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Background: Robotic-assisted total knee arthroplasty (rTKA) has been shown to reduce the number of alignment outliers and to improve component positioning compared to manual TKA (mTKA). The primary purpose of this investigation was to compare the frequency of achieving target postoperative limb alignment and component positioning for rTKA vs mTKA. Methods: A retrospective comparative study was performed on 250 patients undergoing primary TKA by 2 fellowship-trained arthroplasty surgeons. Surgeon A performed predominantly rTKA (103 cases) with the ROSA system (Zimmer Biomet, Warsaw, IN) and less frequently mTKA (44 cases) with conventional instrumentation. Surgeon B performed only mTKA (103 cases). Target limb alignment for surgeon A was 0° for all cases and for surgeon B was 2° varus for varus knees and 0° for valgus knees. Radiographic measurements were determined by 2 reviewers. Target zone was set at ± 2 degrees from the predefined target. Results: When comparing rTKA to mTKA performed by different surgeons, there were no differences in the percentage within the target zone (57.28% vs 53.40%, P = .575), but rTKA did result in a greater percentage for cases with preoperative valgus (71.42% vs 44.12%, P = .031). Patient-reported Outcomes Measurement Information System Global-10 physical scores were statistically higher at both 3 (P = .016) and 6 months (P = .001) postoperatively for rTKA compared to mTKA performed by different surgeons. Conclusions: Although experienced surgeons can achieve target limb alignment correction with similar frequency when comparing rTKA to mTKA for all cases, rTKA may achieve target limb alignment with more accuracy for preoperative valgus deformity. Level of Evidence: Retrospective Cohort Study, Level III.

Background: Many institutions require the routine collection of pathology samples from every primary total knee arthroplasty (TKA) performed. These policies are controversial, and their cost-effectiveness is difficult to define. We sought to judge the cost-effectiveness of one such policy according to World Health Organization recommendations. Methods: We analyzed 3200 consecutive primary TKAs, comparing our presumed preoperative diagnoses against the diagnoses made by the pathologist. Diagnoses were categorized as concordant (matching), discrepant (not matching but without impact to patient management), or discordant (not matching and resulting in a direct change to patient management). An incremental cost-utility ratio analysis was performed to determine the cost-effectiveness of our institution’s policy to routinely collect pathology samples from every primary TKA performed. Cost-effectiveness was defined by World Health Organization guidelines as a cost of less than $228,090 per quality-adjusted life year gained. Results: Twelve pathology samples were lost before reaching a pathologist. From the remaining 3188 samples, we identified 3158 concordant cases, 29 discrepant diagnoses, and 1 discordant diagnosis. It cost an estimated $10,522.60 to identify each discrepant diagnosis and an estimated $305,155.36 to diagnose one discordant case in our cohort. Our incremental cost-utility ratio analysis revealed that we spent $305,155.36 to gain 0 quality-adjusted life years for our patients. Conclusions: Routine histopathologic analysis of TKA samples was cost-ineffective in our patient cohort and may not be necessary during routine TKA.

Background: Successful fixation of the greater trochanter (GT) in total hip arthroplasty (THA) is a challenging task. A wide range of clinical results are reported in the literature despite advancements in fixation technology. Previous studies may have lacked adequate sample sizes to detect differences. This study evaluates nonunion and reoperation rates and determines factors influencing successful fixation of the GT using current-generation cable plate devices. Methods: This retrospective cohort study included 76 patients who underwent surgery requiring fixation of their GT and had at least 1-year radiographic follow-up. Indications for a surgery were periprosthetic fracture (n = 25), revision THA requiring an extended trochanteric osteotomy (n = 30), GT fracture (n = 3), GT fracture nonunion (n = 9), and complex primary THA (n = 3). Primary outcomes were radiographic union and reoperation. Secondary objectives were patient and plate factors influencing radiographic union. Results: At a mean radiographic follow-up of 2.5 years, the union rate was 76.3% with a nonunion rate of 23.7%. Twenty-eight patients underwent plate removal, reasons for removal were pain (n = 21), nonunion (n = 5), and hardware failure (n = 2). Seven patients had cable-induced bone loss. Anatomic positioning of the plate (P = .03) and number of cables used (P = .03) were associated with radiographic union. Nonunion was associated with a higher incidence (+30%) of hardware failure due to broken cable(s) (P = .005). Conclusions: Greater trochanteric nonunion remains a problem in THA. Successful fixation using current-generation cable plate devices may be influenced by plate positioning and number of cables used. Plate removal may be required for pain or cable-induced bone loss.

