Academic and Demographic Characteristics of Orthopedic Adult Reconstruction Division Chiefs.

INTRODUCTION: Division chiefs play crucial leadership, administrative, and instructive roles within orthopedic subspecialties. The purpose of this study is to investigate the demographic and academic characteristics of division chiefs of adult reconstruction at fellowship institutions in the United States. METHODS: Adult reconstruction fellowship programs were identified using the American Association of Hip and Knee Surgeons database. Characteristic information about sex, race, academic rank, additional degrees, fellowship institution, and year of completion were collected. Hirsch indices (h-indices) of the division chiefs were collected from the Scopus database. RESULTS: Of the 120 adult reconstruction fellowship programs identified, 39 had a designated division chief of adult reconstruction. All of the division chiefs were male (n=39). Race breakdown was as follows: 74.4% were White (n=29), 12.8% were Asian (n=5), 7.7% were of mixed ethnicity (n=3), 2.6% were Latinx (n=1), and 2.6% were African American (n=1). The majority (53.8%; n=21) of division chiefs also held the academic rank of professor. The mean time since completion of fellowship was 21.7 ± 8.2 years and the mean h-index of the division chiefs was 24.9 ± 16.2. The fellowship programs that trained the most division chiefs were Massachusetts General Hospital (n=9) and the Hospital for Special Surgery (n=6). DISCUSSION: Division chiefs of adult reconstruction are integral leaders within their orthopedic subspecialty. An analysis of demographic and educational characteristics revealed a lack of diversity among adult reconstruction division chiefs in the United States. Deliberate efforts to increase the diversity of adult reconstruction leadership must be made to address these disparities.

Relative carcinogenicity of tacrolimus vs mycophenolate after solid organ transplantation and its implications for liver transplant care.

BACKGROUND: De novo malignancy is a leading cause of late morbidity and mortality in liver transplant recipients. Cumulative immunosuppression has been shown to contribute to post-transplant malignancy (PTM) risk. There is emerging evidence on the differential carcinogenic risk profile of individual immunosuppressive drugs, independent of the net effect of immunosuppression. Calcineurin inhibitors such as tacrolimus may promote tumourigenesis, whereas mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil, may limit tumour progression. Liver transplantation (LT) is relatively unique among solid organ transplantation in that immunosuppression monotherapy with either tacrolimus or MPA is often achievable, which makes careful consideration of the risk-benefit profile of these immunosuppression agents particularly relevant for this cohort. However, there is limited clinical data on this subject in both LT and other solid organ transplant recipients. AIM: To investigate the relative carcinogenicity of tacrolimus and MPA in solid organ transplantation. METHODS: A literature search was conducted using MEDLINE and Embase databases using the key terms "solid organ transplantation", "tacrolimus", "mycophenolic acid", and "carcinogenicity", in order to identify relevant articles published in English between 1st January 2002 to 11th August 2022. Related terms, synonyms and explosion of MeSH terms, Boolean operators and truncations were also utilised in the search. Reference lists of retrieved articles were also reviewed to identify any additional articles. Excluding duplicates, abstracts from 1230 records were screened by a single reviewer, whereby 31 records were reviewed in detail. Full-text articles were assessed for eligibility based on pre-specified inclusion and exclusion criteria. RESULTS: A total of 6 studies were included in this review. All studies were large population registries or cohort studies, which varied in transplant era, type of organ transplanted and immunosuppression protocol used. Overall, there was no clear difference demonstrated between tacrolimus and MPA in de novo PTM risk following solid organ transplantation. Furthermore, no study provided a direct comparison of carcinogenic risk between tacrolimus and MPA monotherapy in solid organ transplantation recipients. CONCLUSION: The contrasting carcinogenic risk profiles of tacrolimus and MPA demonstrated in previous experimental studies, and its application in solid organ transplantation, is yet to be confirmed in clinical studies. Thus, the optimal choice of immunosuppression drug to use as maintenance monotherapy in LT recipients is not supported by a strong evidence base and remains unclear.

