A triple cysteine motif as major determinant of the modulation of neuronal KV7 channels by the paracetamol metabolite N-acetyl-p-benzo quinone imine.

BACKGROUND AND PURPOSE: The analgesic action of paracetamol involves KV7 channels, and its metabolite N-acetyl-p-benzo quinone imine (NAPQI), a cysteine modifying reagent, was shown to increase currents through such channels in nociceptors. Modification of cysteine residues by N-ethylmaleimide, H2O2, or nitric oxide has been found to modulate currents through KV7 channels. The study aims to identify whether, and if so which, cysteine residues in neuronal KV7 channels might be responsible for the effects of NAPQI. EXPERIMENTAL APPROACH: To address this question, we used a combination of perforated patch-clamp recordings, site-directed mutagenesis, and mass spectrometry applied to recombinant KV7.1 to KV7.5 channels. KEY RESULTS: Currents through the cardiac subtype KV7.1 were reduced by NAPQI. Currents through all other subtypes were increased, either by an isolated shift of the channel voltage dependence to more negative values (KV7.3) or by such a shift combined with increased maximal current levels (KV7.2, KV7.4, KV7.5). A stretch of three cysteine residues in the S2-S3 linker region of KV7.2 was necessary and sufficient to mediate these effects. CONCLUSION AND IMPLICATION: The paracetamol metabolite N-acetyl-p-benzo quinone imine (NAPQI) modifies cysteine residues of KV7 subunits and reinforces channel gating in homomeric and heteromeric KV7.2 to KV7.5, but not in KV7.1 channels. In KV7.2, a triple cysteine motif located within the S2-S3 linker region mediates this reinforcement that can be expected to reduce the excitability of nociceptors and to mediate antinociceptive actions of paracetamol.

The Nevus Lipomatosus Superficialis of Face: A Case Report and Literature Review.

Nevus lipomatosus superficialis (NLS) is a hamartoma of adipose tissue, rarely reported in the past 100 years. We treated one case, and we conducted a systematic review of the literature. A 41-year-old man presented with a cutaneous multinodular lesion in the posterior region near the right auricle. The lesion was excised and examined histopathologically. To review the literature, we searched PubMed with the keyword "NLS." The search was limited to articles written in English and whose full text was available. We analyzed the following data: year of report, nation of corresponding author, sex of patient, age at onset, duration of disease, location of lesion, type of lesion, associated symptoms, pathological findings, and treatment. Of 158 relevant articles in PubMed, 112 fulfilled our inclusion criteria; these referred to a total of 149 cases (cases with insufficient clinical information were excluded). In rare cases, the diagnosis of NLS was confirmed when the lesion coexisted with sebaceous trichofolliculoma and Demodex infestation. Clinical awareness for NLS has increased recently. NLS is an indolent and asymptomatic benign neoplasm that may exhibit malignant behavior in terms of huge lesion size and specific anatomical location. Early detection and curative treatment should be promoted.

The effect of training to target cognitive biases towards social rejection in eating disorders.

OBJECTIVE: This study examined the effect of cognitive bias modification for interpretation (CBM-I) training in Korean women with eating disorders (EDs). METHOD: Sixty-three women with EDs participated in the study. Participants were randomly assigned to the intervention group where they received six sessions of CBM-I training (n = 31) in addition to treatment-as-usual or were put on a waiting list (n = 32). Participants' interpretation and attention biases, emotion regulation, affect, and ED psychopathology were assessed at baseline, end-of-intervention (4 weeks), and follow-up (8 weeks). RESULTS: Participants who completed the CBM-I training displayed greater reductions in negative interpretation bias (Δη2 = 0.107) and emotion dysregulation (Δη2  = 0.085) with medium to large effect sizes compared to the control group, which were maintained from baseline to follow-up. Disengagement from negative faces and a focus on positive faces was found in the intervention group with a moderate effect size at the end-of-intervention (Δη2  = 0.090). Both intervention and control groups showed improvements in ED psychopathology. Baseline neuroticism was positively correlated with CBM-I effect. DISCUSSION: The results suggest that modifying interpretation bias towards ambiguous social stimuli might be an effective adjuvant treatment to reduce negative expectations of social situations and improve emotion regulation in women with bulimia nervosa and anorexia nervosa.