G-Protein Pathway Suppressor 2 (GPS2) is an inhibitor of non-proteolytic K63 ubiquitination mediated by the E2 ubiquitin-conjugating enzyme Ubc13. Previous studies have associated GPS2-mediated restriction of ubiquitination with the regulation of insulin signaling, inflammatory responses and mitochondria-nuclear communication across different tissues and cell types. However, a detailed understanding of the targets of GPS2/Ubc13 activity is lacking. Here, we have dissected the GPS2-regulated K63 ubiquitome in mouse embryonic fibroblasts and human breast cancer cells, unexpectedly finding an enrichment for proteins involved in RNA binding and translation on the outer mitochondrial membrane. Validation of selected targets of GPS2-mediated regulation, including the RNA-binding protein PABPC1 and translation factors RPS1, RACK1 and eIF3M, revealed a mitochondrial-specific strategy for regulating the translation of nuclear-encoded mitochondrial proteins via non-proteolytic ubiquitination. Removal of GPS2-mediated inhibition, either via genetic deletion or stress-induced nuclear translocation, promotes the import-coupled translation of selected mRNAs leading to the increased expression of an adaptive antioxidant program. In light of GPS2 role in nuclear-mitochondria communication, these findings reveal an exquisite regulatory network for modulating mitochondrial gene expression through spatially coordinated transcription and translation., 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 © 2024. Published by Elsevier Ltd.)

Background: Unplanned vascular admissions have a high mortality. Previous studies have indicated that end of life care (EoLC) among this group of patients is low but there exist limited data on EoLC in the United Kingdom. The aim of this study was to evaluate the quality and predictors of EoLC for unplanned vascular admissions to a tertiary center in the United Kingdom., Methods: This was a retrospective single-center cohort study of unplanned vascular surgery admissions from August 1, 2019 to January 22, 2020. Data on patient demographics, markers of quality of palliative care, mortality, and cause of death of unplanned admission to the vascular surgery department were collected from hospital and general practitioner records and evaluated against EoLC to evaluate predictors and efficacy of EoLC. Quality of palliative care markers included documentation of preferred place of death and care priorities, time spent in hospital and the intensive care unit toward the end of life, and realization of documented care objectives. EoLC input was defined as a dedicated palliative care consultation (PCC) by a palliative care professional, medical doctor, surgeon, or advanced care practitioner. We also conducted a subgroup analysis of patients within this group with chronic limb-threatening ischemia (CLTI), diabetic foot, and ruptured aortic aneurysms, as all patients in this group should be offered EoLC according to international guidelines., Results: One-hundred and fifty patients were included. Median age at presentation was 70.5 years, and the cohort consisted of mostly men (72%). CLTI (31%) was the most common reason for admission. Surgical intervention was carried out in 60% of patients. Two-year mortality was 36%, and pneumonia (22%) was the most common cause of death. Seven percent of patients received PCC, which occurred a median of 10 days before death. Only a minority of patients had preferred place of care/death (14%), care priorities (37%), and family involvement during advance care planning (17%) documented in their notes; 29% of patients had Recommended Summary Plan for Emergency Care and Treatment forms in place. A diagnosis of left ventricular systolic dysfunction, chronic kidney disease, and increasing age predicted Recommended Summary Plan for Emergency Care and Treatment form completion. Patients with PCC were more likely to have advance care planning, but this did not translate into improvements in the other markers of quality of palliative and, consequently, EoLC., Conclusions: EoLC was insufficient and of low quality despite a high mortality in this group. Clinical guidelines and pathways are needed to ensure these patients are considered for EoLC and those with CLTI, diabetic foot sepsis or ruptured abdominal aortic aneurysms are offered it by default. Further research is needed to help identify vascular patients who would benefit from EoLC earlier to improve quality at end of life., (Copyright © 2023 Elsevier Inc. All rights reserved.)

A paradigm shift in cancer treatment occurred with the advent of immune checkpoint inhibitors (ICI). ICI therapy has improved tumor response and increased overall survival in patients with solid tumors and hematologic malignancies. While ICI therapy has improved overall patient outcomes in oncology, it has also introduced novel adverse effects called immune-related adverse effects (irAEs). Studies have shown that the development of irAEs is associated with improved overall survival, but certain irAEs like pneumonitis and myocarditis are life threatening, and could result in death if not identified and treated early. Therefore, it is important for radiologists to be aware of complications arising from ICI administration, especially those related to the heart and lungs as they are associated with greater mortality. This paper will review the imaging features of cardiothoracic toxicities, recurrent and chronic irAEs, and atypical tumor responses associated with irAEs., Competing Interests: Declaration of competing interest On behalf of all the authors, I declare that we have no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Robotic-assisted total knee arthroplasty (rTKA) has been shown to reduce the number of alignment outliers and to improve component positioning compared to manual TKA (mTKA). The primary purpose of this investigation was to compare the frequency of achieving target postoperative limb alignment and component positioning for rTKA vs mTKA., Methods: A retrospective comparative study was performed on 250 patients undergoing primary TKA by 2 fellowship-trained arthroplasty surgeons. Surgeon A performed predominantly rTKA (103 cases) with the ROSA system (Zimmer Biomet, Warsaw, IN) and less frequently mTKA (44 cases) with conventional instrumentation. Surgeon B performed only mTKA (103 cases). Target limb alignment for surgeon A was 0° for all cases and for surgeon B was 2° varus for varus knees and 0° for valgus knees. Radiographic measurements were determined by 2 reviewers. Target zone was set at ± 2 degrees from the predefined target., Results: When comparing rTKA to mTKA performed by different surgeons, there were no differences in the percentage within the target zone (57.28% vs 53.40%, P  = .575), but rTKA did result in a greater percentage for cases with preoperative valgus (71.42% vs 44.12%, P  = .031). Patient-reported Outcomes Measurement Information System Global-10 physical scores were statistically higher at both 3 ( P  = .016) and 6 months ( P  = .001) postoperatively for rTKA compared to mTKA performed by different surgeons., Conclusions: Although experienced surgeons can achieve target limb alignment correction with similar frequency when comparing rTKA to mTKA for all cases, rTKA may achieve target limb alignment with more accuracy for preoperative valgus deformity., Level of Evidence: Retrospective Cohort Study, Level III., (© 2023 The Authors.)