Current trends in retraction of plastic surgery and reconstruction research.

BACKGROUND: Various studies regarding retractions of publications have determined the rate of retraction has increased in recent years. Although this trend may apply to any field, there is a paucity of literature exploring the publication of erroneous studies within plastic and reconstructive surgery. The present study aims to identify trends in frequency and reasons for retraction of plastic and reconstructive surgery studies, with analysis of subspecialty and journals. METHODS: A database search was conducted for retracted papers within plastic and reconstructive surgery. The initial search yielded 2347 results, which were analyzed by two independent reviewers. 77 studies were jointly identified for data collection. RESULTS: The most common reasons for retractions were duplication (n = 20, 25.9 %), request of author (n = 15, 19.5 %), plagiarism (n = 9, 11.6 %), error (n = 9, 11.6 %), fraud (n = 2, 2.6 %), and conflict of interest (n = 1, 1.3 %). 15 were basic science studies (19.4 %), 58 were clinical science studies (75.3 %), and 4 were not categorized (5.2 %). Subspecialties of retracted papers were maxillofacial (n = 29, 37.7 %), reconstructive (n = 17, 22.0 %), wound healing (n = 8, 10.4 %), burn (n = 6, 7.8 %), esthetics (n = 5, 6.5 %), breast (n = 3, 3.9 %), and trauma (n = 1, 1.3 %). Mean impact factor was 2.9 and average time from publication to retraction was 32 months. CONCLUSION: Analysis of retracted plastic surgery studies revealed a recent rise in frequency of retractions, spanning a wide spectrum of journals and subspecialties.

Pulmonary hypertension survival and hospitalisations in people living with HIV: a systematic review and meta-analysis.

INTRODUCTION: People living with HIV (PLHIV) have a higher risk of developing pulmonary hypertension (PH) with subsequent poorer prognosis. This review aimed to determine the (1) survival outcomes and (2) proportion of emergency department (ED) visits and hospitalisations of PLHIV and PH. METHODS: We conducted a systematic review and meta-analysis of observational studies reporting survival outcomes for PLHIV and PH. Electronic databases (Medline, EMBASE, PubMed, Web of Science, Global Index Medicus and Cochrane Library), trial registries and conference proceedings were searched until 22 July 2023. We pooled similar measures of effect, assessed apriori subgroups and used meta-regression to determine mortality and associated variables. RESULTS: 5248 studies were identified; 28 studies were included with a total of 5459 PLHIV and PH. The mean survival (95% CI) of PLHIV and PH was 37.4 months (29.9 to 44.8). Participants alive at 1, 2 and 3 years were 85.8% (74.1% to 95.0%), 75.2% (61.9% to 86.7%) and 61.9% (51.8% to 71.6%), respectively. ED visits and hospitalisation rates were 73.3% (32.5% to 99.9%) and 71.2% (42.4% to 94.2%), respectively. More severe disease, measured by echocardiogram, was associated with poorer prognosis (ß -0.01, 95% CI -0.02 to 0.00, p=0.009). Survival was higher in high-income countries compared with lower-income countries (ß 0.50, 95% CI 0.28 to 0.73, p<0.001) and in Europe compared with the America (ß 0.56, 95% CI 0.37 to 0.75, p<0.001). CONCLUSION: Our study confirms poor prognosis and high healthcare utilisation for PLHIV and PH. Prognosis is associated with country income level, geographic region and PH severity. This highlights the importance of screening in this population. PROSPERO REGISTRATION NUMBER: CRD42023395023.

Obstructive sleep apnea in those with idiopathic intracranial hypertension undergoing diagnostic in-laboratory polysomnography.