The mediating role of the left ventricular mass index on the relationship between the fluid balance and left ventricular diastolic function in patients with chronic kidney disease.

BACKGROUND: The pathophysiological mechanism of cardiovascular disease in patients with chronic kidney disease (CKD) is complicated. Mediation analysis is an important statistical tool for gaining insight into the complex mechanisms of exposure-outcome effects. We investigated the potential mediating role of the left ventricular mass index (LVMI) on the association between fluid balance (overhydration/extracellular water, OH/ECW) and left ventricular diastolic function (E/e´ ratio) in patients with CKD not yet on dialysis. METHODS: Bioimpedance spectroscopy, echocardiography, and laboratory evaluations were performed on 425 consecutive patients on the same day. The patients were classified into two groups according to the estimated glomerular filtration rate corresponding to CKD stages 3 and 5. Mediation analysis was performed using the PROCESS macro and bootstrapping methods. RESULTS: OH/ECW and LVMI were positively correlated with the E/e´ ratio in both the CKD stages 3 and five groups. In CKD stage 5, there was a statistically significant association between OH/ECW and LVMI, whereas no correlation was observed in CKD stage 3. In the mediation analysis, LVMI positively mediated the relationship between OH/ECW and E/e´ ratio when controlling for confounders in patients with CKD stage 5 (B = 2.602; Boot 95% confidence interval, 1.313-4.076). CONCLUSION: In our analysis, the indirect effect of mediators was significant in patients with advanced CKD. Therefore, our study suggests that further research on several other risk factors may be needed to determine the underlying mechanisms of association between the associated factors in all CKD stages.

Chat Generative Pretrained Transformer (ChatGPT) and Bard: Artificial Intelligence Does not yet Provide Clinically Supported Answers for Hip and Knee Osteoarthritis.

BACKGROUND: Advancements in artificial intelligence (AI) have led to the creation of large language models (LLMs), such as Chat Generative Pretrained Transformer (ChatGPT) and Bard, that analyze online resources to synthesize responses to user queries. Despite their popularity, the accuracy of LLM responses to medical questions remains unknown. This study aimed to compare the responses of ChatGPT and Bard regarding treatments for hip and knee osteoarthritis with the American Academy of Orthopaedic Surgeons (AAOS) Evidence-Based Clinical Practice Guidelines (CPGs) recommendations. METHODS: Both ChatGPT (Open AI) and Bard (Google) were queried regarding 20 treatments (10 for hip and 10 for knee osteoarthritis) from the AAOS CPGs. Responses were classified by 2 reviewers as being in "Concordance," "Discordance," or "No Concordance" with AAOS CPGs. A Cohen's Kappa coefficient was used to assess inter-rater reliability, and Chi-squared analyses were used to compare responses between LLMs. RESULTS: Overall, ChatGPT and Bard provided responses that were concordant with the AAOS CPGs for 16 (80%) and 12 (60%) treatments, respectively. Notably, ChatGPT and Bard encouraged the use of non-recommended treatments in 30% and 60% of queries, respectively. There were no differences in performance when evaluating by joint or by recommended versus non-recommended treatments. Studies were referenced in 6 (30%) of the Bard responses and none (0%) of the ChatGPT responses. Of the 6 Bard responses, studies could only be identified for 1 (16.7%). Of the remaining, 2 (33.3%) responses cited studies in journals that did not exist, 2 (33.3%) cited studies that could not be found with the information given, and 1 (16.7%) provided links to unrelated studies. CONCLUSIONS: Both ChatGPT and Bard do not consistently provide responses that align with the AAOS CPGs. Consequently, physicians and patients should temper expectations on the guidance AI platforms can currently provide.

