Muscle "islands": an MRI signature distinguishing neurogenic from myopathic causes of early onset distal weakness

Muscle MRI has an increasing role in diagnosis of inherited neuromuscular diseases, but no features are known which reliably differentiate myopathic and neurogenic conditions. Using patients presenting with early onset distal weakness, we aimed to identify an MRI signature to distinguish myopathic and neurogenic conditions. We identified lower limb MRI scans from patients with either genetically (n=24) or clinically (n=13) confirmed diagnoses of childhood onset distal myopathy or distal spinal muscular atrophy. An initial exploratory phase reviewed 11 scans from genetically confirmed patients identifying a single potential discriminatory marker concerning the pattern of fat replacement within muscle, coined “islands”. This pattern comprised small areas of muscle tissue with normal signal intensity completely surrounded by areas with similar intensity to subcutaneous fat. In the subsequent validation phase, islands correctly classified scans from all 12 remaining genetically confirmed patients, and 12/13 clinically classified patients. In the genetically confirmed patients MRI classification of neurogenic/myopathic aetiology had 100% accuracy (24/24) compared with 65% accuracy (15/23) for EMG, and 79% accuracy (15/19) for muscle biopsy. Future studies are needed in other clinical contexts, however the presence of islands appears to highly suggestive of a neurogenic aetiology in patients presenting with early onset distal motor weakness

Stability and sensitivity of water T2 obtained with IDEAL-CPMG in healthy and fat-infiltrated skeletal muscle

Quantifying muscle water T2 (T2 -water) independently of intramuscular fat content is essential in establishing T2 -water as an outcome measure for imminent new therapy trials in neuromuscular diseases. IDEAL-CPMG combines chemical shift fat-water separation with T2 relaxometry to obtain such a measure. Here we evaluate the reproducibility and B1 sensitivity of IDEAL-CPMG T2 -water and fat fraction (f.f.) values in healthy subjects, and demonstrate the potential of the method to quantify T2 -water variation in diseased muscle displaying varying degrees of fatty infiltration. The calf muscles of 11 healthy individuals (40.5 ± 10.2 years) were scanned twice at 3 T with an inter-scan interval of 4 weeks using IDEAL-CPMG, and 12 patients with hypokalemic periodic paralysis (HypoPP) (42.3 ± 11.5 years) were also imaged. An exponential was fitted to the signal decay of the separated water and fat components to determine T2 -water and the fat signal amplitude muscle regions manually segmented. Overall mean calf-level muscle T2 -water in healthy subjects was 31.2 ± 2.0 ms, without significant inter-muscle differences (p = 0.37). Inter-subject and inter-scan coefficients of variation were 5.7% and 3.2% respectively for T2 -water and 41.1% and 15.4% for f.f. Bland-Altman mean bias and ±95% coefficients of repeatability were for T2 -water (0.15, -2.65, 2.95) ms and f.f. (-0.02, -1.99, 2.03)%. There was no relationship between T2 -water (ρ = 0.16, p = 0.07) or f.f. (ρ = 0.03, p = 0.7761) and B1 error or any correlation between T2 -water and f.f. in the healthy subjects (ρ = 0.07, p = 0.40). In HypoPP there was a measurable relationship between T2 -water and f.f. (ρ = 0.59, p < 0.001). IDEAL-CPMG provides a feasible way to quantify T2 -water in muscle that is reproducible and sensitive to meaningful physiological changes without post hoc modeling of the fat contribution. In patients, IDEAL-CPMG measured elevations in T2 -water and f.f. while showing a weak relationship between these parameters, thus showing promise as a practical means of quantifying muscle water in patient populations

Increasing the Effectiveness of Vaginal Microbicides: A Biophysical Framework to Rethink Behavioral Acceptability