Background: Many institutions require the routine collection of pathology samples from every primary total knee arthroplasty (TKA) performed. These policies are controversial, and their cost-effectiveness is difficult to define. We sought to judge the cost-effectiveness of one such policy according to World Health Organization recommendations., Methods: We analyzed 3200 consecutive primary TKAs, comparing our presumed preoperative diagnoses against the diagnoses made by the pathologist. Diagnoses were categorized as concordant (matching), discrepant (not matching but without impact to patient management), or discordant (not matching and resulting in a direct change to patient management). An incremental cost-utility ratio analysis was performed to determine the cost-effectiveness of our institution's policy to routinely collect pathology samples from every primary TKA performed. Cost-effectiveness was defined by World Health Organization guidelines as a cost of less than $228,090 per quality-adjusted life year gained., Results: Twelve pathology samples were lost before reaching a pathologist. From the remaining 3188 samples, we identified 3158 concordant cases, 29 discrepant diagnoses, and 1 discordant diagnosis. It cost an estimated $10,522.60 to identify each discrepant diagnosis and an estimated $305,155.36 to diagnose one discordant case in our cohort. Our incremental cost-utility ratio analysis revealed that we spent $305,155.36 to gain 0 quality-adjusted life years for our patients., Conclusions: Routine histopathologic analysis of TKA samples was cost-ineffective in our patient cohort and may not be necessary during routine TKA., (© 2023 The Authors.)

Background: Multimodal pain management regimens and intraosseous infusion of morphine are two novel techniques that show promise in decreasing postoperative pain and opioid consumption following total knee arthroplasty. However, no study has analyzed the intraosseous infusion of a multimodal pain management regimen in this patient population. The purpose of our investigation was to examine the intraosseous administration of a multimodal pain regimen comprised of morphine and ketorolac during total knee arthroplasty with regard to immediate and 2-week postoperative pain, opioid pain medication intake, and nausea levels., Methods: In this prospective cohort study with comparisons to a historical control group, 24 patients were prospectively enrolled to receive an intraosseous infusion of morphine and ketorolac dosed according to age-based protocols while undergoing total knee arthroplasty. Immediate and 2-week postoperative Visual Analog Score (VAS) pain scores, opioid pain medication intake, and nausea levels were recorded and compared against a historical control group that received an intraosseous infusion of morphine alone., Results: During the first four postoperative hours, patients who received the multimodal intraosseous infusion experienced lower VAS pain scores and required less breakthrough intravenous pain medication than those patients in our historical control group. Following this immediate postoperative period, there were no additional differences between groups in terms of pain levels or opioid consumption, and there were no differences in nausea levels between groups at any time., Conclusions: Our multimodal intraosseous infusion of morphine and ketorolac dosed according to age-based protocols improved immediate postoperative pain levels and reduced opioid consumption in the immediate postoperative period for patients undergoing total knee arthroplasty., 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 Elsevier B.V. All rights reserved.)

Background: Successful fixation of the greater trochanter (GT) in total hip arthroplasty (THA) is a challenging task. A wide range of clinical results are reported in the literature despite advancements in fixation technology. Previous studies may have lacked adequate sample sizes to detect differences. This study evaluates nonunion and reoperation rates and determines factors influencing successful fixation of the GT using current-generation cable plate devices., Methods: This retrospective cohort study included 76 patients who underwent surgery requiring fixation of their GT and had at least 1-year radiographic follow-up. Indications for a surgery were periprosthetic fracture (n = 25), revision THA requiring an extended trochanteric osteotomy (n = 30), GT fracture (n = 3), GT fracture nonunion (n = 9), and complex primary THA (n = 3). Primary outcomes were radiographic union and reoperation. Secondary objectives were patient and plate factors influencing radiographic union., Results: At a mean radiographic follow-up of 2.5 years, the union rate was 76.3% with a nonunion rate of 23.7%. Twenty-eight patients underwent plate removal, reasons for removal were pain (n = 21), nonunion (n = 5), and hardware failure (n = 2). Seven patients had cable-induced bone loss. Anatomic positioning of the plate ( P  = .03) and number of cables used ( P  = .03) were associated with radiographic union. Nonunion was associated with a higher incidence (+30%) of hardware failure due to broken cable(s) ( P  = .005)., Conclusions: Greater trochanteric nonunion remains a problem in THA. Successful fixation using current-generation cable plate devices may be influenced by plate positioning and number of cables used. Plate removal may be required for pain or cable-induced bone loss., (© 2023 Published by Elsevier Inc. on behalf of The American Association of Hip and Knee Surgeons.)

