Genomic diagnostics in polycystic kidney disease: an assessment of real-world use of whole-genome sequencing

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is common, with a prevalence of 1/1000 and predominantly caused by disease-causing variants in PKD1 or PKD2. Clinical diagnosis is usually by age-dependent imaging criteria, which is challenging in patients with atypical clinical features, without family history, or younger age. However, there is increasing need for definitive diagnosis of ADPKD with new treatments available. Sequencing is complicated by six pseudogenes that share 97% homology to PKD1 and by recently identified phenocopy genes. Whole-genome sequencing can definitively diagnose ADPKD, but requires validation for clinical use. We initially performed a validation study, in which 42 ADPKD patients underwent sequencing of PKD1 and PKD2 by both whole-genome and Sanger sequencing, using a blinded, cross-over method. Whole-genome sequencing identified all PKD1 and PKD2 germline pathogenic variants in the validation study (sensitivity and specificity 100%). Two mosaic variants outside pipeline thresholds were not detected. We then examined the first 144 samples referred to a clinically-accredited diagnostic laboratory for clinical whole-genome sequencing, with targeted-analysis to a polycystic kidney disease gene-panel. In this unselected, diagnostic cohort (71 males :73 females), the diagnostic rate was 70%, including a diagnostic rate of 81% in patients with typical ADPKD (98% with PKD1/PKD2 variants) and 60% in those with atypical features (56% PKD1/PKD2; 44% PKHD1/HNF1B/GANAB/ DNAJB11/PRKCSH/TSC2). Most patients with atypical disease did not have clinical features that predicted likelihood of a genetic diagnosis. These results suggest clinicians should consider diagnostic genomics as part of their assessment in polycystic kidney disease, particularly in atypical disease.Subject terms: Genetics research, Polycystic kidney disease, Genetic testing     

Experimental study of a novel fibrin sealant for achieving haemostasis following partial hepatectomy

BACKGROUND: Ensuring adequate haemostasis is a major difficulty in the field of liver surgery. This study aimed to evaluate a novel fibrin sealant (Vivostat), designed for autologous preparation, in a porcine model of partial hepatectomy. METHODS: Thirty-six Large White Landrace pigs underwent partial left hepatectomy by finger fracture under portal vascular inflow occlusion. Animals were randomized to treatment of the resected surface with either fibrin sealant (Vivostat, n = 12) or regenerated oxidized cellulose gauze (Surgicel, n = 12), or were left untreated (controls, n = 12). Blood loss from the resection margin was measured at 2-min intervals for 10 min, and the time to haemostasis was recorded. Following complete haemostasis the animals recovered for 7 days. RESULTS: Median (range) blood loss in the control group was 94.3 (17.3-467.0) g, and was significantly reduced with Vivostat (13.8 (5.5-150.9) g) and Surgicel (22.8 (5.8-67.3) g). Median (range) time to haemostasis in controls (31 (12-52) min) was also significantly reduced by Vivostat (8 (0-32) min) and Surgicel (10 (0-19) min) (both P < 0.001 versus controls, Kruskal-Wallis test). CONCLUSION: The novel fibrin sealant, Vivostat, is as effective as Surgicel cellulose gauze in achieving haemostasis after porcine partial hepatic lobectomy.     

Minimal Incision Surgery as a Risk Factor for Early Failure of Total Knee Arthroplasty

A consecutive series of revision total knee arthroplasty (TKA) performed at 3 centers by 5 surgeons for a 3-year period was reviewed. Revisions performed for infection and rerevisions were excluded. Review of clinical and radiographic data determined incision type, sex, age, time to revision, and primary diagnosis at time of revision. Two-hundred thirty-seven first-time revision TKAs were performed, of which 44 (18.6%) had been a minimal incision surgery (MIS) primary TKA and 193 (81.4%) had been a standard primary TKA. Patients with MIS were younger (62.1 vs 66.2 years, P = .02). Most striking was the difference in time to revision, which was significantly shorter for the MIS group (14.8 vs 80 months, P < .001). Minimal incision surgery TKA accounted for a substantial percentage of revision TKA in recent years at these centers. The high prevalence of MIS failures occurring within 24 months is disturbing and warrants further investigation.     

Chronic pain associated with penile prostheses may persist despite revision or explantation

IntroductionInflatable penile prosthesis (IPP) implantation is the gold standard treatment for medically refractory erectile dysfunction. New chronic pain after IPP implantation is rarely discussed and the optimal treatment is unclear. We evaluated whether IPP re-operation for a primary indication of chronic pain improves patients’ symptoms. Our secondary aim was to explore factors associated with resolution or persistence of pain after IPP reoperation.MethodsWe conducted a retrospective analysis of 315 patients who had an IPP revision or explantation at two high-volume prosthetic centers between May 2007 and May 2017. We excluded patients who had device malfunction, pain for <2 months, pain associated with infection or erosion, and patients without long-term followup data. Persistent pain was diagnosed based on patient self-report.ResultsA total of 31 patients met our criteria for having undergone a surgical revision (n=18) or explantation (n=13) for pain relief. Eighteen (58%) patients had persistent pain despite surgical intervention. Only patients who had pain secondary to a device malposition improved after re-operation (n=13). A prior diagnosis of a chronic pain syndrome was associated with persistent pain despite intervention. Pain improvement was not associated with age, comorbid conditions, duration of implant, or the number of surgical revisions performed.ConclusionsSurgical intervention for chronic penile prosthesis pain is unlikely to relieve symptoms, particularly for patients with chronic pain disorders. Patients should be counselled that IPP reoperative procedures as a treatment for pain should be avoided unless the device is identified to be malpositioned, and consideration of alternative therapeutic options may be more beneficial.     