RATIONALE: The association of obstructive sleep apnea (OSA) with idiopathic intracranial hypertension (IIH) remains unclear, and few studies have used objective in-laboratory polysomnography (PSG) data. Thus, we used PSG data to examine the: 1) association between OSA, and its severity, with IIH and 2) sex differences in OSA severity in those with and without IIH. METHODS: We retrospectively analyzed diagnostic PSG data from January 2015 to August 2023 for patients who were diagnosed with IIH by a neuro-ophthalmologist using the modified Dandy criteria. We selected three age, sex, and body mass index (BMI) matched controls for each IIH patient. We examined potential associations of IIH with OSA using regression. Sex differences were analyzed using ANOVA. RESULTS: Of 3482 patients who underwent PSG, we analyzed 78 IIH patients (16 males) and 234 matched controls (48 males). Five (6.4 %) IIH and 39 (16.7 %) control patients had OSA, defined as AHI≥15. After adjusting for age, sex, BMI, and comorbidities, IIH was negatively associated with the presence of OSA (OR 0.29, 95%CI 0.10-0.87, p = 0.03). However, models that adjusted for acetazolamide use, with or without comorbidities, showed no significant relationship with OSA (OR 0.31, p = 0.20). Males with IIH had a significantly higher age (p = 0.020), OSA severity (p = 0.032), and arousal index (p = 0.046) compared to females with IIH. CONCLUSIONS: IIH treated with acetazolamide was not an independent risk factor for OSA presence or severity. The presence of IIH treated with acetazolamide likely does not warrant routine screening for OSA, but related risk factors may identify appropriate patients.

Describing Engagement in the HIV Care Cascade: A Methodological Study.

Introduction: Engagement in the HIV care cascade is required for people living with HIV (PLWH) to achieve an undetectable viral load. However, varying definitions of engagement exist, contributing to heterogeneity in research regarding how many individuals are actively participating and benefitting from care. A standardized definition is needed to enhance comparability and pooling of data from engagement studies. Objectives: The objective of this paper was to describe the various definitions for engagement used in HIV clinical trials. Methods: Articles were retrieved from CASCADE, a database of 298 clinical trials conducted to improve the HIV care cascade (https://hivcarecascade.com/), curated by income level, vulnerable population, who delivered the intervention, the setting in which it was delivered, the intervention type, and the level of pragmatism of the intervention. Studies with engagement listed as an outcome were selected from this database. Results: 13 studies were eligible, of which five did not provide an explicit definition for engagement. The remaining studies used one or more of the following: appointment adherence (n=6), laboratory testing (n=2), adherence to antiretroviral therapy (n=2), time specification (n=5), intervention adherence (n=5), and quality of interaction (n=1). Conclusion: This paper highlights the existing diversity in definitions for engagement in the HIV care cascade and categorize these definitions into appointment adherence, laboratory testing, adherence to antiretroviral therapy, time specification, intervention adherence, and quality of interaction. We recommend consensus on how to describe and measure engagement.

Which Combination is the Best? A Comparison of the Predictive Potential of Serum Biomarker Combinations to Diagnose Periprosthetic Joint Infection.