The reported prevalence of stroke amongst patients presenting to hospital with acute vertigo and/or imbalance is c. 5%, leading to the pervasive notion amongst emergency and stroke physicians, that stroke is uncommon in this cohort. To interrogate the veracity of this notion, we systematically and retrospectively screened the electronic care records in our institution of patients referred as suspected stroke, to a hyperacute stroke service at a large tertiary referral centre. We screened 24,310 consecutive patients' electronic case records presenting to our hospital as an emergency over a 4-month period, 332 of whom were referred as suspected stroke whose case records were assessed via structured review. Of these 332 cases, 61 presented with a vestibular syndrome, i.e. having at least one of imbalance, dizziness or vertigo. Of the 61 vestibular cases, 38 (62%) were diagnosed as stroke confirmed by imaging in 25/38 or upon clinical grounds only (13/38). None of the 38 vestibular stroke cases received thrombolysis or thrombectomy treatment. In a UK urban population (2.5mn), acute vestibular syndrome cases referred to stroke services have a 50% stroke prevalence. None of the vestibular stroke cases received hyperacute stroke treatment e.g., thrombolysis, due to delay in diagnosis. The high stroke prevalence in our cohort may indicate an excessively high threshold for referring acute vestibular cases for stroke, implying a high number of missed stroke cases. We suggest that early access to vestibular neurologists in acute vestibular cases should improve the proportion of vestibular stroke cases receiving definitive stroke treatment., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Acetabular dysplasia represents a structural pathomorphology associated with hip pain, instability, and osteoarthritis. The wide spectrum of dysplasia anatomically refers to a 3-dimensional volumetric- and surface area-based insufficiency in coverage and is classified based on the magnitude and location of undercoverage. Borderline dysplasia has been variably defined and leads to management challenges. In symptomatic dysplasia, treatment addresses coverage with periacetabular osteotomy. Concomitant simultaneous or staged hip arthroscopy has significant advantages to address intra-articular pathology. In nonarthritic individuals, there is evidence PAO alters the natural history of dysplasia and decreases the risk of hip arthritis and total hip arthroplasty., Competing Interests: Disclosure J.D. Harris: AAOS: Board or committee member; American Orthopaedic Society for Sports Medicine: Board or committee member; Arthroscopy: Editorial or governing board; Arthroscopy Association of North America: Board or committee member; International Society of Arthroscopy and Knee Orthopedic Surgery (ISAKOS): Board or committee member; PatientPop: Stock or stock options; Arthrex/Medinc of Texas: Research support; DePuy, A Johnson & Johnson Company: Research support; Frontiers In Surgery: Editorial or governing board; NIA Magellan: Paid consultant; SLACK Incorporated: Publishing royalties, financial or material support; Smith and Nephew: Paid presenter or speaker, Paid consultant, Research support; Ossur: Paid speaker. B.D. Lewis: Stryker, Paid consultant; Zimmer, Paid consultant. K.J. Park: Journal of Bone and Joint Surgery, British: Editorial/governing board., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Intimate partner violence (IPV) is a global health issue that impacts both civilian and military populations. Factors associated with military service may result in increased risk of IPV perpetration among Veterans and Active Duty military personnel. Six bibliographic databases were searched to identify studies that estimated the prevalence of IPV perpetration among military populations by sociodemographic and military characteristics. Where possible, random effect meta-analyses were conducted to determine pooled prevalence estimates. 42 studies were eligible for inclusion in this systematic review. 28 of these studies met the requirements for inclusion in subsequent meta-analyses. Among studies that measured past-year physical IPV perpetration, the pooled prevalence was higher among men compared to women (26% and 20% respectively). Among Veterans, there were consistently higher prevalences compared to Active Duty samples. Similarly, higher prevalences were found among studies in general military settings compared to clinical settings. Further research that considers the impact of the act(s) of IPV perpetration on the victims is needed. This, along with the use of a consistent measurement tools across studies will help to develop a stronger evidence base to inform prevention and management programs for all types of IPV perpetration among military personnel., (© 2020 The Authors.)

Clear and precise writing is a vital skill for healthcare providers and those involved in global emergency care research. It allows one to publish in scientific literature and present oral and written summaries of their work. However, writing skills for publishing are rarely part of the curriculum in the healthcare education system. This review gives you a step-by-step guide on how to successfully write for scientific publication following the IMRaD principle (Introduction, Methods, Results, and Discussion) with every part supporting the key message. There are specific benefits of writing for publication that justify the extra work involved. Any lessons learned about improving global emergency care delivery can be useful to emergency clinicians. The end result can lead to changing others' practice and pave the way for further research., Competing Interests: The authors declared no conflicts of interest., (© 2020 African Federation for Emergency Medicine. Publishing services provided by Elsevier.)

