Leveraging big data of immune checkpoint blockade response identifies novel potential targets.

BACKGROUND: The development of immune checkpoint blockade (ICB) has changed the way we treat various cancers. While ICB produces durable survival benefits in a number of malignancies, a large proportion of treated patients do not derive clinical benefit. Recent clinical profiling studies have shed light on molecular features and mechanisms that modulate response to ICB. Nevertheless, none of these identified molecular features were investigated in large enough cohorts to be of clinical value. MATERIALS AND METHODS: Literature review was carried out to identify relevant studies including clinical dataset of patients treated with ICB [anti-programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1), anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) or the combination] and available sequencing data. Tumor mutational burden (TMB) and 37 previously reported gene expression (GE) signatures were computed with respect to the original publication. Biomarker association with ICB response (IR) and survival (progression-free survival/overall survival) was investigated separately within each study and combined together for meta-analysis. RESULTS: We carried out a comparative meta-analysis of genomic and transcriptomic biomarkers of IRs in over 3600 patients across 12 tumor types and implemented an open-source web application (predictIO.ca) for exploration. TMB and 21/37 gene signatures were predictive of IRs across tumor types. We next developed a de novo GE signature (PredictIO) from our pan-cancer analysis and demonstrated its superior predictive value over other biomarkers. To identify novel targets, we computed the T-cell dysfunction score for each gene within PredictIO and their ability to predict dual PD-1/CTLA-4 blockade in mice. Two genes, F2RL1 (encoding protease-activated receptor-2) and RBFOX2 (encoding RNA-binding motif protein 9), were concurrently associated with worse ICB clinical outcomes, T-cell dysfunction in ICB-naive patients and resistance to dual PD-1/CTLA-4 blockade in preclinical models. CONCLUSION: Our study highlights the potential of large-scale meta-analyses in identifying novel biomarkers and potential therapeutic targets for cancer immunotherapy.

Photodissociation of ultracold diatomic strontium molecules with quantum state control.

Chemical reactions at ultracold temperatures are expected to be dominated by quantum mechanical effects. Although progress towards ultracold chemistry has been made through atomic photoassociation, Feshbach resonances and bimolecular collisions, these approaches have been limited by imperfect quantum state selectivity. In particular, attaining complete control of the ground or excited continuum quantum states has remained a challenge. Here we achieve this control using photodissociation, an approach that encodes a wealth of information in the angular distribution of outgoing fragments. By photodissociating ultracold (88)Sr2 molecules with full control of the low-energy continuum, we access the quantum regime of ultracold chemistry, observing resonant and nonresonant barrier tunnelling, matter-wave interference of reaction products and forbidden reaction pathways. Our results illustrate the failure of the traditional quasiclassical model of photodissociation and instead are accurately described by a quantum mechanical model. The experimental ability to produce well-defined quantum continuum states at low energies will enable high-precision studies of long-range molecular potentials for which accurate quantum chemistry models are unavailable, and may serve as a source of entangled states and coherent matter waves for a wide range of experiments in quantum optics.

Knowledge, attitudes and practices of neonatal professionals regarding pain management.

Pain management is an important issue which impacts the prognosis of neonates in neonatal intensive care units. Evidence has shown that professionals' knowledge and attitudes regarding pain management can impact the quality of their practice. The purpose of this study was to evaluate the knowledge, attitudes, and practices of neonatal professionals regarding neonatal pain management. A cross-sectional study was performed involving neonatal physicians and nurses, using a research questionnaire to investigate the knowledge and attitudes of professionals as well as to assess their practice of pain management. Research found an apparent discrepancy between the knowledge levels of neonatologists and nurses regarding pain assessment and management, with nurses displaying weaker professional knowledge and more negative attitudes toward pain management than did neonatologists. Additionally, research revealed a lack of knowledge and negative attitudes among participants regarding the provision of sufficient opioid analgesics to sick infants during invasive procedures and even for dying neonates. There is an urgent need for continuing education regarding neonatal pain management with the goal of empowering neonatal professionals; further research is needed into the question of how to translate education into more reliable practice.Conclusion: This research provides useful information regarding the knowledge, attitudes, and clinical practice of neonatal pain management among neonatologists and nurses and points out some differences in the knowledge levels of these two groups. What is Known: •Neonates can perceive and respond to pain stimuli by showing their biological signals similarly to children and adults. •Untreated or insufficient pain management for high-risk neonates has short-term. negative effects and may also induce long-term negative effects. What is New: •The level of knowledge, the attitudes, and the practices regarding neonatal pain in intensive care are different among neonatal professionals. •There is an urgent need to provide interdisciplinary continuing education to improve the knowledge of neonatal professionals and encourage them to more highly prioritize neonatal pain management.

