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Hematogenous metastases are rarely present at diagnosis of ovarian clear cell carcinoma (OCC). Instead dissemination of these tumors is characteristically via direct extension of the primary tumor into nearby organs and the spread of exfoliated tumor cells throughout the peritoneum, initially via the peritoneal fluid, and later via ascites that accumulates as a result of disruption of the lymphatic system. The molecular mechanisms orchestrating these processes are uncertain. In particular, the signaling pathways used by malignant cells to survive the stresses of anchorage-free growth in peritoneal fluid and ascites, and to colonize remote sites, are poorly defined. We demonstrate that the transmembrane glycoprotein CUB-domain-containing protein 1 (CDCP1) has important and inhibitable roles in these processes. In vitro assays indicate that CDCP1 mediates formation and survival of OCC spheroids, as well as cell migration and chemoresistance. Disruption of CDCP1 via silencing and antibody-mediated inhibition markedly reduce the ability of TOV21G OCC cells to form intraperitoneal tumors and induce accumulation of ascites in mice. Mechanistically our data suggest that CDCP1 effects are mediated via a novel mechanism of protein kinase B (Akt) activation. Immunohistochemical analysis also suggested that CDCP1 is functionally important in OCC, with its expression elevated in 90% of 198 OCC tumors and increased CDCP1 expression correlating with poor patient disease-free and overall survival. This analysis also showed that CDCP1 is largely restricted to the surface of malignant cells where it is accessible to therapeutic antibodies. Importantly, antibody-mediated blockade of CDCP1 in vivo significantly increased the anti-tumor efficacy of carboplatin, the chemotherapy most commonly used to treat OCC. In summary, our data indicate that CDCP1 is important in the progression of OCC and that targeting pathways mediated by this protein may be useful for the management of OCC, potentially in combination with chemotherapies and agents targeting the Akt pathway.

The potential of using commercial peroxyacetic acid (PAA) for Vibrio parahaemolyticus sanitization was evaluated. Commercial PAA of 0.005 % (v/v, PAA: 2.24 mg/L, hydrogen peroxide: 11.79 mg/L) resulted in a planktonic cell reduction of >7.00 log 10  CFU/mL when initial V. parahaemolyticus cells averaged 7.64 log 10  CFU/mL. For cells on stainless steel coupons, treatment of 0.02 % PAA (v/v, PAA: 8.96 mg/L, hydrogen peroxide: 47.16 mg/L) achieved >5.00 log 10  CFU/cm 2 reductions in biofilm cells for eight strains but not for the two strongest biofilm formers. PAA of 0.05 % (v/v, PAA: 22.39 mg/L, hydrogen peroxide: 117.91 mg/L) was required to inactivate >5.00 log 10  CFU/cm 2 biofilm cells from mussel shell surfaces. The detection of PAA residues after biofilm treatment demonstrated that higher biofilm production resulted in higher PAA residues (p < 0.05), suggesting biofilm is acting as a barrier interfering with PAA diffusing into the matrices. Based on the comparative analysis of genomes, robust biofilm formation and metabolic heterogeneity within niches might have contributed to the variations in PAA resistance of V. parahaemolyticus biofilms., Competing Interests: Declaration of competing interest The authors declare no competing financial interests or personal relationships., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Vibrio parahaemolyticus biofilms on the seafood processing plant surfaces are a potential source of seafood contamination and subsequent food poisoning. Strains differ in their ability to form biofilm, but little is known about the genetic characteristics responsible for biofilm development. In this study, pangenome and comparative genome analysis of V. parahaemolyticus strains reveals genetic attributes and gene repertoire that contribute to robust biofilm formation. The study identified 136 accessory genes that were exclusively present in strong biofilm forming strains and these were functionally assigned to the Gene Ontology (GO) pathways of cellulose biosynthesis, rhamnose metabolic and catabolic processes, UDP-glucose processes and O antigen biosynthesis (p < 0.05). Strategies of CRISPR-Cas defence and MSHA pilus-led attachment were implicated via Kyoto Encyclopedia of Genes and Genomes (KEGG) annotation. Higher levels of horizontal gene transfer (HGT) were inferred to confer more putatively novel properties on biofilm-forming V. parahaemolyticus. Furthermore, cellulose biosynthesis, a neglected potential virulence factor, was identified as being acquired from within the order Vibrionales. The cellulose synthase operons in V. parahaemolyticus were examined for their prevalence (22/138, 15.94 %) and were found to consist of the genes bcsG, bcsE, bcsQ, bcsA, bcsB, bcsZ, bcsC. This study provides insights into robust biofilm formation of V. parahaemolyticus at the genomic level and facilitates: identification of key attributes for robust biofilm formation, elucidation of biofilm formation mechanisms and development of potential targets for novel control strategies of persistent V. parahaemolyticus., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Vibrio parahaemolyticus is a marine oriented pathogen; and biofilm formation enables its survival and persistence on seafood processing plant, complicating the hygienic practice. The objectives of this study are to assess the ability of V. parahaemolyticus isolated from seafood related environments to form biofilms, to determine the effective sodium hypochlorite concentrations required to inactivate planktonic and biofilm cells, and to evaluate the genetic diversity required for strong biofilm formation. Among nine isolates, PFR30J09 and PFR34B02 isolates were identified as strong biofilm forming strains, with biofilm cell counts of 7.20, 7.08 log 10 CFU/cm 2 , respectively, on stainless steel coupons after incubation at 25 °C. Free available chlorine of 1176 mg/L and 4704 mg/L was required to eliminate biofilm cells of 1.74-2.28 log 10 CFU/cm 2 and > 7 log 10 CFU/cm 2 , respectively, whereas 63 mg/L for planktonic cells, indicating the ineffectiveness of sodium hypochlorite in eliminating V. parahaemolyticus biofilm cells at recommended concentration in the food industry. These strong biofilm-forming isolates produced more polysaccharides and were less susceptible to sodium hypochlorite, implying a possible correlation between polysaccharide production and sodium hypochlorite susceptibility. Genetic diversity in mshA, mshC and mshD contributed to the observed variation in biofilm formation between isolates. This study identified strong biofilm-forming V. parahaemolyticus strains of new multilocus sequence typing (MLST) types, showed a relationship between polysaccharide production and sodium hypochlorite resistance., Competing Interests: Declaration of competing interest The authors declare no competing conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