Characteristics of Very Young Patients Undergoing Total Hip Arthroplasty: A Contemporary Assessment.

Background: This study aims to compare indications, patient characteristics, hospital factors, and complication rates between total hip arthroplasty (THA) patients aged 30 years or younger and those older than 30 years using a large national database. Methods: The Premier Healthcare Database was utilized to identify primary THA patients from 2015 to 2021 who were aged ≤30 or >30 years. Patient demographics, hospital factors, and primary indications were compared for each cohort. Rates of complications and readmissions were assessed for each cohort by primary indication. Differences were assessed through univariate analysis. Results: Overall, 539,173 primary THA patients were identified (age ≤30: 1849; >30: 537,234). Compared to the >30 cohort, the ≤30 cohort was more likely to be male (56.5% vs 44.9%, P < .001) and non-White (34.0% vs 14.2%, P < .001). The most common indications for THA in the ≤30 cohort were osteonecrosis (49.3%), osteoarthritis (17.8%), and congenital hip deformities (16.0%), and in the >30 cohort, they were osteoarthritis (77.0%), other arthritis (11.3%), and osteonecrosis (5.4%). Patients aged ≤30 years had lower rates of respiratory failure (0.16% vs 0.57%, P < .001), acute renal failure (0.32% vs 1.72%, P < .001), and urinary tract infection (0.38% vs 1.11%, P = .003) than those aged >30 years, but higher rates of wound dehiscence (0.59% vs 0.29%, P = .015) and transfusion (3.68% vs 2.21%, P < .001). There were no differences in 90-day readmission rates (P = .811) or 90-day in-hospital death (P = .173) between cohorts. Conclusions: Younger patients undergoing THA differed significantly in indication, patient characteristics, and hospital factors compared to the older population on univariate analysis. Despite differences in indications, the cohorts did not differ markedly with regard to complication rates in this study.

Extended Prophylactic Antibiotics for Primary and Aseptic Revision Total Joint Arthroplasty: A Meta-Analysis.

BACKGROUND: There is growing interest in extended antibiotic prophylaxis (EAP) following total joint arthroplasty (TJA); however, the benefit of EAP remains controversial. For this investigation, both oral and intravenous antibiotic protocols were included in the EAP group. METHODS: The Cochrane Database of Systematic Reviews, Cochrane Register of Controlled Trials, PubMed, MEDLINE, Web of Science, Ovid Embase, Elton B. Stephens CO, and Cumulative Index to Nursing and Allied Health Literature were queried for literature comparing outcomes of primary and aseptic revision total hip arthroplasty (THA) and total knee arthroplasty (TKA) patients who were treated with either ≤24 hours of postoperative antibiotic prophylaxis (standard of care [SoC]) or >24 hours of EAP. The primary outcome was periprosthetic joint infection (PJI). A pooled relative-risk random-effects Mantel-Haenszel model was implemented to compare cohorts. RESULTS: There were 18 studies with a total of 19,153 patients included. There was considerable variation in antibiotic prophylaxis protocols with first-generation cephalosporins being the most commonly implemented antibiotic for both groups. Patients treated with EAP were 35% less likely to develop PJI relative to the SoC (P = .0004). When examining primary TJA, patients treated with EAP were 39% and 40% less likely to develop a PJI for TJA (P = .0008) and THA (P = .02), respectively. There was no significant difference for primary TKA (P = .17). When examining aseptic revision TJA, EAP led to a 36% and 47% reduction in the probability of a PJI for aseptic revision TJA (P = .007) and aseptic revision TKA (P = .008), respectively; there was no observed benefit for aseptic revision THA (P = .36). CONCLUSIONS: This meta-analysis demonstrated that patients treated with EAP were less likely to develop a PJI relative to those treated with the SoC for all TJA, primary TJA, primary THA, aseptic revision TJA, and aseptic revision TKA. There was no significant difference observed between EAP and SoC for primary TKA or aseptic revision THA.