Microbicide candidates delivered via gel vehicles are intended to coat the vaginal epithelium after application. The coating process depends on intrinsic biophysical properties of the gel texture, which restricts the potential choices for an effective product: the gel first must be physically synthesizable, then acceptable to the user, and finally applied in a manner promoting timely adequate coating, so that the user adherence is optimized. We present a conceptual framework anchoring microbicide behavioral acceptability within the fulfillment of the product biophysical requirements.We conducted a semi-qualitative/quantitative study targeting women aged 18-55 in Northern California to assess user preferences for microbicide gel attributes. Attributes included: (i) the wait time between application and intercourse, (ii) the gel texture and (iii) the trade-off between wait time and gel texture. Wait times were assessed using a mathematical model determining coating rates depending upon the gel's physical attributes.71 women participated. Results suggest that women would independently prefer a gel spreading rapidly, in 2 to 15 minutes (P<0.0001), as well as one that is thick or slippery (P<0.02). Clearly, thick gels do not spread rapidly; hence the motivation to study the trade-off. When asked the same question 'constrained' by the biophysical reality, women indicated no significant preference for a particular gel thickness (and therefore waiting time) (P>0.10) for use with a steady partner, a preference for a watery gel spreading rapidly rather than one having intermediate properties for use with a casual partner (P = 0.024).Biophysical constraints alter women's preferences regarding acceptable microbicide attributes. Product developers should offer a range of formulations in order to address all preferences. We designed a conceptual framework to rethink behavioral acceptability in terms of biophysical requirements that can help improve adherence in microbicide use ultimately enhancing microbicide effectiveness

Coproducing Knowledge of the Implementation of Complex Digital Health Interventions for Adults with Acquired Brain Injury and their Communication Partners: Protocol for a Mixed Methods Study.

BACKGROUND: The Social Brain Toolkit, conceived and developed in partnership with stakeholders, is a novel suite of web-based communication interventions for people with brain injury and their communication partners. To support effective implementation, the developers of the Social Brain Toolkit have collaborated with people with brain injury, communication partners, clinicians, and individuals with digital health implementation experience to coproduce new implementation knowledge. In recognition of the equal value of experiential and academic knowledge, both types of knowledge are included in this study protocol, with input from stakeholder coauthors. OBJECTIVE: This study aims to collaborate with stakeholders to prioritize theoretically based implementation targets for the Social Brain Toolkit, understand the nature of these priorities, and develop targeted implementation strategies to address these priorities, in order to support the Social Brain Toolkit's implementation. METHODS: Theoretically underpinned by the Nonadoption, Abandonment, Scale-up, Spread, and Sustainability (NASSS) framework of digital health implementation, a maximum variation sample (N=35) of stakeholders coproduced knowledge of the implementation of the Social Brain Toolkit. People with brain injury (n=10), communication partners (n=11), and clinicians (n=5) participated in an initial web-based prioritization survey based on the NASSS framework. Survey completion was facilitated by plain English explanations and accessible captioned videos developed through 3 rounds of piloting. A speech-language pathologist also assisted stakeholders with brain injury to participate in the survey via video teleconference. Participants subsequently elaborated on their identified priorities via 7 web-based focus groups, in which researchers and stakeholders exchanged stakeholder perspectives and research evidence from a concurrent systematic review. Stakeholders were supported to engage in focus groups through the use of visual supports and plain English explanations. Additionally, individuals with experience in digital health implementation (n=9) responded to the prioritization survey questions via individual interview. The results will be deductively analyzed in relation to the NASSS framework in a coauthorship process with people with brain injury, communication partners, and clinicians. RESULTS: Ethical approval was received from the University of Technology Sydney Health and Medical Research Ethics Committee (ETH20-5466) on December 15, 2020. Data were collected from April 13 to November 18, 2021. Data analysis is currently underway, with results expected for publication in mid-2022. CONCLUSIONS: In this study, researchers supported individuals with living experience of acquired brain injury, of communicating with or clinically supporting someone post injury, and of digital health implementation, to directly access and leverage the latest implementation research evidence and theory. With this support, stakeholders were able to prioritize implementation research targets, develop targeted implementation solutions, and coauthor and publish new implementation findings. The results will be used to optimize the implementation of 3 real-world, evidence-based interventions and thus improve the outcomes of people with brain injury and their communication partners. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/35080