The formation of biofilms is a survival strategy employed by bacteria to help protect them from changing or unfavourable environments. In this research, 319 genes which govern biofilm formation in V. parahaemolyticus, as reported in 1,625 publications, were analysed using protein-protein-interaction (PPI) network analysis. CsrA was identified as a motility-sessility switch and biofilm formation regulator. Through robust rank aggregation (RRA) analysis of GSE65340, the generation of viable but non-culturable (VBNC) cells that may enhance cell tolerance to stress, was found to be associated with the TCA cycle and carbon metabolism biological pathways. The finding that CsrA is likely to play a role in the development of VBNC cells improves understanding of the molecular mechanisms of VBNC formation in V. parahaemolyticus and contributes to on-going efforts to reduce the hazard posed by this foodborne pathogen.

Actin nucleation is the key rate limiting step in the process of actin polymerization, and tight regulation of this process is critical to ensure actin filaments form only at specific times and at defined regions of the cell. WH2 domains are short sequence motifs found in many different actin binding proteins including WASP family proteins which regulate the actin nucleating complex Arp2/3. In this study we reveal a phosphorylation site, Serine 554, within the WH2 domain of the yeast WASP homologue Las17. Both phosphorylation and a phospho-mimetic mutation reduce actin monomer binding affinity while an alanine mutation, generated to mimic the non-phosphorylated state, increases actin binding affinity. The effect of these mutations on the Las17-dependent process of endocytosis in vivo was analysed and leads us to propose that switching of Las17 phosphorylation states may allow progression through distinct phases of endocytosis from site assembly through to the final scission stage. While the study is focused on Las17, the sole WASP family protein in yeast, our results have broad implications for our understanding of how a key residue in this conserved motif can underpin the many different actin regulatory roles with which WH2 domains have been associated.

Aims: The aim of this study was to define the levels of noise exposure for the surgeon, assistant, scrub nurse, and anesthetist during total hip and knee arthroplasty surgery. In addition, we sought to determine whether the noise exposure during these procedures reaches or exceeds the action values set out by the U.K. Noise at Work Regulations (2005)., Materials and Methods: Individual noise exposure during arthroplasty hip and knee surgery was recorded using a personal noise Dosemeter System model 22 (DM22) (Pulsar instruments, Filey, U.K.). Recordings were taken in real-time during five separate theater sessions. Each theater session included two arthroplasty procedures and lasted approximately 4 hrs. Personal noise exposure was expressed in terms of peak sound pressure and an average noise exposure over an 8-hour time-period to reflect the noise experienced by the ear over a working day., Results: In all three sessions involving total hip replacement surgery, the peak sound pressure, for the operating surgeon exceeded the exposure action values set out by the U.K. Noise at Work Regulations. Theater sessions involving total knee replacement surgery did not exceed any exposure action values for LCPeak or LEPd., Conclusion: Arthroplasty surgery is a working environment with significant noise exposure. We recommend any surgeon or theater member who is concerned about the noise generated in their theater to have noise levels formally assessed using appropriately positioned recording devices., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: Chronic pain syndromes in children can carry significant threats to psychological well-being, opioid overuse, functional impairments, and severe disability. While several high-level studies, almost exclusively in adults, have demonstrated the utility of implantable electrical neuromodulation systems for treating various chronic pain syndromes, there exists a paucity of pediatric-specific evidence. Unfortunately, evidence and practice patterns established from adults may not be fully translatable to children given differences in disease manifestations and anatomical variances., Materials and Methods: We performed a systematic review using conventional PRISMA methodology to identify studies reporting use of implantable electrical neuromodulation systems in children. The primary outcome parameters collected were analgesic relief and functional benefits. Additionally, previous interventions attempted, neuromodulation parameters, and limitations were collected as reported., Results: A total of 11 studies was identified, which described 19 patients who were refractory to multidisciplinary pain management strategies. The cohort was mostly adolescent (18/19), suffered from CRPS (14/19), and received SCS (17/19). Nearly all patients, both those with CRPS (13/14) and non-CRPS conditions (4/4), reported significant pain relief and functional recovery following neuromodulation. There were no severe complications reported; limitations included suboptimal benefit or loss of analgesia (3/19), lead or device revision (3/19), and subcutaneous infection (1/19), all of which were congruent with adult outcomes., Conclusion: There exist children with chronic pain refractory to standard of care approaches who could be considered for neuromodulation interventions. The existing data, which was limited and from a low tier of evidence, suggest that these interventions are relatively safe and provide meaningful pain reduction and functional improvements. While not previously reported, we recommend careful consideration of the pubertal growth spurt prior to device lead placement-if reasonable and appropriate-given the possibility of inferior lead migration with physiologic growth in patients with SCS devices or foraminal extrusion in patients with dorsal root ganglion stimulation devices., (© 2021 International Neuromodulation Society.)

To realize the potential of microalgae in the biorefinery context, exploitation of multiple products is necessary for profitability and bioproduct valorization. Appropriate analytical tools are required for growth optimization, culture monitoring, and quality control purposes, with safe, low-tech, and low-cost solutions favorable. Rapid, high-throughput, and user-friendly methodologies were devised for (a) determination of phycobiliproteins, chlorophylls, carotenoids, proteins, carbohydrates, and lipids and (b) qualitative and quantitative carotenoid profiling using UPLC-PDA-MS E . The complementary methods were applied on 11 commercially important microalgal strains including prasinophytes, haptophytes, and cyanobacteria, highlighting the suitability of some strains for coproduct exploitation and the method utility for research and industrial biotechnology applications. The UPLC method allowed separation of 41 different carotenoid compounds in <15 min. Simple techniques are described for further quantification and comparison of pigment profiles, allowing for easy strain selection and optimization for pigment production, with suitability for biotechnological or biomedical applications., (© 2021 The Authors. MicrobiologyOpen published by John Wiley & Sons Ltd.)

