Genotype–phenotype correlation in children with autosomal dominant polycystic kidney disease

Adults with autosomal dominant polycystic kidney disease (ADPKD) and PKD1 mutations have a more severe disease than do patients with PKD2 mutations. The aim of this study was to compare phenotypes between children with mutations in the PKD1/PKD2 genes. Fifty PKD1 children and ten PKD2 children were investigated. Their mean age was similar (8.6 ± 5.4 years and 8.9 ± 5.6 years). Renal ultrasound was performed, and office blood pressure (BP), ambulatory BP, creatinine clearance and proteinuria were measured. The PKD1 children had, in comparison with those with PKD2, significantly greater total of renal cysts (13.3 ± 12.5 vs 3.0 ± 2.1, P = 0.004), larger kidneys [right/left kidney length 0.89 ± 1.22 standard deviation score (SDS) vs 0.17 ± 1.03 SDS, P = 0.045, and 1.19 ± 1.42 SDS vs 0.12 ± 1.09 SDS, P = 0.014, successively] and higher ambulatory day-time and night-time systolic BP (day-time/night-time BP index 0.93 ± 0.10 vs 0.86 ± 0.05, P = 0.021 and 0.94 ± 0.07 vs 0.89 ± 0.04, P = 0.037, successively). There were no significant differences in office BP, creatinine clearance or proteinuria. Prenatal renal cysts (14%), hypertension defined by ambulatory BP (27%) and enlarged kidneys (32%) were observed only in the PKD1 children. This is the first study on genotype–phenotype correlation in children with ADPKD. PKD1 children have more and larger renal cysts, larger kidneys and higher ambulatory BP than do PKD2 children. Renal cysts and enlarged kidneys detected prenatally are highly specific for children with PKD1.     

Ankle fracture classification using deep learning: automating detailed AO Foundation/Orthopedic Trauma Association (AO/OTA) 2018 malleolar fracture identification reaches a high degree of correct classification

Background and purpose — Classification of ankle fractures is crucial for guiding treatment but advanced classifications such as the AO Foundation/Orthopedic Trauma Association (AO/OTA) are often too complex for human observers to learn and use. We have therefore investigated whether an automated algorithm that uses deep learning can learn to classify radiographs according to the new AO/OTA 2018 standards.Method — We trained a neural network based on the ResNet architecture on 4,941 radiographic ankle examinations. All images were classified according to the AO/OTA 2018 classification. A senior orthopedic surgeon (MG) then re-evaluated all images with fractures. We evaluated the network against a test set of 400 patients reviewed by 2 expert observers (MG, AS) independently.Results — In the training dataset, about half of the examinations contained fractures. The majority of the fractures were malleolar, of which the type B injuries represented almost 60% of the cases. Average area under the area under the receiver operating characteristic curve (AUC) was 0.90 (95% CI 0.82–0.94) for correctly classifying AO/OTA class where the most common major fractures, the malleolar type B fractures, reached an AUC of 0.93 (CI 0.90–0.95). The poorest performing type was malleolar A fractures, which included avulsions of the fibular tip.Interpretation — We found that a neural network could attain the required performance to aid with a detailed ankle fracture classification. This approach could be scaled up to other body parts. As the type of fracture is an important part of orthopedic decision-making, this is an important step toward computer-assisted decision-making.

Ankle fractures are recognized among the most common fractures, with peak incidence between 15 and 29 years (67 per 100,000 person-years) and elderly women ≥ 60 years (174 per 100,000 person-years) (Westerman and Porter 2007, Thur et al. 2012). Efforts to classify ankle fractures in clinically relevant entities have a long history, ending in 3 classic systems, i.e., the Lauge-Hansen (Hansen 1942), Danis–Weber, and the AO/OTA classifications (Association Committee for Coding and Classification 1996; Budny and Young 2008), where the Danis–Weber with its A, B, and C classes is probably the most used in everyday practice.The most recent update for the AO/OTA classification system was published in 2018 (Meinberg et al. 2018). The AO/OTA system contains classifications for the entire body. The ankle is divided into (1) malleolar, (2) distal tibia, and (3) fibular fractures. For malleolar fractures, the subcategories correspond to the Danis–Weber ABC classification (Hughes et al. 1979) with the addition of a suffix of 2 digits (range 1–3), e.g., the common intra-syndesmotic B-injury without widening of the mortise corresponds to the B1.1 class. The numbers correspond roughly to the severity of each fracture.The complexity of this classification makes it difficult to learn and apply, limiting inter-observer reliability and reproducibility (Fonseca et al. 2017). This has hindered its use in an everyday clinical setting, suggesting the need for better aid during the classification.During recent years, the resurgence of neural networks, a form of artificial intelligence (AI), has proven highly successful for image classification. In some medical image classification applications neural networks attain (Olczak et al. 2017, Kim and MacKinnon 2018, Gan et al. 2019), and surpass, human expert performance (Esteva et al. 2017, Lee et al. 2017, Chung et al. 2018, Urakawa et al. 2019). Machine learning and neural networks are also becoming more commonplace research tools in orthopedics. They hold great potential, as the diagnostic underpinning and intervention decision relies heavily on medical imaging (Cabitza et al. 2018). The strength of these learning algorithms is their ability to review a vast number of examinations and examples, and the speed and consistency with which they can review each examination and at the same time remember thousands of categories without issue.We therefore hypothesized that a neural network can learn to classify ankle fractures according to the AO/OTA 2018 classification from radiographs.     