Strikingly High Rates of Periprosthetic Joint Infection Following Revision Surgery for Periprosthetic Fractures Regardless of Surgery Timing.

BACKGROUND: Periprosthetic fractures following total hip arthroplasty (THA) often occur in the early postoperative period. Recent data has indicated that early revisions are associated with higher complication rates, particularly periprosthetic joint infection (PJI). The purpose of this study was to assess the effect of timing of periprosthetic fracture surgery on complication rates. We hypothesized that complication rates would be significantly higher in revision surgeries performed within 3 months of the index THA. METHODS: The Medicare Part A claims database was queried from 2010 to 2017 to identify patients who underwent surgery for a periprosthetic fracture following primary THA. Patients were divided based on time between index and revision surgeries: <1, 1 to 2, 2 to 3, 3 to 6, 6 to 9, 9 to 12, and >12 months. Complication rates were compared between groups using multivariate analyses to adjust for demographics, comorbidities, and types of revision surgery. RESULTS: Of 492,340 THAs identified, 4,368 (0.9%) had a subsequent periprosthetic fracture requiring surgery: 1,725 (39.4%) at <1 month, 693 (15.9%) at 1 to 2 months, 202 (4.6%) at 2 to 3 months, 250 (5.7%) at 3 to 6 months, 134 (3.1%) at 6 to 9 months, 85 (19.4%) at 9 to12 months, and 1,279 (29.3%) at >12 months. The risk of PJI was 11.0% in the <1 month group, 11.1% at 1 to 2 months, 7.9% at 2 to 3 months, 6.8% at 3 to 6 months, 8.2% at 6 to 9 months, 9.4% at 9 to 12 months, and 8.5% at >12 months (P = .12). Adjusting for confounding factors, risk of PJI following periprosthetic fracture surgery was similar regardless of timing (P > .05). Rates of subsequent dislocation and aseptic loosening were also similar regardless of timing. CONCLUSIONS: The risk of PJI following repeat surgery for a periprosthetic fracture was strikingly high regardless of timing (6.8 to 11.1%), underscoring the high-risk of complications.

Open-Air Testing of Dual-Comb Time-of-Flight Measurement.

We configured a long-distance ranging apparatus to test the principle of dual-comb time-of-flight measurement using ultrashort lasers. Emphasis was given to the evaluation of open-air performance quantitatively in terms of the measurement resolution and stability. The test results revealed that our dual-comb asynchronous optical pulse sampling permits micrometer-resolved ranging with a repeatability of 2.05 µm over a 648 m distance in dry weather conditions. Further atmospheric effects were evaluated in three different weather conditions with corresponding Allan deviations. Finally, the capability of simultaneous determination of multiple targets was verified with the potential of advanced industrial applications, such as manufacturing, surveying, metrology, and geodesy.

Closed Reduction Technique for Acetabular Fractures with Femoral Head Protrusion and Concomitant Superolateral Impaction: A Case Report.

CASE: Closed reduction of acetabular fractures with femoral head protrusion and superolateral femoral head impaction may be challenging because the intact acetabular roof may block anatomic reduction with traditional maneuvers. We report the use of a 5-step technique for this unique pattern: medializing force to disengage the femoral head, axial traction to clear the intact ilium, lateralizing force to center the head underneath the acetabular roof, confirmation of femoral head stability, and skeletal traction placement. CONCLUSION: Acetabular fractures with femoral head protrusion and concomitant superolateral impaction may be reduced with an initial medializing force followed by axial and lateralizing forces.

Interactions of calmodulin kinase II with the dopamine transporter facilitate cocaine-induced enhancement of evoked dopamine release.