Purpose: Lower limb malalignment is a strong predictor of progression in knee osteoarthritis. The purpose of this study is to identify the individual alignment variables that predict progression in early to moderate osteoarthritis of the knee., Method: A longitudinal cohort study using data from the Osteoarthritis Initiative. In total, 955 individuals (1329 knees) with early to moderate osteoarthritis (Kellgren-Lawrence grade 1, 2 or 3) were identified. All subjects had full-limb radiographs analysed using the Osteotomy module within Medicad ® Classic (Hectec GMBH) to give a series of individual alignment variables relevant to the coronal alignment of the lower limb. Logistic regression models, with generalised estimating equations were used to identify which of these individual alignment variables predict symptom worsening (WOMAC score > 9 points) and or structural progression (joint space narrowing progression in the medial compartment > 0.7mm) over 24 months., Results: Individual alignment variable were associated with both valgus and varus alignment (mechanical Lateral Distal Femoral Angle, Medial Proximal Tibial Angle and mechanical Lateral Distal Tibial Angle). Only the Medial Proximal Tibial Angle was significantly associated with structural progression and none of the variables was associated with symptom progression. The odds of joint space narrowing progression in the medial compartment occurring at 24 months increased by 21% for every one degree decrease (more varus) in Medial Proximal Tibial Angle (p < 0.001) CONCLUSIONS: Our results suggest that the risk of structural progression in the medial compartment is associated with greater varus alignment of the proximal tibia., Level of Evidence: Level III, retrospective cohort study.

Current clinical tests lack the sensitivity needed for detecting subtle balance impairments associated with mild traumatic brain injury (mTBI). Patient-reported symptoms can be significant and have a huge impact on daily life, but impairments may remain undetected or poorly quantified using clinical measures. Our central hypothesis was that provocative sensorimotor perturbations, delivered in a highly instrumented, immersive virtual environment, would challenge sensory subsystems recruited for balance through conflicting multi-sensory evidence, and therefore reveal that not all subsystems are performing optimally. The results show that, as compared to standard clinical tests, the provocative perturbations illuminate balance impairments in subjects who have had mild traumatic brain injuries. Perturbations delivered while subjects were walking provided greater discriminability (average accuracy ≈ 0.90) than those delivered during standing (average accuracy ≈ 0.65) between mTBI subjects and healthy controls. Of the categories of features extracted to characterize balance, the lower limb accelerometry-based metrics proved to be most informative. Further, in response to perturbations, subjects with an mTBI utilized hip strategies more than ankle strategies to prevent loss of balance and also showed less variability in gait patterns. We have shown that sensorimotor conflicts illuminate otherwise-hidden balance impairments, which can be used to increase the sensitivity of current clinical procedures. This augmentation is vital in order to robustly detect the presence of balance impairments after mTBI and potentially define a phenotype of balance dysfunction that enhances risk of injury.

Bacillus cereus is a well-known foodborne pathogen capable of causing two types of gastrointestinal diseases, diarrhoea and emesis. It is of particular concern for the food industry causing food safety issues, due to the formation of spores, biofilms and diarrhoea and/or emetic toxins. This review reveals the possible link between two food safety issues - toxins and spores - and the role of biofilms. The review highlights genetic determinants that are involved in sporulation, toxin production and biofilm formation based on current research, and evidence showing the possible correlation of spore, toxin and biofilm formation of B. cereus. This is the first review highlighting the potential relationship between toxin production and biofilm formation in B. cereus., Competing Interests: Declaration of competing interest This manuscript is original, and no part of the manuscript has been published before. There are no conflicts of interest to disclose., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: Correction of chordee remains a prerequisite prior to urethroplasty in children with severe hypospadias. The use of an interposition graft is indicated when significant chordee (>30 0 ) persists after division of the urethral plate. The use of free dermis or tunica vaginalis are most often used, but the use of a pre-packaged graft material is attractive with regards to efficiency. The success with small intestine submucosa (SIS) has been variable and experience with Alloderm® has not been published., Objective: To determine if Alloderm®, an acellular dermal matrix with regenerative properties, can effectively, safely, and efficiently be used for corporal grafting in cases of severe chordee in children associated with hypospadias or intersex STUDY DESIGN: All boys underwent planned staged repair of severe hypospadias (penoscrotal or more proximal). If artificial erection (AE) demonstrated chordee >45 0 after penile degloving and removal of fibrotic tissue, and again after urethral plate division, the ventral tunica albuginea was incised 180 0 transversely and the oval defect measured in both axes. Alloderm® was trimmed to size and sewn into the defect. AE confirmed chordee correction. At the second stage repair (>6 months later), AE was performed to confirm continued absence of chordee., Conclusion: Alloderm®is safe, effective and simple to use graft material for correcting severe chordee. The benefits include performance efficiency without need for separate harvesting and donor site closure, and redundancy of material, if needed. Additional series and longer follow up must confirm these results and better assess durability., Competing Interests: Conflict of interest None., (Copyright © 2020 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Background: Bone marrow stromal cells (BMSC) have promise in cartilage tissue engineering, but for their potential to be fully realised, the propensity to undergo hypertrophy must be mitigated. The literature contains diverging reports on the effect of parathyroid hormone (PTH) on BMSC differentiation. Cartilage tissue models can be heterogeneous, confounding efforts to improve media formulations., Methods: Herein, we use a novel microwell platform (the Microwell-mesh) to manufacture hundreds of small-diameter homogeneous micro-pellets and use this high-resolution assay to quantify the influence of constant or intermittent PTH(1-34) medium supplementation on BMSC chondrogenesis and hypertrophy. Micro-pellets were manufactured from 5000 BMSC each and cultured in standard chondrogenic media supplemented with (1) no PTH, (2) intermittent PTH, or (3) constant PTH., Results: Relative to control chondrogenic cultures, BMSC micro-pellets exposed to intermittent PTH had reduced hypertrophic gene expression following 1 week of culture, but this was accompanied by a loss in chondrogenesis by the second week of culture. Constant PTH treatment was detrimental to chondrogenic culture., Conclusions: This study provides further clarity on the role of PTH on chondrogenic differentiation in vitro and suggests that while PTH may mitigate BMSC hypertrophy, it does so at the expense of chondrogenesis.