Adult granulosa cell tumor associated with endometrial carcinoma: a case report

<p>Abstract</p> <p>Introduction</p> <p>If strict criteria for the diagnosis of carcinoma are used and all patients with granulosa cell tumors are considered, the best estimate of the incidence of associated endometrial carcinomas is under 5%. In patients with granulosa cell tumors, estrogen-dependent endometrial cancers are rarely found, and most of these endometrial cancers are well-differentiated endometrioid adenocarcinomas that carry a good prognosis when detected early.</p> <p>Case presentation</p> <p>We report the case of a 65-year-old post-menopausal Nigerian woman of the Igbo tribe with an adult granulosa cell tumor that was initially treated as endometrial carcinoma. She underwent a total abdominal hysterectomy and a bilateral salpingo-oophorectomy after histopathologic confirmation of a well-differentiated granulosa cell tumor of the ovary and a nuclear grade 1 adenocarcinoma of the endometrium (International Federation of Obstetricians and Gynecologists stage 1B). She had a good post-operative recovery and was discharged 10 days after treatment.</p> <p>Conclusion</p> <p>The association between adult granulosa cell tumors of the ovary and endometrial carcinomas is rare. A high index of suspicion as well as good imaging and histopathologic analyses are important in making this diagnosis.</p

Lead exposure in adult males in urban Transvaal Province, South Africa during the apartheid era

Human exposure to lead is a substantial public health hazard worldwide and is particularly problematic in the Republic of South Africa given the country’s late cessation of leaded petrol. Lead exposure is associated with a number of serious health issues and diseases including developmental and cognitive deficiency, hypertension and heart disease. Understanding the distribution of lifetime lead burden within a given population is critical for reducing exposure rates. Femoral bone from 101 deceased adult males living in urban Transvaal Province (now Gauteng Province), South Africa between 1960 and 1998 were analyzed for lead concentration by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). Of the 72 black and 29 white individuals sampled, chronic lead exposure was apparent in nearly all individuals. White males showed significantly higher median bone lead concentration (ME = 10.04 µg·g−1), than black males (ME = 3.80 µg·g−1) despite higher socioeconomic status. Bone lead concentration covaries significantly, though weakly, with individual age. There was no significant temporal trend in bone lead concentration. These results indicate that long-term low to moderate lead exposure is the historical norm among South African males. Unexpectedly, this research indicates that white males in the sample population were more highly exposed to lead

Tumor markers in breast cancer - European Group on Tumor Markers recommendations

Recommendations are presented for the routine clinical use of serum and tissue-based markers in the diagnosis and management of patients with breast cancer. Their low sensitivity and specificity preclude the use of serum markers such as the MUC-1 mucin glycoproteins ( CA 15.3, BR 27.29) and carcinoembryonic antigen in the diagnosis of early breast cancer. However, serial measurement of these markers can result in the early detection of recurrent disease as well as indicate the efficacy of therapy. Of the tissue-based markers, measurement of estrogen and progesterone receptors is mandatory in the selection of patients for treatment with hormone therapy, while HER-2 is essential in selecting patients with advanced breast cancer for treatment with Herceptin ( trastuzumab). Urokinase plasminogen activator and plasminogen activator inhibitor 1 are recently validated prognostic markers for lymph node-negative breast cancer patients and thus may be of value in selecting node-negative patients that do not require adjuvant chemotherapy. Copyright (C) 2005 S. Karger AG, Basel

Nipple aspiration and ductal lavage in women with a germline BRCA1 or BRCA2 mutation

