Primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder (PCSM-LPD), recently downgraded from a T-cell lymphoma, is a poorly characterized histopathological entity. Presenting as a solitary lesion that often grows rapidly, it may raise suspicion for a cutaneous B-cell lymphoma. However, classically, the dermal lymphoid proliferation is predominantly CD4+ with a follicular T-helper profile and a smaller B-cell fraction. Diagnostic uncertainty may arise when B cells are present in large numbers, a B-cell clone is present, or large cell populations are seen. To meet the diagnostic criterion of PCSM-LPD, large cells should not constitute more than 30% of the infiltrate. The 2 cases presented in this article caused diagnostic uncertainty owing to the observation of high numbers of large cells and in one case the presence of a B-cell clone, on the background of otherwise typical clinicopathological features of PCSM-LPD. We review the literature specifically regarding the prevalence of large cell populations and their immunophenotypic characteristics and in light of this discuss whether a current diagnostic criterion should be reconsidered.

In an attempt to bridge the osteoarthritis (OA) gap, this study compared biological reconstruction with traditional microfracture (MF) techniques in patients with femoroacetabular impingement and focal cartilage defects. Cohorts of two groups were investigated; age, gender and Tonnis grade matched comparison for outcomes between MF and newer biological reconstruction techniques hip arthroscopy surgery using autologous matrix-induced chondrogenesis and bone marrow aspirate combination. Outcomes investigated were pre-op and post-op mean iHOT-12 scores up to 18 months after surgery with a Kaplan–Meier survivorship analysis. Of 111 patients, 46 patients underwent MF and 65 biological reconstruction hip arthroscopy including cam/pincer osteoplasty and labral repair surgery. Age range was 20–69, mean age 45 years for both groups, Tonnis grading was as follows: Grade 0: 26% versus 30%, Grade 1: 52% versus 47% and Grade 2: 22% versus 23% in MF and biological reconstruction groups, respectively. The mean post-operative iHOT-12 score differences between MF and biological reconstruction were significant at 1-year minimum follow-up (P = 0.01, SD 2.8). Biological reconstruction allowed for an enhanced recovery protocol. The MF group had a 67.4% survivorship for conversion to hip replacement at 18 months (32.6% failure rate for any reason) and biological reconstruction had 100% survivorship at 18 months post-operatively with no failures for any reason. This study provides further support to the evidence base for biological reconstructive techniques as superior to MF in combination with joint preservation arthroscopic surgery, even in the face of focal cartilage defects and offers both surgeons and patients a potential bridging of the OA gap.

To analyse the epidemiology of otosclerosis in a British cohort collected between 2011 and 2017. Retrospective cohort study. Five UK ENT Departments. Patients with surgically confirmed otosclerosis. Questionnaire data documented family history of otosclerosis, age of onset, medical history, and information on associated risk factors for 657 patients. Pre and post-surgical pure-tone audiometry was collected for 154 of these patients. The age of onset, incidence of bilateral disease, tinnitus and vertigo, a higher prevalence of women (65%) than men (35%) are similar to those reported previously for otosclerosis cohorts. No association with measles infection was detected. Patients with a family history (40%) have an earlier age of onset and a higher incidence of bilateral disease and vertigo than non-familial subjects. Pedigree analysis is consistent with an autosomal dominant inheritance with reduced penetrance being apparent in 44/91 pedigrees studied. Women who associate their hearing loss with pregnancy have an earlier age of onset than those that do not (p = 6 × 10). This study confirms that otosclerosis is an early adult onset disease that is more prevalent in women than men with a large minority of patients having a family history of otosclerosis. We report new evidence to support a relationship between pregnancy and otosclerosis progression in a proportion of women. In addition, this is the first study to identify differences in severity between familial and non-familial cases of otosclerosis, highlighting the possibility that more than one etiology may be involved.

Reverse exchange (RE) in dealing with the return, recycle and reuse of products is receiving a growing focus. When properly handled, RE in healthcare can deliver an economic benefit of cost minimisation and has extensive positive impacts on both human health and the environment (Li and Olorunniwo 2008) but to date, RE research is mostly limited to pharmaceutical return. This paper investigates the potential for RE benefits in the UK National Health Service (NHS) supply chain for medical devices. Hearing aids supplied to adults with hearing loss are used as an illustrative example. This research applied a consensus approach through the use of dispersed nominal groups in order to obtain qualitative data on information, barriers, solutions and priorities to support findings. Findings illustrate that the end user behaviour of returning the device, and the requirement by NHS Procurement for manufacturers to meet RE targets are secondary to the importance of audiology departments who have the autonomy to design RE processes and successfully implement initiatives. A schematic highlighting the information and materials flow of the supply chain and the barriers and facilitators to RE is presented for hearing aid devices with potential for transferability to other small medical device supply chains.