Goal: We propose a speech modeling and signal-processing framework to detect and track COVID-19 through asymptomatic and symptomatic stages. Methods: The approach is based on complexity of neuromotor coordination across speech subsystems involved in respiration, phonation and articulation, motivated by the distinct nature of COVID-19 involving lower (i.e., bronchial, diaphragm, lower tracheal) versus upper (i.e., laryngeal, pharyngeal, oral and nasal) respiratory tract inflammation, as well as by the growing evidence of the virus' neurological manifestations. Preliminary results: An exploratory study with audio interviews of five subjects provides Cohen's d effect sizes between pre-COVID-19 (pre-exposure) and post-COVID-19 (after positive diagnosis but presumed asymptomatic) using: coordination of respiration (as measured through acoustic waveform amplitude) and laryngeal motion (fundamental frequency and cepstral peak prominence), and coordination of laryngeal and articulatory (formant center frequencies) motion. Conclusions: While there is a strong subject-dependence, the group-level morphology of effect sizes indicates a reduced complexity of subsystem coordination. Validation is needed with larger more controlled datasets and to address confounding influences such as different recording conditions, unbalanced data quantities, and changes in underlying vocal status from pre-to-post time recordings.

Purpose: To analyze long-term outcomes after treatment discontinuation of anti-programmed death-1 (anti-PD-1) therapy in a cohort of patients with melanoma with the longest follow-up yet available to our knowledge, including a majority of patients treated outside of a clinical trial. We also assessed efficacy of retreatment with anti-PD-1 therapy with or without ipilimumab in relapsing patients., Methods: We retrospectively analyzed all patients with nonuveal, unresectable stage III/IV melanoma treated with single-agent anti-PD-1 therapy at Memorial Sloan Kettering from 2009-2018 who had discontinued treatment and had at least 3 months of follow-up after discontinuation (n = 396). Overall survival for patients with complete response (CR) was calculated from time of CR. Time to treatment failure for patients with CR was time from CR to the next melanoma treatment or death., Results: CRs were seen in 102 of 396 patients (25.8%). The median number of months of treatment after CR was zero (range, stopped before CR to 26 months after CR). With a median follow-up of 21.1 months from time of CR in patients who did not relapse, the probability of being alive and not needing additional melanoma therapy at 3 years was 72.1%. There was no significant association between treatment duration and relapse risk. In multivariable analysis, CR was associated with M1b disease and cutaneous versus mucosal or acral primaries. Among the 78 patients (of 396) retreated after disease progression, response was seen in 5 of 34 retreated patients with single-agent anti-PD-1 therapy and 11 of 44 patients escalated to anti-PD-1 plus ipilimumab., Conclusion: In our cohort, most patients discontinued treatment at the time of CR. Most CRs were durable but the probability of treatment failure was 27% at 3 years. Responses to retreatment were infrequent. The optimal duration of treatment after CR is not yet established.

Elevated CUB-domain containing protein 1 (CDCP1) is predictive of colorectal cancer (CRC) recurrence and poor patient survival. While CDCP1 expression identifies stem cell populations that mediate lung metastasis, mechanisms underlying the role of this cell surface receptor in CRC have not been defined. We sought to identify CDCP1 regulated processes in CRC using stem cell populations, enriched from primary cells and cell lines, in extensive in vitro and in vivo assays. These experiments, demonstrating that CDCP1 is functionally important in CRC tumor initiation, growth and metastasis, identified CDCP1 as a positive regulator of Wnt signaling. Detailed cell fractionation, immunoprecipitation, microscopy, and immunohistochemical analyses demonstrated that CDCP1 promotes translocation of the key regulators of Wnt signaling, β-catenin, and E-cadherin, to the nucleus. Of functional importance, disruption of CDCP1 reduces nuclear localized, chromatin-associated β-catenin and nuclear localized E-cadherin, increases sequestration of these proteins in cell membranes, disrupts regulation of CRC promoting genes, and reduces CRC tumor burden. Thus, disruption of CDCP1 perturbs pro-cancerous Wnt signaling including nuclear localization of β-catenin and E-cadherin.