Nail-patella syndrome (NPS) or hereditary onycho-osteodyaplasia is a rare genetic condition involving a mutation in the LMX1B gene affecting nails, elbows, knees, and pelvis. Due to the regulatory functions of the gene in many developmental processes through the body, patients with NPS experience wide-ranging musculoskeletal problems including patellar instability, fingernail anomalies, iliac exostoses/horns, and elbow abnormalities. The patellar changes often involve aplasia, hypoplasia, and chronic dislocation. Due to these musculoskeletal involvement, arthritis of joints can occur in patients with NPS causing severe pain and disability. This is a case report of a patient with NPS who underwent a total knee arthroplasty for symptomatic knee arthritis., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) is the most common neurodegenerative disorders in the elderly. To identify rare genetic factors other than apolipoprotein E ɛ4 allele (ApoE ɛ4) contributing to the pathogenesis of late-onset AD (LOAD), we conducted a whole-exome analysis of 246 ApoE ɛ4-negative LOAD cases and 172 matched controls in Hong Kong Chinese population. LOAD patients showed a significantly higher burden of rare loss-of-function variants in genes related to immune function than healthy controls. Among the genes involved in immune function, we identified a rare stop-gain variant (p.Q48X) in mixed lineage kinase domain like pseudokinase (MLKL) gene present exclusively in 6 LOAD cases. MLKL is expressed in neurons, and the its expression levels in the p.Q48X carriers were significantly lower than that in age-matched wild-type controls. The ratio of Aβ42 to Aβ40 significantly increased in MLKL knockdown cells compared to scramble controls. MLKL loss-of-function mutation might contribute to late-onset ApoE ɛ4-negative AD in the Hong Kong Chinese population., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: The study aimed to examine the epidemiology of hypertonic contractures and its relationship with minimal trauma fracture (MTF), and to determine the incidence and predictors of (MTF) in long-term care residents., Design: This was a longitudinal cohort study of prospectively collected data. Participants were followed from March 2007 to March 2016 or until death., Setting: A 300-bed long-term care hospital in Hong Kong., Participants: All long-term care residents who were in need of continuous medical and nursing care for their activities of daily living., Measurements: Information on patients' demographic data, severe contracture defined as a decrease of 50% or more of the normal passive range of joint movement of the joint, and severe limb spasticity defined by the Modified Ashworth Scale higher than grade 3, medical comorbidities, functional status, cognitive status, nutritional status including body mass index and serum albumin, past history of fractures, were evaluated as potential risk factors for subsequent MTF., Results: Three hundred ninety-six residents [148 males, mean ± standard deviation (SD), age = 79 ± 16 years] were included for analysis. The presence of severe contracture was highly prevalent among the study population: 91% of residents had at least 1 severe contracture, and 41% of residents had severe contractures involving all 4 limbs. Moreover, there were a significant proportion of residents who had severe limb spasticity with the elbow flexors (32.4%) and knee flexors (33.9%) being the most commonly involved muscles. Twelve residents (3%) suffered from subsequent MTF over a median follow-up of 33 (SD = 30) months. Seven out of these 12 residents died during the follow-up period, with a mean survival of 17.8 months (SD = 12.6) after the fracture event. The following 2 factors were found to independently predict subsequent MTF in a multivariate Cox regression: bilateral severe spastic knee contractures (hazard ratio = 16.5, P < .0001, confidence interval 4.8-56.4) and diabetes mellitus (hazard ratio = 4.0. P = .018, confidence interval 1.3-12.7)., Conclusions: Severe spasticity and contractures are common morbidities in long-term care residents, and bilateral severe spastic knee contractures and diabetes mellitus are 2 independent predictors of subsequent MTF. Spasticity management and prevention of contractures, combined with educational programs for caregivers to identify the high-risk residents and apply proper handling techniques during routine care, may be helpful in reducing the risk of MTF in long-term care residents. Further large-scale longitudinal studies are needed to confirm these findings., (Copyright © 2016 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Background/objectives: The effect of aspirin and clopidogrel in a fixed-dose combination (FDC) on platelet function was compared with separate formulations in patients that had undergone percutaneous coronary intervention (PCI) with drug-eluting stent (DES)., Methods: This was a phase IV, prospective, multicenter, single-arm, non-inferiority study. Patients that had taken aspirin 100 mg and clopidogrel 75 mg once daily as separate formulations for >6 months after PCI with DES were enrolled, and then switched to an aspirin/clopidogrel FDC once-daily for 4 weeks. Platelet reactivity was determined using the VerifyNow® P2Y12 assay at baseline (immediately prior to switching) and 4 weeks later., Results: A total of 648 patients (the full-analysis population; age, 63.6±9.0 years; male, 76.5%) finished the study, and 565 (the per-protocol population) completed without protocol violations. In the per-protocol population, the % inhibitions of P2Y12 and ARU were not significantly different between baseline and after 4 weeks of FDC treatment (29.2±20.0% to 29.0±19.9%, P=0.708; 445.1±69.2 to 446.2±63.0, P=0.799, respectively) and the difference in P2Y12 inhibition observed did not exceed the predetermined limit of non-inferiority (95% CI, -0.9 to 1.3). In the full-analysis population, the % inhibitions of P2Y12, PRU, and ARU were not significantly changed after 4 weeks of FDC treatment., Conclusions: This study demonstrates that the efficacy of platelet inhibition by an aspirin/clopidogrel FDC was not inferior to that of separate aspirin and clopidogrel formulations in patients that had undergone PCI with DES., (Copyright © 2015. Published by Elsevier Ireland Ltd.)