Budesonide in collagenous colitis: a double-blind placebo-controlled trial with histologic follow-up.

BACKGROUND & AIMS: Collagenous colitis (CC) is a well-described entity causing chronic diarrhea and characteristic histologic findings. Several treatment options have been suggested, but no controlled data are available. We conducted a placebo-controlled trial to show the clinical and histologic effects of budesonide in CC. METHODS: Twenty-eight patients were randomly assigned to receive placebo (n = 14) or budesonide 9 mg daily (n = 14) for 8 weeks. Patients were evaluated clinically, and blinded biopsy specimens were analyzed from fixed locations at weeks 0 and 8. Clinical response was defined as a decrease of at least 50% in the disease activity score (number of bowel movements in the last 7 days). At week 8, nonresponders received open-label budesonide for the next 8-week period; responders discontinued treatment and were followed up. RESULTS: Three patients discontinued the study prematurely. Intention-to-treat analysis showed clinical response in 8 of 14 patients in the budesonide group compared with 3 of 14 responders for placebo (P = 0.05) after 8 weeks of blinded therapy, together with improved stool consistency. Histologically, there was no change in the mean thickness of the collagen band but a significant decrease of the lamina propria infiltrate in the budesonide group (P < 0.001). CONCLUSIONS: Budesonide is efficacious in inducing short-term clinical response in CC with significant reduction of the histologic infiltrate in the lamina propria.     

Ankylosing spondylitis and bowel disease

Clinical studies indicate an important role for bowel inflammation in ankylosing spondylitis and other spondyloarthropathies whereby two different aspects have to be considered. First, the gut inflammation is clinically and histologically closely related to Crohn's disease. Recent data on subclinical immune alterations confirm this relationship and suggest that spondyloarthropathy is a unique human model for studying early Crohn's disease. Second, bowel and peripheral joint inflammation are clinically, histologically and pathogenetically linked. The most important clinical implication of these observations is that targeted therapies for Crohn's disease could also be effective for intestinal as well as extra-intestinal disease manifestations in spondyloarthropathy, as evidenced by the recent studies on TNF-alpha blockade. Unravelling the gut-synovium axis in spondyloarthopathy could also contribute to the identification of new therapeutic targets. Finally, assessment of subclinical gut inflammation by histology, serology and genetics could contribute to the stratification of individual patients in subgroups with an optimal response to specific therapeutic interventions.     

Genetic and clinical characterization of sporadic cystic parathyroid tumours

objective The hyperparathyroidism–jaw tumour (HPT–JT) syndrome is one of the familial disorders characterized by primary hyperparathyroidism and has been linked to the chromosomal region of 1q32–q21. The parathyroid tumours related to this syndrome have shown loss of wild‐type alleles at this locus suggesting that inactivation of a tumour suppressor gene might be responsible for the disease. In the majority of these tumours cysts are a prominent feature. By loss of heterozygosity (LOH) studies, we investigated the region of interest in an attempt to clarify its possible role in a series of cystic sporadic parathyroid adenomas. design and subjects A total of 30 patients diagnosed with sporadic hyperparathyroidism were included in the study, genotyped with 17 polymorphic microsatellite markers at chromosome 1q, and additional markers from 1p and 11q13 which are commonly involved in sporadic parathyroid tumours. The cystic parathyroid tumours were characterized clinically, and immunohistochemistry against PTH was carried out to confirm the parathyroid origin of the cysts. results LOH was found in six of 30 tumours (20%) on 1q, six of 30 tumours (20%) on 1p and five of 30 tumours (17%) on 11q13. We found a significant correlation between allelic alterations and the clinical parameters, tumour weight and PTH. Furthermore, we found a significant difference between tumour weight and PTH in cases of cystic parathyroid tumours compared with unselected sporadic cases. conclusions These results suggest that cystic parathyroid tumours might represent a new subgroup among parathyroid tumours based on the genetic and clinical findings. Loss of heterozygosity at 1q further supports the presence of a tumour suppressor gene at this locus.     