Typical and atypical dopamine uptake inhibitors (DUIs) prefer distinct conformations of the dopamine transporter (DAT) to form ligand-transporter complexes, resulting in markedly different effects on behavior, neurochemistry, and potential for addiction. Here we show that cocaine and cocaine-like typical psychostimulants elicit changes in DA dynamics distinct from those elicited by atypical DUIs, as measured via voltammetry procedures. While both classes of DUIs reduced DA clearance rate, an effect significantly related to their DAT affinity, only typical DUIs elicited a significant stimulation of evoked DA release, an effect unrelated to their DAT affinity, which suggests a mechanism of action other than or in addition to DAT blockade. When given in combination, typical DUIs enhance the stimulatory effects of cocaine on evoked DA release while atypical DUIs blunt them. Pretreatments with an inhibitor of CaMKIIα, a kinase that interacts with DAT and that regulates synapsin phosphorylation and mobilization of reserve pools of DA vesicles, blunted the effects of cocaine on evoked DA release. Our results suggest a role for CaMKIIα in modulating the effects of cocaine on evoked DA release without affecting cocaine inhibition of DA reuptake. This effect is related to a specific DAT conformation stabilized by cocaine. Moreover, atypical DUIs, which prefer a distinct DAT conformation, blunt cocaine's neurochemical and behavioral effects, indicating a unique mechanism underlying their potential as medications for treating psychostimulant use disorder.

Interaction Effect of Phase Angle and Age on Femoral Neck Bone Mineral Density in Patients with Non-Dialysis Chronic Kidney Disease Stage 5.

Background: Low bone mass is common in malnourished patients with chronic kidney disease (CKD) and can lead to a higher risk of fractures. Elderly and CKD patients have the same risk factors for protein-energy wasting, sarcopenia, and osteoporosis. Here, we investigated the association between phase angle (PhA) and bone mineral density (BMD) in dialysis-naïve patients with CKD stage 5 (CKD5) and identified a statistical relationship between PhA and age, which affects bone density. Methods: Bio-impedance spectroscopy for evaluating body composition and PhA and dual-energy X-ray absorptiometry for determining the BMD were simultaneously performed in 167 consecutive patients (mean age, 59.65 ± 13.98 years; women, 40.1%). Two-way analysis of variance (ANOVA) was conducted to assess the potential interaction effect of PhA and age on femoral neck BMD (FN-BMD). Results: Our results showed that PhA and age were independently associated with FN-BMD and T-score in multiple linear regressions analyses. A significant interaction effect of PhA and age on FN-BMD was found on two-way ANOVA (p = 0.028). The average BMD values for the first and second tertiles of the PhA were higher in the young versus elderly group, whereas patients in the elderly group had higher BMD in the third tertiles. Conclusions: A relationship was noted between PhA and BMD in patients with advanced-stage CKD. The effect of PhA level on FN-BMD differed between elderly and young patients. Our study suggested that higher PhA levels could be a marker explaining the maintenance of good bone health in elderly patients with CKD5. Further longitudinal analyses are needed to determine whether PhA predicts the risk of CKD-MBD-related fractures during CKD progression.

A Practical and Analytical Comparative Study of Gel-Based Top-Down and Gel-Free Bottom-Up Proteomics Including Unbiased Proteoform Detection.

Proteomics is an indispensable analytical technique to study the dynamic functioning of biological systems via different proteins and their proteoforms. In recent years, bottom-up shotgun has become more popular than gel-based top-down proteomics. The current study examined the qualitative and quantitative performance of these two fundamentally different methodologies by the parallel measurement of six technical and three biological replicates of the human prostate carcinoma cell line DU145 using its two most common standard techniques, label-free shotgun and two-dimensional differential gel electrophoresis (2D-DIGE). The analytical strengths and limitations were explored, finally focusing on the unbiased detection of proteoforms, exemplified by discovering a prostate cancer-related cleavage product of pyruvate kinase M2. Label-free shotgun proteomics quickly yields an annotated proteome but with reduced robustness, as determined by three times higher technical variation compared to 2D-DIGE. At a glance, only 2D-DIGE top-down analysis provided valuable, direct stoichiometric qualitative and quantitative information from proteins to their proteoforms, even with unexpected post-translational modifications, such as proteolytic cleavage and phosphorylation. However, the 2D-DIGE technology required almost 20 times as much time per protein/proteoform characterization with more manual work. Ultimately, this work should expose both techniques' orthogonality with their different contents of data output to elucidate biological questions.