Amyloid beta (Aβ), especially Aβ oligomers, is important in Alzheimer's disease (AD) pathogenesis. We studied plasma Aβ(40), Aβ(42), and Aβ oligomers levels in 44 AD patients and 22 non-demented controls. Cognitive functions were assessed by Chinese version of mini-mental state examination (MMSE), Abbreviated Metal Test (AMT), Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-cog). Plasma Aβ monomers and oligomers levels were measured by ELISA. We found that the median plasma Aβ(40) and Aβ(42) levels were similar between AD and controls, and without significant correlation with cognition. Plasma Aβ oligomers level was higher in AD than controls (642.54 ng/ml [range 103.33-2676.93] versus 444.18 ng/ml [range 150.19-1311.18], p=0.047), and negatively correlated with cognition. In multivariate logistic regression analysis, the highest tertile of Aβ oligomers levels showed an increased risk of AD than the combined group of middle and lowest tertiles (OR=8.85, p=0.013), after adjustment of gender, age and APOE4 genotype. Increased plasma Aβ oligomers level was associated with decreased MMSE and AMT scores (p=0.037, p=0.043, respectively) and increased ADAS-cog score (p=0.036), suggesting negative correlation with cognitive function. We concluded that plasma Aβ oligomers level is an useful biomarker for AD diagnosis., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Clinical outcome of Chinese relapsing remitting multiple sclerosis (RRMS) patients is uncertain., Aim: To study the long-term clinical outcome of Chinese RRMS patients., Method: RRMS patients with duration of 10 years or longer followed up in our hospital is retrospectively studied., Results: 61 RRMS patients (75% female) were studied. Their mean symptom onset age was 25.9 years and mean duration was 20.6 years (range 10-33); 36% patients had received β-interferon and 30% azathioprine. Their mean EDSS scores were 3.3 (range 1-7) and 4.7 (range 1-8) at 10 years and latest follow-up (mean duration 20.6 years) respectively. At 10 years, 30% patients had EDSS score ≤2, 34% EDSS 2.5-3.5, 20% EDSS 4.0-5.5 and 16% ≥6; 18% developed SPMS. At latest follow-up, 15% patients had EDSS ≤2, 20% EDSS 2.5-3.5, 19% EDSS 4.0-5.5 and 46% ≥6.0; 53% developed SPMS. The median time from symptom onset to EDSS 6 was 22 years. No differences were detected in demographic characteristics, presenting neurological features, number of attacks in first 2 years, neuroradiological findings and disease modifying therapies between patients with EDSS <6 and ≥6 at ten years. EDSS scores at 10 years and latest follow-up were similar for patients who had received β-interferon and those who had not., Conclusion: Hong Kong Chinese RRMS patients may have worse long-term clinical outcome than Caucasian patients., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objective: To examine the consumption patterns of energy-dense, nutrient-poor 'extra' foods among Australian children and to determine any changes in consumption since the 1995 National Nutrition Survey (1995 NNS)., Methods: 'Extra' food consumption was analysed by age group and gender using 24-h recall data from the 2007 Australian National Children's Nutrition and Physical Activity Survey (2007 Survey; n = 4380) and the 1995 NNS (n = 2435). Differences in percent consuming, amounts consumed and percent energy contribution were assessed., Results: 'Extra' foods contributed 35% to daily energy intake in the 2007 survey, ranging from 24% in the 2-3 year olds to 38% in the 9-13 and 14-16 year olds. The foods contributing most to energy intake included 'fried potatoes' (2.9%), 'cakes, muffins, slices' (2.9%) and 'potato crisps and similar snacks' (2.6%). Compared to the 1995 NNS, total energy intake was significantly lower in the 2007 Survey (8621 kJ in 1995 versus 8330 kJ in 2007), as was the consumption of 'extra' foods (both in terms of weight and energy) (3645 kJ in 1995 versus 3049 kJ in 2007). All age groups reported a decline in energy intake from 'extra' foods of approximately 600 kJ., Conclusion: The overall consumption of 'extra' foods seems to have decreased from 1995 to 2007. However, 'extra' foods continue to be over-consumed by Australian children and continuous monitoring of 'extra' foods consumption is highly warranted., (© 2011 Published by Elsevier Ltd on behalf of Asia Oceania Assoc. for the Study of Obesity.)