Mucin 5AC is significantly upregulated in exosomes from the nasal lavage fluid and may promote the expression of COX-2, VEGF and MMP-9: an implication in nasal polyp pathogenesis.

BACKGROUND: Exosomes are critical mediators of intercellular communication and could be involved in many human diseases; however, little is known about the role of exosomes in nasal polyps (NP). METHODS: Exosomes in nasal lavage fluids (NLF) were isolated by ultracentrifugation. Exosome identity was validated by nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM) and specific exosomal markers. The exosome proteome was revealed by LC-MS/MS, and the expression of the candidate exosomal protein, mucin 5AC, was confirmed by Western blot analysis and immunohistochemistry (IHC). Cellular uptake of the exosomes was monitored by fluorescence confocal microscopy and the ensuing effects on COX-2, VEGF and MMP-2/MMP-9 were determined by Western blotting, ELISA and gelatin zymography, respectively. RESULTS: Mass spectrometry analysis and subsequent verification by Western blotting identified that mucin 5AC was significantly upregulated in exosomes from NLFs of NP patients. Moreover, the expression of mucin 5AC was increased in the tissue specimens of the NP patients. Functional assays suggest that the mucin 5 AC-enriched exosomes could be effectively taken up by chronic rhinosinusitis without NP (CRSsNP)-derived fibroblasts, the control cells, resulting in a significant increase in the expression of COX-2, VEGF and MMP-9. CONCLUSIONS: Mucin 5AC, the major airway mucin, cannot only be carried and transferred by nasal exosomes, but may also promote tissue remodeling and angiogenesis and thus could be a potential therapeutic target of NP.

Transition Strength Measurements to Guide Magic Wavelength Selection in Optically Trapped Molecules.

Optical trapping of molecules with long coherence times is crucial for many protocols in quantum information and metrology. However, the factors that limit the lifetimes of the trapped molecules remain elusive and require improved understanding of the underlying molecular structure. Here we show that measurements of vibronic line strengths in weakly and deeply bound ^{88}Sr_{2} molecules, combined with ab initio calculations, allow for unambiguous identification of vibrational quantum numbers. This, in turn, enables the construction of refined excited potential energy curves, informing the selection of magic wavelengths that facilitate long vibrational coherence. We demonstrate Rabi oscillations between far-separated vibrational states that persist for nearly 100 ms.

Genetic alterations in primary melanoma in Taiwan.

BACKGROUND: Acral melanoma (AM) is the most common histopathological subtype of malignant melanoma in Asians. However, differences in the mutational profiles underlying AM and nonacral cutaneous melanoma (NAM) in Asians are not well understood. OBJECTIVES: To augment the understanding of the prevalence, patterns and associations of various mutations between different subtypes of melanoma. METHODS: We performed comprehensive genomic profiling of 409 cancer-associated genes, using next-generation sequencing, in 66 primary melanomas comprised of 45 AMs and 21 NAMs. RESULTS: Most of the AMs (n = 27/45; 60%), but only five of 21 (24%) NAMs, were triple wild-type (triple-WT) tumours. Compared with AMs, NAMs exhibited a significantly higher frequency of BRAF mutations. The frequencies of NRAS/KRAS mutations, cell-cycle aberrations, copy number gains in BIRC2, BIRC3 and BIRC5, and gains of receptor tyrosine kinase genes were significantly higher in AMs. Ulceration was found at significantly higher rates in the AMs and NAMs with cell-cycle aberrations and gains of receptor tyrosine kinase genes. Notably, cell-cycle aberrations and copy number gains in BIRC2, BIRC3 and BIRC5 were significantly associated with poor melanoma-specific survival in the 66 patients with melanoma and especially in the 45 patients with AM. Multivariate analysis showed that lymph node metastasis and cell-cycle aberrations were independent prognostic factors of melanoma-specific survival. CONCLUSIONS: This study strengthens our understanding of the patterns and clinical associations of oncogenic mutations in AMs and NAMs in Asians. What's already known about this topic? Mutation frequencies of driver genes vary between melanoma subtypes. Acral melanoma is the most common subtype of melanoma in Asians. KIT mutations and copy number variations occur more frequently in the acral subtype of melanoma than in the nonacral subtype What does this study add? NRAS/KRAS mutations, cell-cycle aberrations, copy number gains in BIRC2, BIRC3 and BIRC5, and amplifications of receptor tyrosine kinase genes were significantly enriched in acral melanoma and could be potential targets for treatment. Melanomas with cell-cycle aberrations and gains in receptor tyrosine kinase genes were significantly more likely to contain ulceration. What is the translational message? Cell-cycle aberrations and copy number gains in BIRC2, BIRC3 and BIRC5 were significantly associated with poor melanoma-specific survival. These observations should be explored further for future drug development.