Background: Osteoarthritis affecting the knee is common and represents a continuum of disease from early cartilage thinning to full-thickness cartilage loss, bony erosion, and deformity. Many studies do not stratify their results based on the severity of the disease at baseline or recruitment., Objectives: To assess the benefits and harms of surgical intervention for the management of symptomatic mild to moderate knee osteoarthritis defined as knee pain and radiographic evidence of non-end stage osteoarthritis (Kellgren-Lawrence grade 1, 2, 3 or equivalent on MRI/arthroscopy). Outcomes of interest included pain, function, radiographic progression, quality of life, short-term serious adverse events, re-operation rates and withdrawals due to adverse events., Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase up to May 2018. We also conducted searches of ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform for ongoing trials. Authors of trials were contacted if some but not all their participants appeared to fit our inclusion criteria., Selection Criteria: We included randomised controlled trials that compared surgery to non-surgical interventions (including sham and placebo control groups, exercise or physiotherapy, and analgesic or other medication), injectable therapies, and trials that compared one type of surgical intervention to another surgical intervention in people with symptomatic mild to moderate knee osteoarthritis., Data Collection and Analysis: Two review authors independently selected trials and extracted data using standardised forms. We analysed the quality of evidence using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach., Main Results: A total of five studies involving 566 participants were identified as eligible for this review. Single studies compared arthroscopic partial meniscectomy to physical therapy (320 participants), arthroscopic surgery (debridement ± synovectomy ± chondroplasty) to closed needle joint lavage with saline (32 participants) and high tibial osteotomy surgery to knee joint distraction surgery (62 participants). Two studies (152 participants) compared arthroscopic surgery (washout ± debridement; debridement) to a hyaluronic acid injection. Only one study was at low risk of selection bias, and due to the difficulty of blinding participants to their treatment, all studies were at risk of performance and detection bias.Reporting of results in this summary has been restricted to the primary comparison: surgical intervention versus non-surgical intervention.A single study, included 320 participants with symptoms consistent with meniscal tear. All subjects had the meniscal tear confirmed on knee MRI and radiographic evidence of mild to moderate osteoarthritis (osteophytes, cartilage defect or joint space narrowing). Patients with severe osteoarthritis (KL grade 4) were excluded. The study compared arthroscopic partial meniscectomy and physical therapy to physical therapy alone (a six-week individualised progressive home exercise program). This study was at low risk of selection bias and outcome reporting biases, but was susceptible to performance and detection biases. A high rate of cross-over (30.2%) occurred from the physical therapy group to the arthroscopic group.Low-quality evidence suggests there may be little difference in pain and function at 12 months follow-up in people who have arthroscopic partial meniscectomy and those who have physical therapy. Evidence was downgraded to low quality due to risk of bias and imprecision.Mean pain was 19.3 points on a 0 to 100 point KOOS pain scale with physical therapy at 12 months follow-up and was 0.2 points better with surgery (95% confidence interval (CI) 4.05 better to 3.65 points worse with surgery, an absolute improvement of 0.2% (95% CI 4% better to 4% worse) and relative improvement 0.4% (95% CI 9% better to 8% worse) (low quality evidence). Mean function was 14.5 on a 0 to 100 point KOOS function scale with physical therapy at 12 months follow-up and 0.8 points better with surgery (95% CI 4.3 better to 2.7 worse); 0.8% absolute improvement (95% CI 4% better to 3% worse) and 2.1% relative improvement (95% CI 11% better to 7% worse) (low quality evidence).Radiographic structural osteoarthritis progression and quality of life outcomes were not reported.Due to very low quality evidence, we are uncertain if surgery is associated with an increased risk of serious adverse events, incidence of total knee replacement or withdrawal rates. Evidence was downgraded twice due to very low event rates, and once for risk of bias.At 12 months, the surgery group had a total of three serious adverse events including fatal pulmonary embolism, myocardial infarction and hypoxaemia. The physical therapy alone group had two serious adverse events including sudden death and stroke (Peto OR 1.58, 95% CI 0.27 to 9.21); 1% more events with surgery (95% CI 2% less to 3% more) and 58% relative change (95% CI 73% less to 821% more). One participant in each group withdrew due to adverse events.Two of 164 participants (1.2%) in the physical therapy group and three of 156 in the surgery group underwent conversion to total knee replacement within 12 months (Peto OR 1.76, 95% CI 0.43 to 7.13); 1% more events with surgery (95% CI 2% less to 5% more); 76% relative change (95% CI 57% less to 613% more)., Authors' Conclusions: The review found no placebo-or sham-controlled trials of surgery in participants with symptomatic mild to moderate knee osteoarthritis. There was low quality evidence that there may be no evidence of a difference between arthroscopic partial meniscectomy surgery and a home exercise program for the treatment of this condition. Similarly, low-quality evidence from a few small trials indicates there may not be any benefit of arthroscopic surgery over other non-surgical treatments including saline irrigation and hyaluronic acid injection, or one type of surgery over another. We are uncertain of the risk of adverse events or of progressing to total knee replacement due to very small event rates. Thus, there is uncertainty around the current evidence to support or oppose the use of surgery in mild to moderate knee osteoarthritis. As no benefit has been demonstrated from the low quality trials included in this review, it is possible that future higher quality trials for these surgical interventions may not contradict these results.

Background: Since 2011, the knee service at the Nuffield Orthopaedic Centre has been offering a neutralising medial opening wedge high tibial osteotomy (HTO) to a specific group of patients with genu varum and early knee osteoarthritis. An observation was made concerning this group of patients and the presence of CAM deformity at the hip. The aim of this study is to establish whether or not any association exists between the OA phenotype shared by our HTO group and the incidence of CAM deformity at the hip., Methods: A cross-sectional study was designed to estimate the prevalence of CAM-type lesions across different groups of individuals. Our HTO group (n=30) was compared to a pre-arthroplasty group (n=20) and control group (n=20). A total of 70 subjects were identified across the different groups all of whom had long-leg radiographs (LLRs) available for analysis. LLRs were analysed using an in house developed Matlab®-based (Matlab R2009b; MathWorks) software package for hip measurements and MediCAD® (Hectec GmbH, Germany) for lower limb alignment measurements., Results: The HTO group had a significantly higher prevalence of CAM lesions (57%) than both the pre-arthroplasty (40%) and control (30%) groups. This difference was maintained when results were adjusted for potential confounding factors (age, gender and laterality). Across the groups, individuals with tibia vara were more likely to have CAM-deformity of the hip (p=0.021)., Conclusion: Patients with symptomatic early knee OA and varus deformity of the knee have a high prevalence of CAM deformity in the hip., (Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.)