Effect of modifying negative interpretation bias toward ambiguous social stimuli across eating and personality disorders.

OBJECTIVE: Heightened sensitivity toward social rejection has been implicated in eating disorders (ED) and personality disorder (PD). This study examined the effect of a cognitive bias modification training (CBM-I) targeting the interpretation of ambiguous social situations in individuals with comorbid ED and PD. METHOD: A total of 128 participants [33 with ED and PD, 22 with ED-only, 22 with PD-only, and 51 healthy controls (HC)] were recruited from a hospital and university settings, and included in the final analyses. The participants were randomly assigned to a CBM-I task with benign resolutions or a control task with neutral resolutions in a counterbalanced order in two sessions using a within-subject design. Interpretation bias toward social stimuli was measured using the ambiguous sentence completion task before and after completing the assigned task. RESULTS: The CBM-I task increased benign and decreased negative interpretations with large effect sizes in the diagnostic groups, and with a moderate effect size in the HC group. Participants' anxiety levels were also reduced after the task. The size of the change in negative interpretation was positively associated with baseline negative affect, and negatively associated with baseline positive affect. DISCUSSION: The results suggest that modifying interpretation bias has the potential as a transdiagnostic target of treatment for ED and PD, and a fully powered clinical trial with consecutive sessions would be warranted. PUBLIC SIGNIFICANCE: Participants with eating disorders and/or personality disorder, and healthy controls completed a single session of a cognitive training intervention targeting rejection sensitivity. The training produced a large decrease in negative interpretation in the diagnostic groups, and a moderate effect in healthy controls. The findings indicate that training for positive processing of social information may be of value to augment treatment in conditions such as eating disorders and personality disorder, in which there are high levels of rejection sensitivity.

Short-Term Indwelling Foley Catheters Do Not Reduce the Risk of Postoperative Urinary Retention in Uncomplicated Primary THA and TKA: A Randomized Controlled Trial.

BACKGROUND: The purpose of this randomized controlled trial was to determine whether a short-term Foley catheter (inserted in the operating room and removed upon arrival to the orthopaedic floor) would reduce the risk of postoperative urinary retention (POUR) in patients undergoing primary total hip (THA) and total knee arthroplasty (TKA). METHODS: Three hundred and eighty-eight patients undergoing inpatient primary TKA (n = 228) or THA (n = 160) with spinal anesthesia were randomized to receive a short-term Foley catheter (n = 194) or no Foley (n = 194). There were 143 male and 245 female patients. The primary outcome was POUR, defined as requiring ≥2 straight catheterizations or the placement of an indwelling urinary catheter when indicated by retention of ≥450 mL on bladder scans. Secondary outcomes included urinary tract infections (UTIs) within 3 weeks and the need for ≥1 straight catheterization. A power analysis determined that 194 patients per group were required to detect a 7% minimal clinically important difference in POUR rates at 80% power and alpha of 0.05. Intention-to-treat and as-treated analyses were performed (2 patients received the non-allocated treatment). Outcomes were compared between the groups using univariate and multivariate analyses, with alpha < 0.05. RESULTS: Nine patients developed POUR: 4 in the short-term Foley group and 5 in the control group (2.1% versus 2.6%; p = 1.00). Of those who developed POUR, 8 were male and 1 was female (88.9% versus 11.1%; p = 0.002). Twenty-four patients required ≥1 straight catheterization: 10 in the Foley group and 14 in the control group (5.2% versus 7.2%; p = 0.40). Four patients developed UTIs: 3 in the Foley group and 1 in the control group (1.5% versus 0.5%; p = 0.62) on intention-to-treat analysis, and 4 in the Foley group and none in the control group (2.1% versus 0.0%; p = 0.12) on as-treated analysis. CONCLUSIONS: The use of a short-term Foley catheter inserted in the operating room and removed on arrival to the orthopaedic floor does not decrease the rate of POUR. LEVEL OF EVIDENCE: Therapeutic Level I . See Instructions for Authors for a complete description of levels of evidence.

