Yield of Muscle Biopsy in Patients with Findings of Myopathy on Electrodiagnostic Testing

Background: The evaluation of neuromuscular diseases includes detailed clinical assessment, blood testing, electrodiagnostic studies (EDS), biopsy, and genetic tests. EDS alone cannot provide a specific diagnosis. Further testing in the form of genetic tests or muscle biopsy (MB) is required. Objective The objective of the study is to evaluate the yield of MB in patients with findings of myopathy on electrodiagnostic testing and assess the factors affecting an abnormal biopsy outcome. Methods: Electromyography (EMG)/nerve conduction studies (NCS) performed for suspected myopathy over 5 years from 2011 to 2016, at the neurophysiology department of a tertiary care center in Pakistan, were reviewed. Based on inclusion criteria, records of 58 patients were retrospectively reviewed. Results: After an EMG/NCS diagnosis of myopathy, the frequency of MB testing was only 10.1%. The median age of patients was 26.5 years. The clinically suspected diagnosis was categorized into hereditary myopathy (n = 15, 25.9%) and acquired myopathy (n = 18, 31%). The positive predictive value of EMG is 77.2%. Twenty-eight (48.2%) patients had abnormal MB whereas 20 (34.4%) revealed normal findings. Factors significantly influencing an abnormal outcome of biopsy included moderate-to-severe elevation of creatine kinase (\u3e2,000 U/L),presence of denervation changes, and severe myopathy on EMG. Conclusion: Even though the overall yield of MB testing may not be very high in our setting due to the unavailability of special techniques and expertise, certain factors can help to improve the diagnostic yield. Clinicians should encourage MB testing, especially in cases with strong clinical, laboratory and electrodiagnostic suspicion, and absence of genetic testing for suspected myopathy

Aetiology, course and treatment of acute tubulointerstitial nephritis in paediatric patients : A cross-sectional web-based survey

Publisher Copyright: © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.Background Acute tubulointerstitial nephritis (TIN) is a significant cause of acute renal failure in paediatric and adult patients. There are no large paediatric series focusing on the aetiology, treatment and courses of acute TIN. Patients, design and setting We collected retrospective clinical data from paediatric patients with acute biopsy-proven TIN by means of an online survey. Members of four professional societies were invited to participate. Results Thirty-nine physicians from 18 countries responded. 171 patients with acute TIN were included (54% female, median age 12 years). The most frequent causes were tubulointerstitial nephritis and uveitis syndrome in 31% and drug-induced TIN in 30% (the majority of these caused by non-steroidal anti-inflammatory drugs). In 28% of patients, no initiating noxae were identified (idiopathic TIN). Median estimated glomerular filtration rate (eGFR) rose significantly from 31 at time of renal biopsy to 86 mL/ min/1.73 m2 3-6 months later (p<0.001). After 3-6 months, eGFR normalised in 41% of patients (eGFR ≥90 mL/ min/1.73 m2), with only 3% having severe or end-stage impairment of renal function (<30 mL/min/1.73 m2). 80% of patients received corticosteroid therapy. Median eGFR after 3-6 months did not differ between steroid-treated and steroid-untreated patients. Other immunosuppressants were used in 18% (n=31) of patients, 21 of whom received mycophenolate mofetil. Conclusions Despite different aetiologies, acute paediatric TIN had a favourable outcome overall with 88% of patients showing no or mild impairment of eGFR after 3-6 months. Prospective randomised controlled trials are needed to evaluate the efficacy of glucocorticoid treatment in paediatric patients with acute TIN.Peer reviewe

Understanding the Public Perception and Satisfaction of a UK Police Constabulary

This study explores the public perception of a community in Britain, towards a police constabulary in the UK. The study sought to explore how the levels of satisfaction between Black and Minority Ethnicities (BME) and non BME communities towards this police force in the UK. Using a mixed-methods approach, data was obtained by the use of self-completion questionnaires of 112 participants in an area in the UK and the use of a total of 31 semistructured interviews. The findings show that participants questioned police competence, the duty of police officers, policing conduct in relation to investigations, experiences of prejudice and expectations communities have of the police. The results for this study showed that there is some support for the idea that the perception of the police during the first contact with a member of the public is likely to be the most powerful predictor of future opinions on the police. This comes from the idea that the public are concerned not only with what the police do in the community, but how they do their work. Finally, as the current study is concerned with policing the local communities, it is important to remember that members of the community will respond positively to being included in police procedure deliberations and audits. The findings suggest that there is still much work to be done by the police service in order to improve the relationship with the communities that they serve. We argue much more emphasis should be placed on community work and increased engagement with younger people in schools and the wider general public