CUB domain containing protein 1 (CDCP1) is a transmembrane protein involved in progression of several cancers. When located on the plasma membrane, full-length 135kDa CDCP1 can undergo proteolysis mediated by serine proteases that cleave after two adjacent amino acids (arginine 368 and lysine 369). This releases from the cell surface two 65kDa fragments, collectively termed ShE-CDCP1, that differ by one carboxyl terminal residue. To evaluate the function of CDCP1 and its potential utility as a cancer biomarker, in this study we developed an enzyme-linked immunosorbent assay (ELISA) to reliably and easily measure the concentration of ShE-CDCP1 in biological samples. Using a reference standard we demonstrate that the developed ELISA has a working range of 0.68-26.5ng/ml, and the limit of detection is 0.25ng/ml. It displays high intra-assay (repeatability) and high inter-assay (reproducibility) precision with all coefficients of variation ≤7%. The ELISA also displays high accuracy detecting ShE-CDCP1 levels at ≥94.8% of actual concentration using quality control samples. We employed the ELISA to measure the concentration of ShE-CDCP1 in human serum samples with our results suggesting that levels are significantly higher in serum of colorectal cancer patients compared with serum from individuals with benign conditions (p<0.05). Our data also suggest that colorectal cancer patients with stage II-IV disease have at least 50% higher serum levels of ShE-CDCP1 compared with stage I cases (p<0.05). We conclude that the developed ELISA is a suitable method to quantify ShE-CDCP1 concentration in human serum., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Microwell platforms are frequently described for the efficient and uniform manufacture of 3-dimensional (3D) multicellular microtissues. Multiple partial or complete medium exchanges can displace microtissues from discrete microwells, and this can result in either the loss of microtissues from culture, or microtissue amalgamation when displaced microtissues fall into common microwells. Herein we describe the first microwell platform that incorporates a mesh to retain microtissues within discrete microwells; the microwell-mesh. We show that bonding a nylon mesh with an appropriate pore size over the microwell openings allows single cells to pass through the mesh into the microwells during the seeding process, but subsequently retains assembled microtissues within discrete microwells. To demonstrate the utility of this platform, we used the microwell-mesh to manufacture hundreds of cartilage microtissues, each formed from 5 × 10(3) bone marrow-derived mesenchymal stem/stromal cells (MSC). The microwell-mesh enabled reliable microtissue retention over 21-day cultures that included multiple full medium exchanges. Cartilage-like matrix formation was more rapid and homogeneous in microtissues than in conventional large diameter control cartilage pellets formed from 2 × 10(5) MSC each. The microwell-mesh platform offers an elegant mechanism to retain microtissues in microwells, and we believe that this improvement will make this platform useful in 3D culture protocols that require multiple medium exchanges, such as those that mimic specific developmental processes or complex sequential drug exposures., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Abstinence self-efficacy, or the confidence in ones' beliefs in one's ability to effectively engage in behaviors to maintain substance use abstinence, is a crucial recovery resource. However, little research has been conducted on what predicts increases in this recovery resource. Understanding predictors of abstinence self-efficacy could help social service practitioners in creating effective treatment plans/interventions while extending what is presently known in this small body of research. Predictors of abstinence self-efficacy were analyzed among a sample of ex-offenders (224 men and 46 women) who were completing inpatient treatment for substance use disorders. Hierarchical linear regression was conducted to examine changes in participants' abstinence self-efficacy in relation to factors directly related (HIV-risk drug use behaviors, substance use, 12-step meeting attendance) and indirectly related (HIV-risk sexual behaviors, incarceration histories) to substance use. HIV-risk sexual behaviors and substance use predicted significant decreases in abstinence self-efficacy whereas 12-step meeting attendance predicted significant increases. However, incarceration histories and HIV-risk drug use behaviors were not significant predictors of abstinence self-efficacy. Findings suggest HIV-risk sexual behavior should be considered when assessing relapse prevention for persons with substance use disorders, and that researchers should examine behaviors that are not directly related to substance use when investigating recovery resources.

The two main functions of the ovary are the production of oocytes, which allows the continuation of the species, and secretion of female sex hormones, which control many aspects of female development and physiology. Normal development of the ovaries during embryogenesis is critical for their function and the health of the individual in later life. Although the adult ovary has been investigated in great detail, we are only starting to understand the cellular and molecular biology of early ovarian development. Here we show that the adult stem cell marker Lgr5 is expressed in the cortical region of the fetal ovary and this expression is mutually exclusive to FOXL2. Strikingly, a third somatic cell population can be identified, marked by the expression of NR2F2, which is expressed in LGR5- and FOXL2 double-negative ovarian somatic cells. Together, these three marker genes label distinct ovarian somatic cell types. Using lineage tracing in mice, we show that Lgr5-positive cells give rise to adult cortical granulosa cells, which form the follicles of the definitive reserve. Moreover, LGR5 is required for correct timing of germ cell differentiation as evidenced by a delay of entry into meiosis in Lgr5 loss-of-function mutants, demonstrating a key role for LGR5 in the differentiation of pre-granulosa cells, which ensure the differentiation of oogonia, the formation of the definitive follicle reserve, and long-term female fertility., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Coeliac disease is the commonest immunological gastrointestinal disorder in the Western world. The symptoms of coeliac disease in adults are often non-specific, and a high index of suspicion may be required for timely diagnosis. We describe the case of a 46-year-old woman, with known dilated cardiomyopathy and pulmonary hypertension, who presented with non-specific abdominal symptoms, not initially attributed to gastrointestinal disease. Radiological investigations demonstrated transient small bowel intussusception without other abnormality, leading to the suggestion of coeliac disease as a cause, which was subsequently confirmed as the diagnosis., (2014 BMJ Publishing Group Ltd.)

A number of studies require the determination of the genetic sex of mouse embryos before sexual differentiation and/or of mutant mice that display partial or complete sex reversal. The majority of current methods for sexing by PCR involve multiplexing of 2 primer pairs. We have developed a novel sexing PCR using a single primer pair that amplifies fragments from the X and the Y chromosome with a clear size difference between the respective amplicons. This assay provides a rapid and reliable method to identify the genetic sex of mice across different mouse strains., (Copyright © 2013 S. Karger AG, Basel.)

In contrast to the developing testis, molecular pathways driving fetal ovarian development have been difficult to characterise. To date no single master regulator of ovarian development has been identified that would be considered the female equivalent of Sry. Using a genomic approach we identified a number of novel protein-coding as well as non-coding genes that were detectable at higher levels in the ovary compared to testis during early mouse gonad development. We were able to cluster these ovarian genes into different temporal expression categories. Of note, Lrrc34 and AK015184 were detected in XX but not XY germ cells before the onset of sex-specific germ cell differentiation marked by entry into meiosis in an ovary and mitotic arrest in a testis. We also defined distinct spatial expression domains of somatic cell genes in the developing ovary. Our data expands the set of markers of early mouse ovary differentiation and identifies a classification of early ovarian genes, thus providing additional avenues with which to dissect this process.

Small bowel perforation following a capsule endoscopy (CE) is a rare but dreadful complication. We report a CE induced small bowel perforation in a patient with Crohn's disease where preoperative investigations failed to reveal any strictures.