INTRODUCTION: The aim of this study was to collect serial samples of nipple aspirate (NA) and ductal lavage (DL) fluid from women with germline BRCA1/2 mutations in order to create a biorepository for use in identifying biomarkers of breast cancer risk. METHODS: Between March 2003 and February 2005, 52 women with germline BRCA1 or BRCA2 mutations (median age 43 years, range 27 to 65 years) were scheduled for six-monthly NA, DL and venesection. DL was attempted for all NA fluid-yielding (FY) and any non-FY ducts that could be located at each visit. RESULTS: Twenty-seven (52%) women were postmenopausal, predominantly (19/27) from risk reducing bilateral salpingo-oophorectomy (BSO). FY ducts were identified in 60% of all women, 76% of premenopausal women versus 44% of postmenopausal (P = 0.026). Eighty-five percent of women had successful DL. Success was most likely in women with FY ducts (FY 94% versus non-FY 71% (P = 0.049). DL samples were more likely to be cellular if collected from FY ducts (FY 68% versus non-FY 43%; P = 0.037). Total cell counts were associated with FY status (FY median cell count 30,996, range 0 to >1,000,000 versus non-FY median cell count 0, range 0 to 173,577; P = 0.002). Four women (8%) had ducts with severe atypia with or without additional ducts with mild epithelial atypia; seven others had ducts with mild atypia alone (11/52 (21%) in total). Median total cell count was greater from ducts with atypia (105,870, range 1920 to >1,000,000) than those with no atypia (174, 0 to >1,000,000; P ≤ 0.001). CONCLUSION: It is feasible to collect serial NA and DL samples from women at high genetic risk of breast cancer, and we are creating a unique, prospective collection of ductal samples that have the potential to be used for discovery of biomarkers of breast cancer risk and evaluate the ongoing effects of risk reducing BSO. DL cellular atypia was not predictive of a current breast cancer and longer follow up is needed to determine whether atypia is an additional marker of future breast cancer risk in this population already at high genetic risk of breast cancer

Postcopulatory Sexual Selection Is Associated with Reduced Variation in Sperm Morphology

The evolutionary role of postcopulatory sexual selection in shaping male reproductive traits, including sperm morphology, is well documented in several taxa. However, previous studies have focused almost exclusively on the influence of sperm competition on variation among species. In this study we tested the hypothesis that intraspecific variation in sperm morphology is driven by the level of postcopulatory sexual selection in passerine birds.Using two proxy measures of sperm competition level, (i) relative testes size and (ii) extrapair paternity level, we found strong evidence that intermale variation in sperm morphology is negatively associated with the degree of postcopulatory sexual selection, independently of phylogeny.Our results show that the role of postcopulatory sexual selection in the evolution of sperm morphology extends to an intraspecific level, reducing the variation towards what might be a species-specific 'optimum' sperm phenotype. This finding suggests that while postcopulatory selection is generally directional (e.g., favouring longer sperm) across avian species, it also acts as a stabilising evolutionary force within species under intense selection, resulting in reduced variation in sperm morphology traits. We discuss some potential evolutionary mechanisms for this pattern

Paclitaxel and concomitant radiotherapy in high-risk endometrial cancer patients: preliminary findings

BACKGROUND: There is still much debate about the best adjuvant therapy after surgery for endometrial cancer (EC) and there are no current guidelines. Radiotherapy (RT) alone does not seem to improve overall survival. We investigated whether concomitant Paclitaxel (P) and RT gave better clinical results. METHODS: Twenty-three patients with high-risk EC (stage IIB, IIIA, IIIC or IC G3 without lymphadenectomy or with aneuploid tumor) underwent primary surgery and were then referred for adjuvant therapy. P was given at a dose of 60 mg/m2 once weekly for five weeks during RT, which consisted of a total radiation dose of 50.4 Gy. Three further weekly cycles of P at a dose of 80 mg/m2 were given at the end of RT. Overall survival and disease-free survival were calculated from the time of surgery. Patterns of failure were recorded by the sites of failure. RESULTS: A total of 157 cycles of P were administered both during radiotherapy and consolidation chemotherapy. Relapses occurred in five patients (21.7%). Median time to recurrence was 18.6 months (range 3–28). Survival rate for all the patients was 78.2%. Overall survival for the patients who completed chemo-radiation was of 81%. In this group median time to recurrence was 19.2 months (range 3–28). All recurrences were outside the radiation field. Mortality rate was 14.2%. CONCLUSION: This small series demonstrates pelvic radiotherapy in combination with weakly P followed by three consolidation chemotherapy cycles as an effective combined approach in high risk endometrial carcinoma patients