BACKGROUND: Without a gold-standard test, recent periprosthetic joint infections (PJI) literature has explored the utility of combining serological results, with promising findings. However, previous studies evaluated fewer than 200 patients and often studied only 1 to 2 test combinations. The purpose of this study was to accumulate a large single-institution cohort of revision total joint arthroplasty (rTJA) patients to determine the diagnostic utility of combination serum biomarkers to identify PJI. METHODS: A single institution longitudinal database was assessed to identify all patients who underwent rTJA from 2017 to 2020. There were 1,363 rTJA patients (715 rTKA patients and 648 rTHA patients) including 273 PJI cases (20%) analyzed. The PJI was diagnosed post-rTJA utilizing 2011 Musculoskeletal Infection Society (MSIS) criteria. Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), D-dimer, and interleukin 6 (IL-6) were systematically collected for all patients. RESULTS: The rTKA combination markers of CRP + ESR (sensitivity: 78.3%, specificity: 88.8%, positive predictive value (PPV): 70.0%, negative predictive value (NPV): 92.5%), CRP + D-dimer (sensitivity: 60.5%, specificity: 92.6%, PPV: 63.4%, NPV: 91.7%), and CRP + IL-6 (sensitivity: 38.5%, specificity: 100.0%, PPV: 100.0%, NPV: 92.9%) all yielded higher specificity than CRP alone (sensitivity: 94.4%, specificity: 75.0%, PPV: 55.5%, NPV: 97.6%). Similarly, the rTHA combination markers of CRP + ESR (sensitivity: 70.1%, specificity: 88.8%, PPV: 58.1%, NPV: 93.1%), CRP + D-dimer (sensitivity: 57.1%, specificity: 90.1%, PPV: 43.2%, NPV: 94.1%), and CRP + IL-6 (sensitivity: 21.4%, specificity: 98.4%, PPV: 60.0%, NPV: 91.7%) all yielded higher specificity than CRP alone (sensitivity: 84.7%, specificity: 77.5%, PPV: 45.4%, NPV: 95.8%). CONCLUSION: Overall, in diagnosing PJI for both rTKA and rTHA, 2-marker combinations yielded higher specificity, while 3-marker combinations yielded higher sensitivity compared to CRP alone. However, compared to all 2-marker and 3-marker combinations, CRP demonstrated superior overall diagnostic utility. These findings suggest that routine combination testing of markers for PJI diagnosis may be excessive and an unnecessary use of resources, especially in resource-limited situations.

The Amyloid Precursor Protein Modulates the Position and Length of the Axon Initial Segment.

The amyloid precursor protein (APP) is linked to the genetics and pathogenesis of Alzheimer's disease (AD). It is the parent protein of the ß-amyloid (Aß) peptide, the main constituent of the amyloid plaques found in an AD brain. The pathways from APP to Aß are intensively studied, yet the normal functions of APP itself have generated less interest. We report here that glutamate stimulation of neuronal activity leads to a rapid increase in App gene expression. In mouse and human neurons, elevated APP protein changes the structure of the axon initial segment (AIS) where action potentials are initiated. The AIS is shortened in length and shifts away from the cell body. The GCaMP8f Ca2+ reporter confirms the predicted decrease in neuronal activity. NMDA antagonists or knockdown of App block the glutamate effects. The actions of APP on the AIS are cell-autonomous; exogenous Aß, either fibrillar or oligomeric, has no effect. In culture, APPSwe (a familial AD mutation) induces larger AIS changes than wild type APP. Ankyrin G and ßIV-spectrin, scaffolding proteins of the AIS, both physically associate with APP, more so in AD brains. Finally, in humans with sporadic AD or in the R1.40 AD mouse model, both females and males, neurons have elevated levels of APP protein that invade the AIS. In vivo as in vitro, this increased APP is associated with a significant shortening of the AIS. The findings outline a new role for the APP and encourage a reconsideration of its relationship to AD.SIGNIFICANCE STATEMENT While the amyloid precursor protein (APP) has long been associated with Alzheimer's disease (AD), the normal functions of the full-length Type I membrane protein have been largely unexplored. We report here that the levels of APP protein increase with neuronal activity. In vivo and in vitro, modest amounts of excess APP alter the properties of the axon initial segment. The ß-amyloid peptide derived from APP is without effect. Consistent with the observed changes in the axon initial segment which would be expected to decrease action potential firing, we show that APP expression depresses neuronal activity. In mouse AD models and human sporadic AD, APP physically associates with the scaffolding proteins of the axon initial segment, suggesting a relationship with AD dementia.

Alcohol reverses the effects of KCNJ6 (GIRK2) noncoding variants on excitability of human glutamatergic neurons.