Effects of quorum quenching on temporal succession of activated sludge microbial community in a membrane bioreactor.

AIMS: Quorum quenching (QQ) is an attractive strategy for mitigating biofouling in membrane bioreactors (MBRs). However, the effects of QQ on the activated sludge (AS) process have not been adequately evaluated. This study investigated the long-term effects of QQ on a laboratory-scale anoxic-oxic MBR, focusing on AS performance and microbial community. METHODS AND RESULTS: Anoxic-oxic MBRs with and without QQ were operated for 91 days. QQ did not affect COD and TN removal efficiencies over the experimental period, during which its activity remained >90%. QQ reduced floc size by approximately 8% but had no effect on biomass concentration. AS microbial communities were regularly analysed using massively parallel sequencing. AS bacterial communities were temporally dynamic irrespective of QQ presence, for example, a temporal increase in bacterial diversity and a temporal decay of community similarity. QQ counteracted the temporal change in diversity and the temporal distance-community decay. Community comparison revealed that QQ changed the successional trajectory of the AS community at a late period, because it decelerated temporal changes of specific members, such as Thiothrix and Sphingomonadaceae*. Correlation networks revealed that QQ increased network clustering, complexity and density. The combined results suggest that the tighter microbial association by QQ increased the community resistance. CONCLUSIONS: QQ can enhance the diversity and stability of the AS community in MBR by counteracting the innate temporal change in community structure. SIGNIFICANCE AND IMPACT OF THE STUDY: Our findings are useful for the further advancement of QQ-based strategies in engineered microbial environments.

Benign postoperative hepaticojejunostomy stricture: percutaneous recanalisation using the reverse end of a microwire.

AIM: To evaluate the technical feasibility and safety of percutaneous recanalisation of benign postoperative hepaticojejunostomy strictures using the reverse end of a microwire. MATERIALS AND METHODS: Twenty-one patients with benign postoperative hepaticojejunostomy strictures that had failed to recanalise following management with conventional percutaneous techniques from January 2012 to March 2019 were included in the study. The stricture was punctured by the reverse end of a microwire. Subsequently, serial balloon dilatation and covered stent placement was performed. Technical as well as clinical success, complications, and patency of the hepaticojejunostomy were evaluated. RESULTS: Technical success was achieved in 19 of 21 (90.5%) patients. The mean number of treatment sessions was 1.2 (range, 1-2). The obstructive symptoms were resolved within 3 days after the procedure in 19 patients (100%). There were no major complications. The 1-year and 3-year patency rates were 76.9% and 61.5%, respectively. CONCLUSION: Percutaneous recanalisation using the reverse end of a microwire is technically feasible and safe in the treatment of benign postoperative hepaticojejunostomy strictures. This technique is useful when the conventional percutaneous technique cannot be used to cross the stricture.

Clopidogrel may decrease the risk of post-stroke infection after ischaemic stroke.

