easy to memorize. For this purpose, the ‘Prostate interdisciplinary communication and mapping algorithm for biopsy and pathology’ (PIC-MABP) was developed. This study evaluated the accuracy of the PIC-MABP system.

Methods

PIC-MABP was tested and validated in findings of 10 randomly selected patients from routine clinical practise with 18 histologically proven cancer lesions. Patients received an mpMRI of the prostate prior to prostatectomy. After surgery the prostates were prepared as whole-mount step sections. Cancer lesions, which were found suspicious on mpMRI, were assigned to the according PIC-MABP sectors by a radiologist. MpMRI slides were masked and sent to seven urologists from different centres, providing only the PIC-MABP location of each lesion. Urologists marked the accordant regions. Then mpMRI slides were unmasked, and the correctness of each mark was evaluated.

Results

One hundred and seventeen of the 126 marks (93 %) were correctly assigned. Detection rates differed for lesions >0.5 cc compared with lesions <0.5 cc (p < 0.005): 3/7 (43 %) marks were correctly assigned in lesions <0.3 cc, 16/21 (76 %) in lesions with 0.3–0.5 cc, and 98/98 (100 %) in lesions >0.5 cc. Interobserver agreement was good for lesions >0.5 cc and poor for lesions <0.3 cc (Fleiss Kappa 1 vs. 0.0175).

Conclusion

PIC-MABP seems to be a reliable system to communicate the location of mpMRI findings >0.5 cc between different disciplines and can be a useful guidance for cognitive mpMRI/TRUS fusion biopsy.

     

Is prenatal urethral descent a risk factor for urinary incontinence during pregnancy and the postpartum period?

Introduction and hypothesis

Obstetric trauma during childbirth is considered a major risk factor for postpartum urinary incontinence (UI), particularly stress urinary incontinence. Our aim was to investigate the relation between postpartum UI, mode of delivery, and urethral descent, and to define a group of women who are particularly at risk of postnatal UI.

Methods

A total of 186 women were included their first pregnancy. Validated questionnaires about urinary symptoms during pregnancy, 2 and 12 months after delivery, were administered. Urethral descent was assessed clinically and by ultrasound at inclusion. Multivariate logistic regression analysis was used to determine the risk factors for UI during pregnancy, at 2 months and 1 year after first delivery.

Results

The prevalence of UI was 38.6, 46.5, 35.6, and 34.4 % at inclusion, late pregnancy, 2 months postpartum, and 1 year postpartum respectively. No significant association was found between UI at late pregnancy and urethral descent assessed clinically or by ultrasound. The only risk factor for UI at 2 months postpartum was UI at inclusion (OR 6.27 [95 % CI 2.70–14.6]). The risk factors for UI at 1 year postpartum were UI at inclusion (6.14 [2.22–16.9]), body mass index (BMI), and urethral descent at inclusion, assessed clinically (7.21 [2.20–23.7]) or by ultrasound. The mode of delivery was not associated with urethral descent.

Conclusions

Prenatal urethral descent and UI during pregnancy are risk factors for UI at 1 year postpartum. These results indicate that postnatal UI is more strongly influenced by susceptibility factors existing before first delivery than by the mode of delivery.

     

The role of bradykinin B1 and B2 receptors for secondary brain damage after traumatic brain injury in mice

Inflammatory mechanisms are known to contribute to the pathophysiology of traumatic brain injury (TBI). Since bradykinin is one of the first mediators activated during inflammation, we investigated the role of bradykinin and its receptors in posttraumatic secondary brain damage. We subjected wild-type (WT), B₁-, and B₂-receptor-knockout mice to controlled cortical impact (CCI) and analyzed tissue bradykinin as well as kinin receptor mRNA and protein expression up to 48 h thereafter. Brain edema, contusion volume, and functional outcome were assessed 24 h and 7 days after CCI. Tissue bradykinin was maximally increased 2 h after trauma (P<0.01 versus sham). Kinin B₁ receptor mRNA was upregulated up to four-fold 24 h after CCI. Immunohistochemistry showed that B₁ and B₂ receptors were expressed in the brain and were significantly upregulated in the traumatic penumbra 1 to 24 h after CCI. B₂R^−/− mice had significantly less brain edema (−51% versus WT, 24 h; P<0.001), smaller contusion volumes (∼50% versus WT 24 h and 7 d after CCI; P<0.05), and better functional outcome 7 days after TBI as compared with WT mice (P<0.05). The present results show that bradykinin and its B₂ receptors play a causal role for brain edema formation and cell death after TBI.     