Parasites of an Arctic scavenger; the wolverine (Gulo gulo)

Parasites are fundamental components within all ecosystems, shaping interaction webs, host population dynamics and behaviour. Despite this, baseline data is lacking to understand the parasite ecology of many Arctic species, including the wolverine (Gulo gulo), a top Arctic predator and scavenger. Here, we combined traditional count methods (i.e. adult helminth recovery, where taxonomy was confirmed by molecular identification) with 18S rRNA high-throughput sequencing to document the wolverine parasite community. Further, we investigated whether the abundance of parasites detected using traditional methods were associated with host metadata, latitude, and longitude (ranging from the northern limit of the boreal forest to the low Arctic and Arctic tundra in Nunavut, Canada). Adult parasites in intestinal contents were identified as Baylisascaris devosi in 72% (n = 39) of wolverines and Taenia spp. in 22% (n = 12), of which specimens from 2 wolverines were identified as T. twitchelli based on COX1 sequence. 18S rRNA high-throughput sequencing on DNA extracted from faeces detected additional parasites, including a pseudophyllid cestode (Diplogonoporus spp. or Diphyllobothrium spp.), two metastrongyloid lungworms (Angiostrongylus spp. or Aelurostrongylus spp., and Crenosoma spp.), an ascarid nematode (Ascaris spp. or Toxocara spp.), a Trichinella spp. nematode, and the protozoan Sarcocystis spp., though each at a prevalence less than 13% (n = 7). The abundance of B. devosi significantly decreased with latitude (slope = -0.68; R2 = 0.17; P = 0.004), suggesting a northerly limit in distribution. We describe B. devosi and T. twitchelli in Canadian wolverines for the first time since 1978, and extend the recorded geographic distribution of these parasites ca 2000 km to the East and into the tundra ecosystem. Our findings illustrate the value of molecular methods in support of traditional methods, encouraging additional work to improve the advancement of molecular screening for parasites

Mutations in FRMD7, a newly identified member of the FERM family, cause X-linked idiopathic congenital nystagmus.

Idiopathic congenital nystagmus is characterized by involuntary, periodic, predominantly horizontal oscillations of both eyes. We identified 22 mutations in FRMD7 in 26 families with X-linked idiopathic congenital nystagmus. Screening of 42 singleton cases of idiopathic congenital nystagmus (28 male, 14 females) yielded three mutations (7%). We found restricted expression of FRMD7 in human embryonic brain and developing neural retina, suggesting a specific role in the control of eye movement and gaze stability

Is clarithromycin a potential treatment for cachexia in people with lung cancer?: a feasibility study

Clarithromycin may improve cachexia and survival in non-small cell lung cancer (NSCLC), but adequately controlled data are lacking. This study was undertaken primarily to inform the feasibility and scale of a phase III trial. Eligible consenting patients with stage IV NSCLC and cachexia were to be randomized to receive either clarithromycin 250 mg twice daily or placebo for eight weeks. Aspects of trial feasibility recorded included numbers eligible, approached and recruited, together with adherence and completion of treatment and assessments. Over 6 months, none of 125 patients identified fulfilled the entry criteria. The commonest reasons for ineligibility were the use of an excluded concurrent drug (45, 36%), brain metastases (22, 18%), poor performance status (21, 17%) and current chemotherapy (15, 12%). A phase III trial of clarithromycin using these entry criteria is not feasible in this setting. Other macrolides that have a lower risk of a drug–drug interaction may be more practical to pursue

Targeting CD73 with flavonoids inhibits cancer stem cells and increases lymphocyte infiltration in a triple-negative breast cancer mouse model