BACKGROUND AND PURPOSE: The P2Y12 receptor, a well-known factor in the platelet activation pathway, plays a role in thrombosis as well as systemic inflammation. Clopidogrel, a prototype P2Y12 receptor antagonist, reportedly decreases inflammation and systemic infection. The aim of this study was to evaluate whether clopidogrel use decreases the risk of post-stroke infection following ischaemic stroke. METHODS: A total of 1643 patients with acute ischaemic stroke (within 7 days after onset) were included for analysis between March 2010 and December 2015. Patients were categorized into two groups (clopidogrel users versus clopidogrel non-users), and clinical characteristics and risks of post-stroke infection were compared between the two groups. The inverse probability of treatment weighting using propensity scores for baseline imbalance adjustments was applied. RESULTS: Of the included patients (mean age 67.7 years; men 60.6%), 670 (40.8%) patients were clopidogrel users and 164 (10.0%) patients had post-stroke infection. The proportion of patients with post-stroke infection was significantly lower in clopidogrel users compared to clopidogrel non-users (6.7% vs. 12.2%, P ≤ 0.001). Moreover, clopidogrel users were less likely to be admitted to the intensive care unit (13.3% vs. 35.3%, P = 0.006). A multivariate analysis with inverse probability of treatment weighting revealed that clopidogrel users exhibited a lower risk of post-stroke infection (odds ratio 0.56, 95% confidence interval 0.42-0.75) and intensive care unit admission (odds ratio 0.34, 95% confidence interval 0.22-0.53). CONCLUSIONS: The study suggested that clopidogrel users exhibit a lower risk of infection and develop less severe infections after ischaemic stroke. Further prospective studies are needed.

Revision adenoidectomy in children: a meta-analysis.

BACKGROUND: To estimate the rate of revision surgery after previous adenoidectomy in children and to compare the rate of revision adenoidectomy in children with different conditions and by using different surgical techniques. METHODOLOGY: The study protocol was registered on PROSPERO (CRD42018107877). Two authors independently searched databases, specifically PubMed, MEDLINE, EMBASE, and the Cochrane Review database. The keywords used were "adenoids","adenoidectomy","reoperation","revision"and "regrowth". The revision rate was pooled using a random-effect model. Subgroup analyses were conducted for children based on different settings, countries, risks of bias, and surgical techniques. RESULTS: A total 16 studies with 95 727 children were analyzed (mean age: 4.69 (1.62) years; 60% boys; sample size: 5983 patients). Five studies had a low risk of bias, 10 studies had a moderate risk of bias, and one study had a high risk of bias. The rate of revision adenoidectomy was 1.9%. Ages at initial surgery and follow-up were not significantly associated with revision surgeries. The revision rate was not significantly different in children receiving surgeries in different settings (single center vs multicenter vs population-based, country (non-United States vs United States, and risk of bias. Moreover, surgical techniques, such as curettage, suction cautery, microdebridement, and coblation did not significantly affect revision rates in children who received adenoidectomy. CONCLUSIONS: Revision surgery was undertaken with a frequency of 1.9% in children who underwent adenoidectomy. A lack of strong evidence exists to correlate surgical techniques with revision rate in pediatric adenoidectomy.

Crossover from the Ultracold to the Quasiclassical Regime in State-Selected Photodissociation.

Processes that break molecular bonds are typically observed with molecules occupying a mixture of quantum states and successfully described with quasiclassical models, while a few studies have explored the distinctly quantum mechanical low-energy regime. Here, we use photodissociation of diatomic strontium molecules to demonstrate the crossover from the ultracold, quantum regime where photofragment angular distributions strongly depend on the kinetic energy to the quasiclassical regime. Using time-of-flight imaging for photodissociation channels with millikelvin reaction barriers, we explore photofragment energies in the 0.1-300 mK range experimentally and up to 3 K theoretically, and discuss the energy scale at which the crossover occurs. We find that the effects of quantum statistics can persist to high photodissociation energies.

Control of Ultracold Photodissociation with Magnetic Fields.

Photodissociation of a molecule produces a spatial distribution of photofragments determined by the molecular structure and the characteristics of the dissociating light. Performing this basic reaction at ultracold temperatures allows its quantum mechanical features to dominate. In this regime, weak applied fields can be used to control the reaction. Here, we photodissociate ultracold diatomic strontium in magnetic fields below 10 G and observe striking changes in photofragment angular distributions. The observations are in excellent agreement with a multichannel quantum chemistry model that includes nonadiabatic effects and predicts strong mixing of partial waves in the photofragment energy continuum. The experiment is enabled by precise quantum-state control of the molecules.

The potential of salivary biomarkers for predicting the sensitivity and monitoring the response to nonsurgical periodontal therapy: A preliminary assessment.