Outcomes of patients with multiple sclerosis at a neurorehabilitation unit in Saudi Arabia

Objectives:To assess the impact of inpatient multidisciplinary rehabilitation on a Saudi Arabian population of patients with multiple sclerosis (MS).Methods:We retrospectively analyzed the data of patients with MS who underwent inpatient rehabilitation between 2009 and 2015 at King Fahad Medical City (KFMC). Differences in Functional Independence Measure (FIM) scores (used in rehabilitation settings to assess the functional independence of patients) and length of stay (LOS) were measured between patients of different ages, sexes, and types of MS and analyzed using the independent t-test. The Pearson correlation coefficient was used to investigate the correlation between FIM, LOS, and other variables.Results:In total, 24 patients were identified, with an average age of 36 years. The average age at disease onset was 31 years. Disease duration ranged from 1-20 years, with a mean of 7 years. The most common type of MS was relapsing-remitting (45.8%). The mean FIM score at admission was 77.5 and at discharge 97.25. Functional independence measure gain ranged from 2-51, with a mean of 18.58. Functional independence measure efficiency (FIM gain divided by LOS) ranged between 0.09-0.95. The length of stay ranged between 21-95 days, with a mean of 37.79 days. There was a significant association between age and FIM efficiency (p=0.043).Conclusions:Inpatient rehabilitation is an important intervention that improves the functional independence of patients with chronic MS.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating autoimmune disease with a female preponderance and an estimated prevalence of 30-190 cases per 100,000 people in Europe.1 Because of its early onset, progressive course, and long survival time, MS can lead to long-term disability with a significant negative impact on personal and social life.2,3 Among neurologic diseases, it is the third most common cause of disability, with 50% of patients requiring a walking aid and 10% requiring a wheelchair within 15 years of onset; within 25 years of onset, more than 90% of patients experience significant functional impairments.4,5 Life expectancy in patients with MS is reduced by about 5-10 years compared with age-matched individuals without MS.6 Around 2 million people worldwide are affected by MS.7 In young adults, this disabling neurodegenerative disease of the central nervous system is considered the leading cause of non-traumatic disability.8 In the Middle East, the risk of MS has recently been reported to be moderate to high.9 The Kurtzke classification places the Middle East in a low-risk zone for MS; however, a moderate-to-high prevalence in areas within the region (31-55 cases per 100,000 individuals), especially among women, has recently been reported.10,11 Thus, MS represents a considerable burden to Middle Eastern countries. In the Kingdom of Saudi Arabia, the prevalence of MS is poorly documented. Reviews of epidemiologic studies have suggested that it is underdiagnosed and that its prevalence is increasing.10,11 A few studies have reported an increase in the prevalence of MS in the Kingdom of Saudi Arabia to 40/100,000 in 2008 from 25/100,000 in 1998.9,12 Likewise, there are no data on the effects of inpatient rehabilitation in the Arabian Peninsula. In the literature, common treatment strategies are based on a combination of pharmacotherapy and rehabilitation. In daily practice, multidisciplinary rehabilitation (MDR) is often recommended to patients with MS. However, the evidence regarding the outcomes of MDR is contradictory. Some trials have reported improvements in impairment and in the mental component of a health-related quality of life measure, but others have shown that MDR improves the experience of people with MS in terms of activity and participation without changing the level of impairment.13,14-16 The overall evidence on the efficacy of MDR is limited by variation in the clinical presentation of MS and problems associated with study methodology.13 In this study, we assessed the impact of short-term inpatient MDR in a Saudi-Arabian population of patients with MS to identify the clinical predictors of effective rehabilitation treatment. At KFMC, both inpatient and outpatient services are included in the neurorehabilitation program. King Fahad Medical City treats patients from all regions of the country, including those internally transferred from the National Neuroscience Institute within KFMC. The integrated neurorehabilitation program was deemed to meet the standards of the Commission on Accreditation of Rehabilitation Facilities.17     

Daily fluctuation of emotions and memories thereof: Design and methods of an experience sampling study of major depression,social phobia,and controls

Symptom fluctuations and the dynamic contexts provoking these are poorly understood. This deficit is compounded by people's limited ability to accurately report about such dimensions in retrospect. Utilizing the advantages of experience sampling methodology (ESM), this study rigorously describes and tests proximal environmental, neurobiological and psychological factors associated with symptoms and mood states. Participants were assigned to three diagnostic groups: Major Depressive Disorder (MDD; n = 118), Social Phobia (SP; n = 47), or a Control Group without SP or MDD (CG; n = 119). Laboratory assessments included cognitive abilities, memory, constructs, and brain derived neurotrophic factor (BDNF). ESM lasted seven days, with six assessments per day covering symptoms, affect, daily events, social interactions, post‐event processing, well‐being, etc. Morning cortisol and actigraphy were also assessed during ESM. Thereafter, participants provided subjective retrospective recall estimates of the emotions they reported during ESM. The multi‐level data of >10,000 observations will allow for thorough examination of fluctuations of psychopathology and well‐being in two highly prevalent disorders. Using two clinical groups and a non‐affected control group, the clinical specificity versus generalizability of processes can be directly tested, thus providing stimulating information about the overlap and differences between anxiety and affective disorders. This research informs about the development, fluctuation, and maintaining factors of emotions and symptoms and examines the accuracy with which participants recall these dimensions.