Vitamin D3 Supplementation Prior to Total Knee Arthroplasty: A Randomized Controlled Trial.

BACKGROUND: The purpose of this randomized controlled trial was to determine if a one-time dose of vitamin D3 prior to total knee arthroplasty improves function and patient-reported outcomes, while decreasing complications. METHODS: One hundred seven patients undergoing primary total knee arthroplasty were randomized to receive 50,000 international units vitamin D3 (57 patients) or placebo (50 patients) on the morning of surgery. Power analysis determined 45 patients were required in each cohort to detect a minimal clinically important difference of 6 points in the functional component of the 2011 version of the Knee Society Score (KSS), assuming an alpha of 0.05 and power of 80%. KSS and a Timed Up and Go Test (TUGT) were measured preoperatively and at 3 and 6 weeks postoperatively. RESULTS: There was no difference in improvement of KSS at 3 weeks (+4.8 points vitamin D3 versus +3.0 points placebo; P = .6) or 6 weeks (+14.5 points vitamin D3 versus +12.4 points placebo; P = .5) from baseline. There was no difference in change in TUGT at 3 weeks (+1.2 seconds vitamin D3 versus +0.6 seconds placebo; P = .6) or 6 weeks (-0.3 seconds vitamin D3 versus -0.9 seconds placebo; P = .6) from baseline. There were 4 complications in the placebo cohort within the first 90 days postoperatively and 5 complications in the vitamin D3 cohort (P = 1.0). CONCLUSION: Supplementation with 50,000 international units vitamin D3 on the day of surgery failed to demonstrate statistical significant differences in functional KSS, TUGT times, or complications in the early postoperative period compared to placebo. LEVEL OF EVIDENCE: Level I, therapeutic study.

Ceramic Femoral Heads Exhibit Lower Wear Rates Compared to Cobalt Chrome: A Meta-Analysis.

BACKGROUND: Wear between the femoral head and acetabular liners continues to limit the longevity of total hip arthroplasty implants despite advances in implant materials. The purpose of this meta-analysis was to compare linear wear rates of cobalt-chromium (CoCr) and fourth-generation ceramic femoral heads on highly cross-linked polyethylene (XLPE) liners. METHODS: A systematic review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was conducted to identify all studies between 2003 and 2020 that examined in vivo wear rates of either fourth-generation ceramics or CoCr femoral heads on XLPE liners. Studies were analyzed in a weighted means analysis of wear rates and a random effects meta-analysis. RESULTS: A total of 36 studies met inclusion criteria (1,657 CoCr and 659 ceramic patients). The pooled, weighted mean wear rate was 0.063 mm/year (standard deviation [SD]: 0.061, confidence interval [CI]: 0.049-0.077) for CoCr and 0.047 mm/year (SD: 0.057, CI: 0.033-0.062; P < .01) for ceramic (P < .01). A meta-analysis of 4 studies directly comparing ceramic and CoCr found that CoCr heads demonstrated 0.029 mm/year more wear than ceramic heads (95% CI: 0.026-0.059, P = .306). Mean wear for 32-mm heads was significantly higher for ceramic (P < .01), while mean wear for 36-mm heads was significantly higher for CoCr (P < .01). CONCLUSION: Fourth-generation ceramic femoral heads were found to have significantly lower wear rates than CoCr heads. Unlike previous studies, this meta-analysis included only in vivo studies and those with the same generation of highly XLPE liners.

Phosphatidylinositol 4,5-bisphosphate (PIP2) facilitates norepinephrine transporter dimerization and modulates substrate efflux.