BACKGROUND AND OBJECTIVE: The response to nonsurgical periodontal treatment varied among patients. This study assessed the potential of salivary biomarkers for predicting the sensitivity and monitoring the response to nonsurgical periodontal therapy. MATERIAL AND METHODS: This study recruited 34 participants with severe chronic periodontitis (the test group) and 20 participants without periodontal destruction in any teeth (the control group) from September 6, 2013 to August 25, 2017. Participants in the test group received nonsurgical periodontal therapy and were further divided into 2 subgroups of 17 low responders and 17 high responders, based on probing depth reduction. Clinical periodontal parameters were recorded, and saliva samples were harvested before and after nonsurgical periodontal therapy. Salivary biomarkers, including interleukin (IL)-1beta (IL-1ß), IL-1 receptor antagonist (IL-1ra), IL-6, IL-8, platelet-derived growth factor-BB, vascular endothelial growth factor, MMP-8, MMP-9, C-reactive protein, and lactoferrin were analyzed. RESULTS: Compared with participants in the control group, participants in the test group had significantly greater periodontal pocket depth, clinical attachment level, and salivary IL-1ß and MMP-8 levels, and all of these parameters were significantly reduced after nonsurgical periodontal therapy. The pretreatment levels of IL-1ß, MMP-8, and lactoferrin were significantly higher in participants of the high-responder subgroup than participants of the low-responder subgroup.Based on the analysis from a dichotomous table, MMP-8 and lactoferrin showed odds ratios of 5.76, with 71% sensitivity and 71% specificity, and statistical significance (P = .02) for discriminating between the high- and low-responder subgroups. CONCLUSION: Salivary IL-1ß and MMP-8 might be useful for diagnosing periodontitis and monitoring the recovery of periodontitis following nonsurgical periodontal therapy. MMP-8 and lactoferrin showed potential for predicting the sensitivity to the treatment.

Clinicopathological features and course of cutaneous protothecosis.

BACKGROUND: Protothecosis is an uncommon infection caused by the achlorophyllic algae found more commonly in tropical areas. Only a limited number of cases have been reported. OBJECTIVE: We aimed to evaluate the clinicopathological features and treatment outcomes of cutaneous protothecosis. METHODS: We retrospectively identified 20 pathology-confirmed cases of cutaneous protothecosis based on skin biopsies in two tertiary medical centres in Taiwan from 1997 to 2015. RESULTS: The age of the patients at the time of diagnosis ranged from 48 to 85 years (mean age of 74 years). All lesions developed on the limbs. Twelve (60%) patients had adrenal insufficiency, but no patients had active malignancy at diagnosis. Interestingly, four (20%) patients had concurrent scabies infestation. Clinically, most lesions were erythematous plaques studded with punctate ulcers. Microscopically, the most common finding was granulomatous inflammation. Nineteen (95%) cases were successfully treated with itraconazole for 14-148 days with only one case of recurrence. Concomitant scabies should be suspected if pruritus is recalcitrant despite itraconazole treatment. CONCLUSION: Despite its rarity, cutaneous protothecosis has become more significant due to an increased prevalence of immunocompromised individuals. Steroid overuse or iatrogenic adrenal insufficiency predisposes individuals to high-risk infections. Neglecting the disease leads to a chronic and incurable state. Protothecosis should be suspected in chronic eczematous and ulcerative plaques on the limbs refractory to conventional antibacterial and antiviral treatments, especially in patients with adrenal insufficiency. Clinical suspicion should be confirmed by skin biopsies, and confirmed cases can be successfully treated with itraconazole.

Vertebral bone attenuation on low-dose chest CT: quantitative volumetric analysis for bone fragility assessment.

This study evaluated the use of low-dose chest computed tomography (LDCT) for detecting bone fragility. LDCT-measured vertebral bone attenuation by volumetric methods showed good correlation with bone mineral density (BMD) measured by dual-energy x-ray absorptiometry (DXA, and good diagnostic performance for identifying osteoporosis and compression fractures. The results of this study suggest the feasibility of obtaining comprehensive information on bone health in subjects undergoing LDCT. INTRODUCTION: Osteoporosis is a prevalent but underdiagnosed disease that increases fracture risk. This study evaluated the utility of vertebral attenuation derived from low-dose chest computed tomography (LDCT) compared to dual-energy x-ray absorptiometry (DXA) for detecting bone fragility. METHODS: A total of 232 subjects (78 men and 154 women) aged above 50 years who underwent both LDCT and DXA within 30 days were evaluated. LDCT-measured bone attenuation in Hounsfield units (HU) of four vertebrae (T4, T7, T10, and L1) was evaluated using volumetric methods for correlation with DXA-measured bone mineral density (BMD) and for the diagnosis of compression fractures, osteoporosis, and low BMD (osteoporosis or osteopenia) in men and women, with DXA measurements as the reference standard. RESULTS: The average attenuation of the four vertebrae showed strong correlation with DXA-measured BMD of the lumbar spine (r = 0.726, p < 0.05). In receiver-operating characteristic (ROC) analyses, the area under the curve (AUC) across LDCT-measured thresholds of the average attenuation to distinguish compression fractures was 0.827, and a threshold of 129.5 HU yielded 90.9 % sensitivity and 64.4 % specificity. Similarly, average attenuation showed high AUCs and good diagnostic performance for detecting osteoporosis and low BMD in both men and women. Among 44 subjects with compression fractures, the average bone attenuation showed strong negative correlation with both the worst fracture grade (r = -0.525, p < 0.05) and cumulative fracture grade score (r = -0.633, p < 0.05). CONCLUSION: LDCT-measured bone attenuation by volumetric methods showed good correlation with BMD measured by DXA and good diagnostic performance for identifying bone fragility.