Gallbladder volvulus: An unexpected “twist”

Gallbladder volvulus is a rare entity. It has been attributed to an elongated gallbladder mesentery, predisposing the gallbladder to twisting, obstructing the cystic duct and vessels, thus leading to ischemia and gangrene. Preoperative diagnosis can be elusive, but radiological features across multiple modalities have been described in the literature. We report a case of gallbladder volvulus in which the gallbladder appeared to be left-sided based on imaging, and present the radiological findings in keeping with a volvulus. Unlike cholecystitis, the treatment for volvulus is prompt detorsion and cholecystectomy; thus, accurate and timely diagnosis is paramount.     

Feeling,caring, knowing: different types of empathy deficit in boys with psychopathic tendencies and autism spectrum disorder

Background: Empathy dysfunction is one of the hallmarks of psychopathy, but it is also sometimes thought to characterise autism spectrum disorders (ASD). Individuals with either condition can appear uncaring towards others. This study set out to compare and contrast directly boys with psychopathic tendencies and boys with ASD on tasks assessing aspects of affective empathy and cognitive perspective taking. The main aim of the study was to assess whether a distinct profile of empathy deficits would emerge for boys with psychopathic tendencies and ASD, and whether empathy deficits would be associated with conduct problems in general, rather than psychopathic tendencies or ASD specifically. Methods: Four groups of boys aged between 9 and 16 years (N = 96) were compared: 1) psychopathic tendencies, 2) ASD, 3) conduct problems and 4) comparison. Tasks were included to probe attribution of emotions to self, empathy for victims of aggression and cognitive perspective‐taking ability. Results: Boys with psychopathic tendencies had a profile consistent with dysfunctional affective empathy. They reported experiencing less fear and less empathy for victims of aggression than comparison boys. Their cognitive perspective‐taking abilities were not statistically significantly different from those of comparison boys. In contrast, boys with ASD had difficulties with tasks requiring cognitive perspective taking, but reported emotional experiences and victim empathy that were in line with comparison boys. Boys with conduct problems did not differ from comparison boys, suggesting that the affective empathy deficit seen in boys with psychopathic tendencies was specific to that group, rather than common to all boys with conduct problems. Conclusions: Although both groups can appear uncaring, our findings suggest that the affective/information processing correlates of psychopathic tendencies and ASD are quite different. Psychopathic tendencies are associated with difficulties in resonating with other people’s distress, whereas ASD is characterised by difficulties in knowing what other people think.     

(Re-)conceptualisation in Asperger’s Syndrome and Typical Individuals with Varying Degrees of Autistic-like Traits

The abilities to form new concepts from scratch (conceptualisation), and to flexibly switch from one concept to another (re-conceptualisation), were investigated in adults with Asperger’s Syndrome and in typically-developed adults with low and high autism spectrum quotients. In consecutively presented morphs, containing increasing percentages of animate or inanimate objects, the emerging objects had to be identified. The abilities to conceptualise and reconceptualise became increasingly impaired with increasing autistic(-like) traits. Across both tasks, all groups recognised animate objects quicker than inanimate objects. However, this ‘animate advantage’ was differently affected by the two tasks. In the Reconceptualisation task, the ‘animate advantage’ gradually disappeared with increasing autistic(-like) traits, whereas in the Conceptualisation task it remained present.     

High frequency of latent and clinical human papillomavirus cervical infections in immunocompromised human immunodeficiency virus-infected women.

In 32 human immunodeficiency virus (HIV)-infected women, routine gynecologic examination was performed with colposcopy and Papanicolaou smear; cervical swabs were collected for human papillomavirus (HPV) DNA screening and typing; and immune status was assessed by CD4 T-cell count. Dot blot analysis was specifically chosen for HPV DNA screening to detect only relatively substantial HPV DNA infections. Polymerase chain reaction analysis was used for precise DNA typing of dot blot-positive samples. The HPV data were assessed for immune status; a subject with a CD4 T-cell count below 200/microL was considered functionally immunosuppressed. The frequency of dot blot positivity was fivefold higher among immunocompromised (nine of ten) than relatively immunocompetent (four of 22) HIV-infected women. Moreover, four immunosuppressed women, compared with no immunocompetent subjects, had evidence of HPV DNA without signs of HPV-associated lesions by cytology or histology (ie, latent HPV infection). Furthermore, four of nine of the immunocompromised, compared with four of 21 immunocompetent, subjects had cervical intraepithelial neoplasia. These frequencies are high compared with those reported in the general population. Finally, HPV 18 was detected in five of the ten women with CD4 T-cell counts below 200/microL and in only one of the 22 with CD4 T-cell counts above that level. These results suggest that the normal immune system suppresses latent and clinical HPV cervical infections and that the efficiency of suppression may be HPV type-specific. Furthermore, impaired immune status, as reflected by CD4 T-cell count, is an important factor increasing the severity of HPV-induced cervical infections in this population.