IntroductionChemotherapy remains the mainstay treatment for triple-negative breast cancer (TNBC) due to the lack of specific targets. Given a modest response of immune checkpoint inhibitors in TNBC patients, improving immunotherapy is an urgent and crucial task in this field. CD73 has emerged as a novel immunotherapeutic target, given its elevated expression on tumor, stromal, and specific immune cells, and its established role in inhibiting anti-cancer immunity. CD73-generated adenosine suppresses immunity by attenuating tumor-infiltrating T- and NK-cell activation, while amplifying regulatory T cell activation. Chemotherapy often leads to increased CD73 expression and activity, further suppressing anti-tumor immunity. While debulking the tumor mass, chemotherapy also enriches heterogenous cancer stem cells (CSC), potentially leading to tumor relapse. Therefore, drugs targeting both CD73, and CSCs hold promise for enhancing chemotherapy efficacy, overcoming treatment resistance, and improving clinical outcomes. However, safe and effective inhibitors of CD73 have not been developed as of now.MethodsWe used in silico docking to screen compounds that may be repurposed for inhibiting CD73. The efficacy of these compounds was investigated through flow cytometry, RT-qPCR, CD73 activity, cell viability, tumorsphere formation, and other in vitro functional assays. For assessment of clinical translatability, TNBC patient-derived xenograft organotypic cultures were utilized. We also employed the ovalbumin-expressing AT3 TNBC mouse model to evaluate tumor-specific lymphocyte responses.ResultsWe identified quercetin and luteolin, currently used as over-the-counter supplements, to have high in silico complementarity with CD73. When quercetin and luteolin were combined with the chemotherapeutic paclitaxel in a triple-drug regimen, we found an effective downregulation in paclitaxel-enhanced CD73 and CSC-promoting pathways YAP and Wnt. We found that CD73 expression was required for the maintenance of CD44highCD24low CSCs, and co-targeting CD73, YAP, and Wnt effectively suppressed the growth of human TNBC cell lines and patient-derived xenograft organotypic cultures. Furthermore, triple-drug combination inhibited paclitaxel-enriched CSCs and simultaneously improved lymphocyte infiltration in syngeneic TNBC mouse tumors.DiscussionConclusively, our findings elucidate the significance of CSCs in impairing anti-tumor immunity. The high efficacy of our triple-drug regimen in clinically relevant platforms not only underscores the importance for further mechanistic investigations but also paves the way for potential development of new, safe, and cost-effective therapeutic strategies for TNBC

Tomographic galaxy clustering with the Subaru Hyper Suprime-Cam first year public data release

We analyze the clustering of galaxies in the first public data release of the HSC Subaru Strategic Program. Despite the relatively small footprints of the observed fields, the data are an excellent proxy for the deep photometric datasets that will be acquired by LSST, and are therefore an ideal test bed for the analysis methods being implemented by the LSST DESC. We select a magnitude limited sample with $i<24.5$ and analyze it in four redshift bins covering $0.15\lesssim z \lesssim1.5$. We carry out a Fourier-space analysis of the two-point clustering of this sample, including all auto- and cross-correlations. We demonstrate the use of map-level deprojection methods to account for fluctuations in the galaxy number density caused by observational systematics. Through an HOD analysis, we place constraints on the characteristic halo masses of this sample, finding a good fit up to scales $k_{\rm max}=1\,{\rm Mpc}^{-1}$, including both auto- and cross-correlations. Our results show monotonically decreasing average halo masses, which can be interpreted in terms of the drop-out of red galaxies at high redshifts for a flux-limited sample. In terms of photometric redshift systematics, we show that additional care is needed in order to marginalize over uncertainties in the redshift distribution in galaxy clustering, and that these uncertainties can be constrained by including cross-correlations. We are able to make a $\sim3\sigma$ detection of lensing magnification in the HSC data. Our results are stable to variations in $\sigma_8$ and $\Omega_c$ and we find constraints that agree well with measurements from Planck and low-redshift probes. Finally, we use our pipeline to study the clustering of galaxies as a function of limiting flux, and provide a simple fitting function for the linear galaxy bias for magnitude limited samples as a function of limiting magnitude and redshift. [abridged]Comment: 65 pages, 30 figures, 5 tables, to be submitted to JCA

Mutations in FRMD7, a newly identified member of the FERM family, cause X-linked idiopathic congenital nystagmus

Idiopathic congenital nystagmus (ICN) is characterised by involuntary, periodic, predominantly horizontal, oscillations of both eyes. We identified 22 mutations in FRMD7 in 26 families with X-linked idiopathic congenital nystagmus. Screening of 42 ICN singleton cases (28 male, 14 females) yielded three mutations (7%). We found restricted expression of FRMD7 in human embryonic brain and developing neural retina suggesting a specific role in the control of eye movement and gaze stability

The Google voter: search engines and electoral information flows in the new media ecology

This paper explores key Internet search trends for electoral information vis-à-vis the broader media ecology in the UK and the US. An innovative methodology is introduced that maps the informational trajectories of key election events by combining Google Trends data linked to significant news events during the campaigns. While the research found spikes of search that suggested a seemingly trivial event in the US could drive voters to search out deeper information on related policy issues, the study did not find the same phenomenon in the UK. This invites a reflection on the opportunities available to Internet users/voters in the changing informational landscape and how scholars can leverage Google Trends records to better understand how voters seek information in new and evolving media ecologies