Unlike seminomas in humans, seminomas in animals are not typically sub-classified as classical or spermatocytic types. To compare testicular germ cell tumours (TGCT) in dogs with those of men, archived tissues from 347 cases of canine testicular tumours were morphologically evaluated and characterized using human classification criteria. Histopathological and immunohistological analysis of PLAP, KIT, DAZ and DMRT1 expression revealed that canine seminomas closely resemble human spermatocytic seminomas. In addition, a relatively frequent concomitant presence of somatic cell tumours was noted in canine TGCT. None of the canine TGCT evaluated demonstrated the presence of carcinoma in situ cells, a standard feature of human classical seminomas, suggesting that classical seminomas either do not occur in dogs or are rare in occurrence. Canine spermatocytic seminomas may provide a useful model for this rare human neoplasm., (© 2011 The Authors. International Journal of Andrology © 2011 European Academy of Andrology.)

Purpose: Isolated reported cases of familial torsion yield modest information on incidence, genetics or clinical features. We present what is to our knowledge the largest series of familial torsion, including the first 3 generation case and a review of the literature., Materials and Methods: Since 2006, we have questioned the presence of a positive family history in all patients with torsion at the initial consultation. We compiled data on familial relationship, laterality, age and outcomes of the proband and affected relatives. We collected previously published cases to better understand clinical features and genetics., Results: Eight of 70 boys (11.4%) with torsion had affected family members. Another 2 families were included from a historical perspective. One relative was affected in 7 families, 2 were affected in 2 and 3 were affected in 1. First degree relatives were most commonly affected. In 1 family torsion occurred in 3 consecutive generations. Despite a family history 50% of patients experienced testicular loss. Brothers were affected in each of the 10 previously reported cases. In 3 families fathers were also affected. There were 3 sets of monozygotic twins. We noted laterality concordance 5 times and discordance 6 times. Age at torsion in probands was adolescence except in 2 with neonatal torsion. No clear inheritance mode was found., Conclusions: Familial torsion occurs in about 10% of probands and can affect multiple relatives and generations. A positive family history may be useful for torsion diagnosis and management. Relatives of affected patients need education on the signs and symptoms of torsion, and the importance of early presentation to improve outcome., (Copyright © 2011 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: Retrograde ureteral access after cross-trigonal ureteral reimplantation can be challenging. We present our experience with percutaneous retrograde ureteral catheterization, status post cross-trigonal ureteral reimplantation., Materials and Methods: We evaluated all patients who underwent attempted percutaneous retrograde ureteral catheterization after cross-trigonal ureteral reimplantation. All clinical data, radiographic images and operative reports were reviewed. Ureteral access was obtained by percutaneously entering the bladder with an intravenous needle/catheter under cystoscopic guidance. The needle was then removed leaving the catheter in place. The ureteral orifice was then accessed through the intravenous catheter by a ureteral access wire and/or ureteral catheter under cystoscopic guidance., Results: From 1978 to 2008, 13 patients (11 boys and 2 girls) with a history of cross-trigonal ureteral reimplantation underwent percutaneous retrograde ureteral catheterization. The procedure was unilateral in 12 patients and bilateral in one. Indications for the procedure included: retrograde pyelography and double-J stent insertion for ureteropelvic junction or ureterovesical junction obstruction (10); removal of migrated stent (2); and treatment of a ureteral stone (1). The procedure was performed successfully in all patients and without complications., Conclusions: Percutaneous retrograde ureteral catheterization is a safe, straightforward, and effective modality for obtaining retrograde ureteral access in children, status post cross-trigonal ureteral reimplantation., (Copyright © 2010 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Inconspicous penis refers to a constellation of conditions that make the penis look diminutive and small. This could be secondary to short penile shaft often termed as micropenis. But more commonly, this inconspicuous appearance is secondary to other causes ranging from congenital conditions such as penoscrotal webbing or megaprepuce, developmental conditions like prepubic adiposity that overhang the penis, and iatrogenic causes like trapped penis after adhesions secondary to circumcision. In this paper, we propose to define these entities and provide their descriptions and then to describe their management including surgical correction.

In the United States, circumcision is a commonly performed procedure. It is a relatively safe procedure with a low overall complication rate. Most complications are minor and can be managed easily. Though uncommon, complications of circumcision do represent a significant percentage of cases seen by pediatric urologists. Often they require surgical correction that results in a significant cost to the health care system. Severe complications are quite rare, but death has been reported as a result in some cases. A thorough and complete preoperative evaluation, focusing on bleeding history and birth history, is imperative. Proper selection of patients based on age and anatomic considerations as well as proper sterile surgical technique are critical to prevent future circumcision-related adverse events.

The development of the mononuclear phagocyte system requires macrophage colony-stimulating factor (CSF-1) signaling through the CSF-1 receptor (CSF1R, CD115). We examined the effect of an antibody against CSF1R on macrophage homeostasis and function using the MacGreen transgenic mouse (csf1r-enhanced green fluorescent protein) as a reporter. The administration of a novel CSF1R blocking antibody selectively reduced the CD115(+)Gr-1(neg) monocyte precursor of resident tissue macrophages. CD115(+)Gr-1(+) inflammatory monocytes were correspondingly increased, supporting the view that monocytes are a developmental series. Within tissue, the antibody almost completely depleted resident macrophage populations in the peritoneum, gastrointestinal tract, liver, kidney, and skin, but not in the lung or female reproductive organs. CSF1R blockade reduced the numbers of tumor-associated macrophages in syngeneic tumor models, suggesting that these cells are resident type macrophages. Conversely, it had no effect on inflammatory monocyte recruitment in models, including lipopolysaccharide-induced lung inflammation, wound healing, peritonitis, and severe acute graft-versus-host disease. Depletion of resident tissue macrophages from bone marrow transplantation recipients actually resulted in accelerated pathology and exaggerated donor T-cell activation. The data indicate that CSF1R signaling is required only for the maturation and replacement of resident-type monocytes and tissue macrophages, and is not required for monocyte production or inflammatory function.