Novel biochemical strategies are needed to identify the next generation of protein kinase inhibitors. One promising new assay format is a competition binding approach that employs time-resolved fluorescence resonance energy transfer (TR-FRET). In this assay, a FRET donor is bound to the kinase via a purification tag, whereas a FRET acceptor is bound via a tracer-labeled inhibitor. Displacement of the tracer by an unlabeled inhibitor eliminates FRET between the fluorophores and provides a readout on binding. Although promising, this technique has so far been limited in applicability in part by a lack of signal strength is some cases and also by an inability to predict whether a particular tagging strategy will show robust FRET. In this work, we sought to better understand the factors that give rise to a strong FRET signal in this assay. We determined the magnitude of FRET for several tyrosine kinases using different purification tags (biotin, glutathione S-transferase [GST], and His) placed at either the N terminus or C terminus of the kinase. It was observed that coupling the FRET acceptor to the kinase C terminus using a biotin/streptavidin interaction resulted in the greatest increase in FRET. Specifically, for multiple kinases, the signal/background ratio was at least 3-fold better using C-terminal biotinylation compared with tagging at the N terminus using a His/anti-His antibody or GST/anti-GST antibody interaction. In one case, the FRET signal using C-terminal biotin tagging was more than 150-fold over background. This strong FRET signal facilitated development of improved inhibitor binding assays that required only tens of picomolar enzyme or tracer-labeled inhibitor. Together, these results indicate that C-terminal biotinylation is a promising tagging strategy for developing an optimal FRET-based competition binding assay for tyrosine kinases.

A clear understanding of how diet alters gastrointestinal communities is important given the suggested link between gut community composition and a wide variety of disease pathologies. To characterize this link for commonly consumed dietary fiber sources, we investigated the change in the fecal community of rats fed diets containing 5% nonnutritive fiber (control), 3% (wt:wt) oat bran plus 2% nonnutritive fiber (OB), or 5% (w/w) wheat bran (WB) over a 28-d feeding trial using both molecular- and cultivation-based methodologies. Pooled fecal samples from 8 rats fed the same diet were analyzed at 4 time points. On d 28, bran-fed rats had approximately twice the total cultivable bacteria than rats fed the control diet. Over the course of feeding, the cultivable community was initially dominated by bacteroides, then by bifidobacteria, lactobacilli, enterococci, and various enterics. In contrast, molecular analysis revealed the appearance of new operational taxonomic units (phylotypes) that were both temporally and inequitably distributed throughout the fecal community. The majority of change occurred in 2 major lineages within the Firmicutes: the Clostridium coccoides group and the Clostridium leptum subgroup. The time course of change depended on the source of bran, with the majority of new phylotypes appearing by d 14 (OB) or d 28 (WB), although adaptation of the fecal community was slow and continued over the entire feeding trial. Bacterial community richness was higher in bran-fed rats than in those fed the control diet. Change within the C. coccoides and C. leptum lineages likely reflect their high abundance within the gut bacterial community and the role of clostridia in fiber digestion. The results illustrate the limitations of relying solely on cultivation to assess bacterial changes and illustrate that community changes are complex in an ecosystem containing high numbers of interdependent and competing species of bacteria.

Neurotensin (NT) is a neuropeptide implicated in the pathophysiology of schizophrenia and in mediating the efficacy of antipsychotic drugs. NT is also involved in the regulation of body temperature and pain sensitivity. Using neurotensin receptor 1 (NTR1) knockout (KO) and wild-type (WT) mice, these studies evaluated the involvement of NTR1 in the behavioral responses produced by peripheral administration of NT agonists (NT-2 and NT69L). Animals were characterized in paradigms designed to assess hypothermia, antinociception, and antipsychotic-like effects. Under basal conditions, there were no phenotypic differences between NTR1 KO and WT mice. In WT mice, both NTR1 agonists decreased core body temperature (active doses in mg/kg, i.p., for NT-2 and NT69L, respectively: 1 and 3), increased tail withdrawal latencies (1 and 3), produced decreased spontaneous climbing (0.1, 0.3, 1 and 1, 3, 10) and reversed apomorphine-induced climbing (0.3, 1 and 1, 3). In contrast, none of the effects of either agonist were present in KO mice. These results suggest that NTR1: (1) does not play a major role in the control of basal thermoregulation, nociception or psychomotor stimulation in mice (barring possible developmental plasticity), (2) does mediate these behavioral responses to NT agonists, and (3) may play a role in the potential antipsychotic effects of these agonists.

Development of an outpatient finger-prick glomerular filtration rate (GFR) procedure suitable for epidemiological studies. In clinical practice, reference GFR procedures are rarely used; in large-scale research studies, a great deal of effort and experience is required to obtain them, which is a considerable disincentive to using GFR as an end point. The major problem for both clinical staff and the subject is the length of time that the procedure takes, requiring continuous attendance in the outpatient clinic or its vicinity. Using iohexol as a marker, we therefore propose an alternative approach, which addresses this fundamental deterrent to a more widespread use of GFR measurement. Eighty-two GFR measurements were performed in a mixture of healthy subjects and patients with differing degrees of renal impairment with a wide range of GFRs. Serum was obtained from blood samples to enable a reference GFR to be calculated. Blood spots were collected on filter paper at the same intervals (120, 180, and 240 min), allowed to dry, and then sent through the post. Serum and blood spots were analyzed simultaneously for each individual by automated reverse-phase high-pressure liquid chromatography. Standard linear regression analyses confirmed a good agreement (r2 = 0.953) between the iohexol serum GFR and iohexol blood spots GFR. Bland-Altman analysis confirmed that there was no concentration bias. Paired comparisons (Wilcoxon's paired signed rank test) showed no significant difference between the two measurements. Capillary sampling is simple, effective, and significantly reduces the time and costs of performing plasma clearance GFR measurements. This approach will make the GFR measurement more accessible for clinical practice and large-scale epidemiological studies may become feasible.