ImportancePatients with amnestic mild cognitive impairment (aMCI) may progress to clinical Alzheimer disease (AD), remain stable, or revert to normal. Earlier progression to AD among patients who were β-amyloid positive vs those who were β-amyloid negative has been previously observed. Current research now accepts that a combination of biomarkers could provide greater refinement in the assessment of risk for clinical progression.ObjectiveTo evaluate the ability of flutemetamol F 18 and other biomarkers to assess the risk of progression from aMCI to probable AD.Design, Setting, and ParticipantsIn this multicenter cohort study, from November 11, 2009, to January 16, 2014, patients with aMCI underwent positron emission tomography (PET) at baseline followed by local clinical assessments every 6 months for up to 3 years. Patients with aMCI (365 screened; 232 were eligible) were recruited from 28 clinical centers in Europe and the United States. Physicians remained strictly blinded to the results of PET, and the standard of truth was an independent clinical adjudication committee that confirmed or refuted local assessments. Flutemetamol F 18–labeled PET scans were read centrally as either negative or positive by 5 blinded readers with no knowledge of clinical status. Statistical analysis was conducted from February 19, 2014, to January 26, 2018.InterventionsFlutemetamol F 18–labeled PET at baseline followed by up to 6 clinical visits every 6 months, as well as magnetic resonance imaging and multiple cognitive measures.Main Outcomes and MeasuresTime from PET to probable AD or last follow-up was plotted as a Kaplan-Meier survival curve; PET scan results, age, hippocampal volume, and aMCI stage were entered into Cox proportional hazards logistic regression analyses to identify variables associated with progression to probable AD.ResultsOf 232 patients with aMCI (118 women and 114 men; mean [SD] age, 71.1 [8.6] years), 98 (42.2%) had positive results detected on PET scan. By 36 months, the rates of progression to probable AD were 36.2% overall (81 of 224 patients), 53.6% (52 of 97) for patients with positive results detected on PET scan, and 22.8% (29 of 127) for patients with negative results detected on PET scan. Hazard ratios for association with progression were 2.51 (95% CI, 1.57-3.99; P < .001) for a positive β-amyloid scan alone (primary outcome measure), 5.60 (95% CI, 3.14-9.98; P < .001) with additional low hippocampal volume, and 8.45 (95% CI, 4.40-16.24; P < .001) when poorer cognitive status was added to the model.Conclusions and RelevanceA combination of positive results of flutemetamol F 18–labeled PET, low hippocampal volume, and cognitive status corresponded with a high probability of risk of progression from aMCI to probable AD within 36 months.

Otosclerosis is a common form of hearing loss which typically presents in young adults. The disease has a familial, monogenic form and a non-familial form with a more complex aetiology. A previous genome wide association study identified evidence that variants within RELN are associated with the condition. Other genes in which an association has been reported include BMP2, COL1A1, FGF2, PPP2R5B and TGFB1. However, follow up studies have often failed to replicate initial positive results. The aim of this study was to establish if an association exists between eight single nucleotide polymorphisms (SNPs) in these six previously implicated genes and otosclerosis in a British case–control cohort (n = 748). Evidence of an association between rs1800472 in TGFB1 and otosclerosis was found (p = 0.034), this association was strongest amongst non-familial cases (p = 0.011). No evidence of an association was detected with variants in COL1A1, FGF2, BMP2, and PPP2R5B. No association between variation in RELN and otosclerosis was observed in the whole cohort. However, a significant association (p = 0.0057) was detected between one RELN SNP (rs39399) and otosclerosis in familial patients. Additionally, we identify expression of one RELN transcript in 51 of 81 human stapes tested, clarifying previous conflicting data as to whether RELN is expressed in the affected tissue. Our findings strengthen the association of TGFB1 (rs1800472) with otosclerosis and support a relationship between RELN and familial otosclerosis only, which may explain previous variable replications.

Otosclerosis is a relatively common heterogenous condition, characterized by abnormal bone remodelling in the otic capsule leading to fixation of the stapedial footplate and an associated conductive hearing loss. Although familial linkage and candidate gene association studies have been performed in recent years, little progress has been made in identifying disease-causing genes. Here, we used whole-exome sequencing in four families exhibiting dominantly inherited otosclerosis to identify 23 candidate variants (reduced to 9 after segregation analysis) for further investigation in a secondary cohort of 84 familial cases. Multiple mutations were found in the SERPINF1 (Serpin Peptidase Inhibitor, Clade F) gene which encodes PEDF (pigment epithelium-derived factor), a potent inhibitor of angiogenesis and known regulator of bone density. Six rare heterozygous SERPINF1 variants were found in seven patients in our familial otosclerosis cohort; three are missense mutations predicted to be deleterious to protein function. The other three variants are all located in the 5′-untranslated region (UTR) of an alternative spliced transcript SERPINF1-012. RNA-seq analysis demonstrated that this is the major SERPINF1 transcript in human stapes bone. Analysis of stapes from two patients with the 5′-UTR mutations showed that they had reduced expression of SERPINF1-012. All three 5′-UTR mutations are predicted to occur within transcription factor binding sites and reporter gene assays confirmed that they affect gene expression levels. Furthermore, RT-qPCR analysis of stapes bone cDNA showed that SERPINF1-012 expression is reduced in otosclerosis patients with and without SERPINF1 mutations, suggesting that it may be a common pathogenic pathway in the disease.