Synthesis and Evaluation of Long-Acting D-Penicillamine Derivatives

This study extends the use of two lathyrogens, β-aminopropionitrile (BAPN) and D-penicillamine (DPA) from daily systemic or local-topical administration to long-time acting agents. This was achieved by converting the hydrophilic drugs into lipophilic derivatives. The synthesis of functional derivatives of DPA consisted in esterification with methyl-, hexyl-, or benzyl alcohols in the presence of thionylchloride. The esters formed were hydrochlorides, acidic and soluble in water. During neutralization in vitro or in vivo by tissue fluid, an oily substance is formed that elutes from a hydrogel polymer at a much slower rate than hydroplilic DPA itself. The degree of lipophilicity, measured as a partition coefficient between octanol/water, was highest for hexyl ester and lowest for methyl ester DPA. A single injection of either DPA hexyl ester HCl or 3-hexyl(amino) propionitrile into the full thickness skin incision wound in rats significantly lowered the breaking strength of the wound 12 days after injection, indicating the interference with collagen cross-linking. Both agents injected into the breast adenocarcinoma in Fisher rats significantly inhibited tumor growth without any signs of local or systemic toxicity. We conclude that these lipophilic lathyrogens with prolonged effectiveness are suitable in the treatment of pathologies, consisting of excessively cross-linked or deposited collagen (fibrotic adhesions, strictures, stenosis, and scar contractures) and in the treatment of single, solitary tumors, malignant and benign.     

Employment loss during economic crisis and suicidal thoughts in Belgium: a survey in general practice

Background

The economic crisis of 2009 led to a wave of corporate reorganisations and bankruptcies, with many dismissals of employees. GPs were confronted with subsequent health consequences.

Aim

To assess the possible relationship between losing one’s job and having suicidal thoughts.

Design and setting

A survey of patients aged 18–49 years recruited from GP practices in Belgium in Deurne (Flemish region) and La Louvière (Walloon region) from September to December 2010.

Method

Anonymous self-administered questionnaire.

Results

Of all eligible patients (n = 1818), 831 were offered the questionnaire and 377 completed it (45.4%). More than one in five had been confronted with employment loss in the past year (the responder or someone close losing their job). Almost one in ten had lost their job themselves in the past year. More than one in four had experienced suicidal thoughts and 11.7% had seriously considered ending their life in the past year. In the logistic regression analysis, the following characteristics showed a statistically significant relationship with having suicidal thoughts: being single (odds ratio [OR] = 4.8, 95% confidence interval [CI] = 1.7 to 13.8), not having satisfying social contacts (OR = 5.1, 95% CI = 1.6 to 16.2), having depressive complaints (OR = 18.4, 95% CI = 5.8 to 58.4), and having lost one’s employment in the past year (OR = 8.8, 95% CI = 2.0 to 39.3).

Conclusion

This study points to a statistically significant relationship between losing one’s employment in the past year and having suicidal thoughts. It emphasises the important role of the GP in the continuous and reinforced assessment of suicidal risk in times of recession.     

Pain associated with the musculoskeletal system in children from Warsaw schools

Objective

To assess the prevalence of pain in the musculoskeletal system and possible reasons for these complaints among early age children from Warsaw schools.

Material and methods

The study was conducted in 34 randomly selected primary schools in Warsaw in 2011. 2748 survey-questionnaires were given to parents or legal guardians by children. Of these, 1509 surveys were subject to a final analysis. The survey included 66 questions regarding, among other things, pain in the musculoskeletal system in children. Additionally, there were questions about possibly occurring diseases, any postural defects, significant obesity, as well as effects of these complaints on the child''s physical activity. Survey data regarded 6–7-year-old children.

Results

In the group of 1509 respondents, 242 children (16%) complained about pain in the musculoskeletal system. Pain was located most frequently in the knee joints, and more rarely in the spine and joints in the upper extremities. In the group of children who complained about pain, moderate physical activity was statistically significantly limited. According to parents, physicians did not diagnose any medical conditions in 106 children. Joint disease was diagnosed in 33 children. Postural defects were diagnosed in 589 children. In 123 children complaining about pain at least one postural defect was diagnosed. Such defects were diagnosed statistically significantly more rarely (p = 0.011) in 1234 children who did not complain about pain (460 children). Platypodia or other foot deformation was observed in 25% of these children, spinal curvature in 12%, abnormal knee joint position in 11% and uneven hip position in 2% children. Of note, 17% of all children were significantly overweight. In overweight children the prevalence of pain, especially in the knee joints and feet, was significantly higher.

Conclusions

This study aims to underline the problem of musculoskeletal pain in early-age children which limits their physical activity. Also the authors draw attention to the issue of postural defects in a large group of school children. This issue undoubtedly requires more attention and a plan how to create more effective methods of prevention.