Enhanced Th2 cell differentiation and function in the absence of Nox2.

BACKGROUND: Patients with chronic granulomatous disease (CGD), whom inherit abnormal function of NADPH oxidase 2 (Nox2), suffer from hyperinflammatory responses in lung as well as bacterial and fungal infection. There have been studies to reveal the function of Nox2 in hyperinflammatory diseases, especially in asthma, but the exact role of Nox2 in asthma is still unclear and controversial. Therefore, we attempted to clarify the exact role of Nox2 in asthma, using various experimental asthma models. METHODS: Asthma phenotypes were analyzed in response to various allergen-induced experimental asthma using Nox2-deficient mice and recombinase gene-activating-1-deficient mice. To understand the underlying mechanisms of exaggerated Th2 effector functions, we investigated the degree of T-cell activation, levels of activation-induced cell death (AICD), and regulatory T (Treg)-cell differentiation in Nox2-deficient T cells. RESULTS: Asthma phenotypes were increased through enhanced Th2 differentiation and function in Nox2-null mice regardless of dose and route of various allergens. Nox2-deficient T cells also showed hyperactivation, reduced AICD, and diminished Treg-cell differentiation through increased AKT phosphorylation (T308/S473) and enhanced mitochondrial ROS production. CONCLUSION: Our findings indicate that Nox2 deficiency results in exaggerated experimental asthma, which is caused by enhanced Th2 effector function in a T-cell-intrinsic manner.

Abnormal perfusion in patellofemoral subchondral bone marrow in the rat anterior cruciate ligament transection model of post-traumatic osteoarthritis: a dynamic contrast-enhanced magnetic resonance imaging study.

OBJECTIVE: Although anterior cruciate ligament (ACL) injury is a well-recognized risk factor for developing knee post-traumatic osteoarthritis (PTOA), the process in the patellofemoral (PF) joint after ACL injury is still under-researched. Our aim was to investigate the perfusion changes in PF subchondral bone marrow in the rat ACL transection (ACLX) model of PTOA using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). DESIGN: Eighteen male Sprague Dawley rats were randomly separated into three groups (n = 6 each group): a normal control group and groups receiving ACLX and sham-surgery, respectively, in the right knee. Perfusion parameters in the patellar and femoral subchondral bone marrows of all rats were measured on DCE-MRI at 0, 4, 8, and 16 weeks after respective treatment. After the last MRI at week 16, the rats were sacrificed and their right knees were harvested for histologic examination. In addition, to observe the long-term histologic change in PF joints, 9 additional rats (n = 3 in each group) were included and sacrificed at week 32 for histologic examination. RESULTS: In the ACLX group vs the sham and control groups, the perfusion parameters were significantly changed in both patellar and femoral subchondral bone marrows at week 16. Histologic examination revealed cartilage defects in ACLX rats at 32 weeks after surgery. CONCLUSIONS: These data point to a possible functional relationship between subchondral bone marrow perfusion abnormalities and cartilage breakdown in PTOA. Moreover, the perfusion parameters derived from DCE-MRI can potentially serve as biomarkers of early OA.

An estimation of the incidence of tuberous sclerosis complex in a nationwide retrospective cohort study (1997-2010).