The aim of the present study was to investigate the attachment mechanisms that enable the thermophile Anoxybacillus flavithermus (B12) to attach to stainless-steel surfaces. Passing a B12 culture through a column of stainless-steel chips, collecting the first cells to pass through, re-culturing, and repeating the process six times, resulted in the isolation of a mutant, labeled X7, with tenfold reduced ability to attach to stainless steel as well as a reduced ability to attach to plastic. A comparison of bacterial cell-surface properties indicated that X7 was less hydrophobic than its parental strain B12. Cell-surface charge measurements also suggest that X7 had a lower net-negative surface charge. Disruption of extracellular polysaccharides and DNA appeared to have no effect on the attachment process. Removal of surface proteins caused a reduction in attachment of both B12 and X7, suggesting surface protein involvement in attachment.

The management of urological emergencies during pregnancy presents unique clinical challenges for the treating physician. Clinical signs and symptoms are often subtle while diagnostic and therapeutic options are limited in treating patients to avoid fetal morbidity. A high index of suspicion with early diagnosis and treatment are essential for the management of genitourologic emergencies in pregnant women. It is essential for patients to be managed on an individual basis using a multidisciplinary approach., (Copyright 2010 Elsevier Inc. All rights reserved.)

Objectives: Avagard is a waterless, scrubless, and brushless hand antiseptic approved by the Food and Drug Administration as a replacement for traditional presurgical brush hand scrubbing. We evaluated the use of Avagard compared with hand brush scrub preparation for inpatient and outpatient pediatric urological operations., Methods: We evaluated the first 1800 patients for whom we used Avagard as a preoperative hand antiseptic and compared them with the last 1800 consecutive patients for whom we performed traditional antiseptic-impregnated hand-brush scrubbing. All patients underwent a variety of inpatient and outpatient open, endoscopic, and laparoscopic pediatric urological procedures. Patients were monitored postoperatively for wound infection, and patients and surgeon were monitored for side effects. A cost analysis was performed., Results: The incidence of wound infection was 2/1800 (0.11%) in the Avagard group and 3/1800 (0.17%) in the hand-scrub group (P > .99 Fisher's exact test). All wound infections were successfully treated with a single course of oral antibiotics. No side effects for the patients or surgeon were noted, including skin irritations or allergic reactions in either group. The traditional hand scrub is nearly 2 times more expensive per application than Avagard., Conclusions: The incidence of wound infections in pediatric urological procedures is low (0.09%). We observe that Avagard provides comparable hand antisepsis to the traditional surgical scrub in a variety of pediatric urological procedures. Avagard is superior to the surgical hand scrub in cost-effectiveness and time efficiency. Urologists should consider using Avagard for hand antisepsis before surgery., (Copyright 2010 Elsevier Inc. All rights reserved.)

Developmental exposure to the agricultural fungicide vinclozolin can impair reproductive function in male rabbits and was previously found to decrease the number of immunoreactive-gonadotrophin-releasing hormone (GnRH) neurones in the region of the organum vasculosum of the lamina terminalis and rostral preoptic area by postnatal week (PNW) 6. In the present study, in an aim to further examine the disruption of GnRH neurones by foetal vinclozolin exposure, pregnant rabbits were dosed orally with vinclozolin, flutamide or carrot paste vehicle for the last 2 weeks of gestation. Offspring were euthanised at birth (males and females), PNW 6 (females), PNW 26 (adult males) or PNW 30 (adult females) of age. At birth and in adults, brains were sectioned and processed for immunoreactive GnRH. The numbers of immunoreactive GnRH neuronal perikarya were significantly decreased in vinclozolin-treated rabbits at birth and in adult littermates. By contrast, there was an increase in GnRH immunoreactivity in the terminals in the region of the median eminence. Analysis of PNW 6 female brains by radioimmunoassay revealed a two-fold increase in GnRH peptide content in the mediobasal hypothalamus in vinclozolin-treated rabbits. This finding was complemented by immunofluorescence analyses, which revealed a 2.8-fold increase in GnRH immunoreactivity in the median eminence of vinclozolin compared to vehicle-treated females at PNW 30. However, there was no difference between treatment groups in the measures of reproduction that were evaluated: ejaculation latency, conception rates or litter size. These results indicate that sub-acute, prenatal vinclozolin treatment is sufficient to create perdurable alterations in the GnRH neuronal network that forms an important input into the reproductive axis. Finally, the effect of vinclozolin on the GnRH neuronal network was not comparable to that of flutamide, suggesting that vinclozolin was not acting through anti-androgenic mechanisms.

Purpose: Ungated extracorporeal shock wave lithotripsy (SWL) is unsynchronized to the patient's electrocardiogram. Although ungated extracorporeal shock wave lithotripsy (SWL) is associated with cardiac arrhythmias in adults, the incidence of arrhythmias in children has not been established. We report on the safety and efficacy of ungated SWL of renal calculi in children., Materials and Methods: We evaluated all children less than 18 years of age undergoing ungated SWL for renal calculi. Lithotripsy with gradual incremental energy increase was used to treat the stones. Patients were monitored for arrhythmias and other standard monitoring intraoperatively and postoperatively., Results: Twenty-four consecutive children (10 boys and 14 girls) between 3.5 and 17 years of age underwent 32 ungated SWL procedures for renal calculi. The stone size ranged from 5 mm to 19 mm. No patient had cardiac arrhythmias or other intraoperative complications, required to have the procedure terminated prematurely, or conversion to gated SWL. The overall stone free rate was 87% based on radiographic imaging., Conclusions: This series supports our initial series that ungated SWL is safe and efficacious in children less than 18 years of age. The arrhythmias associated with adults do no appear to occur in children undergoing ungated SWL.

The majority of pregnant women in the U.S. undergo prenatal ultrasonography and approximately 0.5% of these examinations will detect fetal malformations. Up to one-half of these abnormalities include the genitourinary system and the most common urological finding is hydronephrosis. Some conditions associated with prenatal hydronephrosis portend a poor prognosis, while others can follow a fairly benign course. This review focuses on the definition and prenatal assessment of hydronephrosis, fetal intervention, and postnatal management.