The plasmalemmal norepinephrine transporter (NET) regulates cardiovascular sympathetic activity by clearing extracellular norepinephrine in the synaptic cleft. Here, we investigate the subunit stoichiometry and function of NET using single-molecule fluorescence microscopy and flux assays. In particular, we show the effect of phosphatidylinositol 4,5-bisphosphate (PIP2) on NET oligomerization and efflux. NET forms monomers (~60%) and dimers (~40%) at the plasma membrane. PIP2 depletion results in a decrease in the average oligomeric state and decreases NET-mediated substrate efflux while not affecting substrate uptake. Mutation of the putative PIP2 binding residues R121, K334, and R440 to alanines does not affect NET dimerization but results in decreased substrate efflux that is not altered upon PIP2 depletion; this indicates that PIP2 interactions with these residues affect NET-mediated efflux. A dysregulation of norepinephrine and PIP2 signaling have both been implicated in neuropsychiatric and cardiovascular diseases. This study provides evidence that PIP2 directly regulates NET organization and function.

Structural basis of organic cation transporter-3 inhibition.

Organic cation transporters (OCTs) facilitate the translocation of catecholamines, drugs and xenobiotics across the plasma membrane in various tissues throughout the human body. OCT3 plays a key role in low-affinity, high-capacity uptake of monoamines in most tissues including heart, brain and liver. Its deregulation plays a role in diseases. Despite its importance, the structural basis of OCT3 function and its inhibition has remained enigmatic. Here we describe the cryo-EM structure of human OCT3 at 3.2 Å resolution. Structures of OCT3 bound to two inhibitors, corticosterone and decynium-22, define the ligand binding pocket and reveal common features of major facilitator transporter inhibitors. In addition, we relate the functional characteristics of an extensive collection of previously uncharacterized human genetic variants to structural features, thereby providing a basis for understanding the impact of OCT3 polymorphisms.

Comparison and calibration of dose delivered by137Cs and x-ray irradiators in mice.

Objective.The Office of Radiological Security, U.S. Department of Energy's National Nuclear Security Administration, is implementing a radiological risk reduction program which seeks to minimize or eliminate the use of high activity radiological sources, including137Cs, by replacing them with non-radioisotopic technologies, such as x-ray irradiators. The main goal of this paper is to evaluate the equivalence of the dose delivered by gamma- and x-ray irradiators in mice using experimental measurements and Monte Carlo simulations. We also propose a novel biophantom as anin situdose calibration method.Approach.We irradiated mouse carcasses and 3D-printed mouse biophantoms in a137Cs irradiator (Mark I-68) and an x-ray irradiator (X-Rad320) at three voltages (160 kVp, 225 kVp and 320 kVp) and measured the delivered radiation dose. A Geant4-based Monte Carlo model was developed and validated to provide a comprehensive picture of gamma- and x-ray irradiation in mice.Main Results.Our Monte Carlo model predicts a uniform dose delivered in soft-tissue for all the explored irradiation programs and in agreement with the absolute dose measurements. Our Monte Carlo model shows an energy-dependent difference between dose in bone and in soft tissue that decreases as photon energy increases. Dose rate depends on irradiator and photon energy. We observed a deviation of the measured dose from the target value of up to -9% for the Mark I-68, and up to 35% for the X-Rad320. The dose measured in the 3D-printed phantoms are equivalent to that in the carcasses within 6% uncertainty.Significance.Our results suggest that 320 kVp irradiation is a good candidate to substitute137Cs irradiation barring a few caveats. There is a significant difference between measured and targeted doses for x-ray irradiation that suggests a strong need forin situcalibration, which can be achieved with 3D-printed mouse biophantoms. A dose correction is necessary for bone doses, which can be provided by a Monte Carlo calculation. Finally, the biological implications of the differences in dose rates and dose per photon for the different irradiation methods should be carefully assessed for each small-animal irradiation experiment.