BACKGROUND: Tuberous sclerosis complex (TSC) is caused by mutations in TSC1 and TSC2, leading to mammalian target of rapamycin hyperactivation. Patients with TSC develop hamartomas in brain, lungs, liver and skin. Two epidemiological studies, performed in Minnesota, U.S.A., have estimated the incidence of TSC to be 0·28-0·56 per 100 000 person-years (PY), based on < 12 patients. Furthermore, whether common comorbidities are associated with this rare disease is not known. OBJECTIVES: To estimate the incidence of TSC and investigate the associations of TSC with other comorbidities, including diabetes, peptic ulcers, stroke and myocardial infarction. METHODS: We estimated the incidence and prevalence of TSC and its comorbidities from 1997 to 2010, based on the Catastrophic Illness Certificate disease database and a beneficiary cohort of 1 million people. RESULTS: The incidence of TSC in Taiwan is 0·153 per 100 000 PY. The number of patients identified with TSC in Taiwan doubled from 206 in 2006 to 471 in 2010. In 2010, the prevalence of TSC in Taiwan was estimated to be 1·58 in 100 000. We confirmed that female patients with TSC are more likely to develop renal tumours than male patients. Surprisingly, patients with TSC have a significantly decreased risk of developing peptic ulcers compared with controls. CONCLUSIONS: This is the first large-scale and longitudinal incidence study of TSC. This study provides compelling evidence that TSC mutations in humans are associated with a decreased risk of peptic ulcers.

Presence of the Merkel cell polyomavirus in Merkel cell carcinoma combined with squamous cell carcinoma in a patient with chronic arsenism.

We present a case of Merkel cell carcinoma (MCC) coincident with squamous cell carcinoma (SCC) on the breast of a woman with chronic arsenism. This case demonstrates the distinct association of chronic arsenism with two different primary cutaneous carcinomas. Merkel cell polyomavirus (MCPyV) was identified in the lesional skin of the MCC but not in that of the SCC, suggesting there are different interactions of MCPyV in the pathogenesis of SCC and MCC related to arsenic. Physicians need to be vigilant in the occurrence of both SCC and MCC in patients with chronic arsenism. To our knowledge, this is the first study to show the presence of MCPyV in the MCC but not the SCC portion of an arsenic-induced tumour.

Polysomnographic findings after adenotonsillectomy for obstructive sleep apnoea in obese and non-obese children: a systematic review and meta-analysis.

BACKGROUND: Use of polysomnography (PSG) is the gold standard of diagnosis and measurement of treatment effectiveness for paediatric obstructive sleep apnoea (OSA). Although adenotonsillectomy (T&A) is effective in diminishing the apnoea-hypopnoea index (AHI), a meta-analysis of postoperative changes for all other PSG parameters and outcome comparisons between obese and non-obese children following T&A have never been conducted. OBJECTIVE OF REVIEW: To comprehensively review polysomnographic findings after surgery for obese and non-obese children with OSA. SEARCH STRATEGY: Study protocol was registered on PROSPERO (CRD42013004737). Two authors independently searched databases including PubMed, MEDLINE, EMBASE and Cochrane Review from January 1997 to July 2014. The keywords used included the following: sleep apnea, OSA, sleep apnea syndromes, tonsillectomy, adenoidectomy, infant, child, adolescent, and Humans. EVALUATION METHOD: A comprehensive systematic review and meta-analysis for literature for OSA children treated by T&A with polysomnography data. Random-effects model was applied to determine postoperative sleep parameter changes and the surgical success rate between obese and non-obese groups. The quality of studies was assessed using the Newcastle-Ottawa Scale. RESULTS: In total, 51 studies with 3413 subjects were enrolled. After surgery, sleep architecture was altered by a significant decrease in sleep stage 1, and an increase in slow-wave sleep and the rapid eye movement stage, and enhanced sleep efficiency. The mean difference between pre- and postoperative was a significant reduction of 12.4 event/h in AHI, along with a reduction of obstructive index, hypopnoea index, central index and arousal index. Mean and minimum oxygen saturation increased significantly after surgery. The overall success rate was 51% for postoperative AHI <1 (obese versus non-obese versus combined, 34% versus 49% versus 56%), and 81% for AHI <5 (obese versus non-obese versus combined, 61% versus 87% versus 84%). Meta-regression analyses demonstrate that postoperative AHI was positively correlated with AHI and body mass index z score before surgery. CONCLUSIONS: Meta-analysis of current literature shows T&A offers prominent improvement in a variety of sleep parameters. Improvements in non-obese children exceeded those for obese children. Postoperative residual OSA remained in roughly half of the children, especially those with severe disease and obesity, making additional treatment strategies and/or long-term follow-up highly desirable.