Background: We postulated that in mesangial cells exposed to high glucose, protein kinase C-zeta (PKC-zeta) is necessary for the generation of reactive oxygen species (ROS) by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and that the requirement of PKC-zeta for filamentous (F)-actin disassembly may involve ROS. To identify signaling mechanisms relevant to PKC-zeta activation and ROS generation, including phosphoinositide 3 kinase (PI3 kinase), we examined mesangial cell stimulation with platelet-derived growth factor (PDGF)., Methods: In primary rat mesangial cells cultured in 5.6 mmol/L or 30 mmol/L d-glucose, PKC-zeta expression was identified with immunoblotting and activity was analyzed in cell membrane immunoprecipitates and by confocal immunofluorescence imaging. ROS generation was measured by dichlorofluorescein fluorescence using confocal microscopy and was inhibited by transfection of antisense against NADPH subunits p22(phox) or p47(phox) or with Tempol. F-actin disassembly was observed by dual-channel confocal fluorescence imaging. PI3 kinase activity was detected by immunoblotting of phosphorylated Akt., Results: In high glucose, generation of NADPH oxidase-dependent ROS was dependent on PKC-zeta. Conversely, sustained PKC-zeta activity was dependent on ROS generation, suggesting a positive feedback. PKC-zeta-dependent F-actin disassembly in high glucose required ROS generation. PDGF stimulated NADPH oxidase generation of ROS through a PKC-zeta mechanism that was independent of Akt phosphorylation and remained unchanged in high glucose., Conclusion: In high glucose, mesangial cell PKC-zeta is required for ROS generation from NADPH oxidase similar to PDGF stimulation of PKC-zeta-dependent ROS generation through a pathway independent of PI3 kinase. F-actin disassembly in high glucose also requires ROS. A positive feedback loop occurs between ROS and the activation of PKC-zeta in high glucose.

Exophiala (Wangiella) dermatitidis is a dermatiaceous mold that is an occasional cause of infection in the immunocompromised. We report a case of continuous ambulatory peritoneal dialysis-associated peritonitis probably due to environmental contamination with this organism. Prompt catheter removal and aggressive treatment with amphotericin B allowed an eventual return to peritoneal dialysis.

We describe a case of a large sinus of Valsalva aneurysm originating from the noncoronary sinus. The aneurysm compressed the roof of the left atrium rendering the annulus and the anterior leaflet of the mitral valve severely distorted and, as a result, incompetent. The neck of the aneurysm was closed with a patch from the side of the aortic sinus, but we had to replace the mitral valve as the distorted structure did not resume its original shape even though we opened the aneurysm and debrided all thrombotic material inside the aneurysm.

Over the past 2 years, we have examined all patients with a functioning renal allograft attending a regional nephrology unit. A total of 291 patients were examined. 172 (59%) were found to have cutaneous warts, and 64 (21.9%) had non-melanoma skin cancer (NMSC). The proportion of patients with both warts and NMSC increased with time from transplantation: 40% of patients who had been transplanted for more than 9 years had NMSC. Fifteen patients had extensive dysplastic change in all sun-exposed areas, particularly the dorsal aspect of the hands. This subgroup of patients develop large numbers of tumours, particularly squamous cell carcinomas (SCC), and require close surveillance and frequent surgery. One patient has died as a result of rapidly evolving metastases from an SCC on the dorsum of the hand. Excision and grafting of the backs of the hands in four patients, and long term etretinate therapy in 6 patients have led to a marked reduction in the frequency of surgery to remove tumours. The very high rate of NMSC, frequently multiple, found in this study of UK residents is a source of concern and indicates the need for close dermatological monitoring of allograft recipients, with intensive surveillance of patients with extensive dysplasia, who may develop tumours requiring surgery every few weeks.

It could be advantageous for the parathyroids to be able to sense not only the absolute concentration of extracellular Ca2+, but also the rate and direction of change of Ca2+, thereby allowing the parathyroids to respond earlier to threats to Ca2+ homeostasis. By using high and low Ca2+ dialysis in a single session, we examined the parathyroid response to direction of change of Ca2+ during acute Ca2+ perturbation in nine hemodialysis patients. Separate PTH/ionized calcium (PTH/iCa) response curves were generated for rising Ca2+ and falling Ca2+. Significant directional hysteresis (higher PTH level during falling than during rising Ca2+) was found. During hypercalcemia, PTH levels were between 2.2 and 1.6 times higher at iCa concentrations of between 0 and +0.1 mM above the baseline iCa, when Ca2+ was falling than when it was rising. During the phase of induced hypocalcemia, parathyroid fatigue was seen in six of the nine patients. Fatigue patients tended to have higher basal PTH (1-84) levels than those not showing fatigue. The existence of fatigue provides an explanation for directional hysteresis during hypocalcemia, and therefore parathyroid sensing of the direction of change of Ca2+ could not be assessed during hypocalcemia. These studies demonstrate a capacity of the parathyroids to sense the direction of movement of Ca2+ during hypercalcemia.