Synonymous and noncoding single nucleotide polymorphisms (SNPs) in the KCNJ6 gene, encoding G protein-gated inwardly rectifying potassium channel subunit 2 (GIRK2), have been linked with increased electroencephalographic frontal theta event-related oscillations (ERO) in subjects diagnosed with alcohol use disorder (AUD). To identify molecular and cellular mechanisms while retaining the appropriate genetic background, we generated induced excitatory glutamatergic neurons (iN) from iPSCs derived from four AUD-diagnosed subjects with KCNJ6 variants ("Affected: AF") and four control subjects without variants ("Unaffected: UN"). Neurons were analyzed for changes in gene expression, morphology, excitability and physiological properties. Single-cell RNA sequencing suggests that KCNJ6 AF variant neurons have altered patterns of synaptic transmission and cell projection morphogenesis. Results confirm that AF neurons express lower levels of GIRK2, have greater neurite area, and elevated excitability. Interestingly, exposure to intoxicating concentrations of ethanol induces GIRK2 expression and reverses functional effects in AF neurons. Ectopic overexpression of GIRK2 alone mimics the effect of ethanol to normalize induced excitability. We conclude that KCNJ6 variants decrease GIRK2 expression and increase excitability and that this effect can be minimized or reduced with ethanol.

Adaptive immune responses in patients requiring revision after total knee arthroplasty.

Dissatisfaction occurs in nearly 20% of patients after total knee arthroplasty (TKA); however, there remains only limited understanding of the biologic mechanisms that may contribute to suboptimal postoperative outcomes requiring revision surgery. Expansion of effector T and B cells, could promote an abnormal healing response via local or peripheral immune system mechanisms and contribute to inferior outcomes necessitating revision TKA. In this pilot study, we hypothesized that patients suffering from complications of arthrofibrosis or instability may exhibit differences in adaptive immune function. Patients (n = 31) undergoing revision TKA for an indication of arthrofibrosis or instability were prospectively enrolled. Whole blood and synovial fluid (SF) from the operative knee were collected at time of surgery. Peripheral blood mononuclear cells were isolated and analyzed by flow cytometry. Serum and SF were assessed for immunoglobulin levels by Luminex and antiphospholipid antibodies by enzyme-linked immunoassay. No significant differences were observed in peripheral blood T/B cell populations or serum immunoglobulins levels between groups. SF analysis demonstrated significant differences between the two groups, with higher levels of immunoglobulin G1 (IgG1) (p = 0.0184), IgG3 (p = 0.0084) and antiphosphatidyl serine IgG (p = 0.034) in arthrofibrosis relative to instability patients. Increased levels of both IgG subclasses and antiphospholipid antibodies in the SF suggest that intra-articular T-B cell interactions, potentially triggered by exposure to apoptotic components generated during post-op healing, could be functioning as a source of immune complexes that fuel fibrous tissue growth in arthrofibrotic patients.

Gene therapy with Pellino-1 improves perfusion and decreases tissue loss in Flk-1 heterozygous mice but fails in MAPKAP Kinase-2 knockout murine hind limb ischemia model.

OBJECTIVES: In the United States, over 8.5 million people suffer from peripheral arterial disease (PAD). Previously we reported that Pellino-1(Peli1) gene therapy reduces ischemic damage in the myocardium and skin flaps in Flk-1 [Fetal Liver kinase receptor-1 (Flk-1)/ Vascular endothelial growth factor receptor-2/VEGFR2] heterozygous (Flk-1+/--) mice. The present study compares the angiogenic response and perfusion efficiency following hind limb ischemia (HLI) in, Flk-1+/- and, MAPKAPKINASE2 (MK2-/-) knockout (KO) mice to their control wild type (WT). We also demonstrated the use of Peli1 gene therapy to improve loss of function following HLI. STUDY DESIGN AND METHODS: Femoral artery ligation (HLI) was performed in both Flk-1+/- and MK2-/- mice along with their corresponding WT. Another set of Flk-1+/- and MK2-/- were injected with either Adeno-LacZ (Ad.LacZ) or Adeno-Peli1 (Ad.Peli1) after HLI. Hind limb perfusion was assessed by laser doppler imaging at specific time points. A standardized scoring scale is used to quantify the extent of ischemia. Histology analysis performed includes capillary density, fibrosis, pro-angiogenic and anti-apoptotic proteins. RESULTS: Flk-1+/- and MK2-/- had a slower recovery of perfusion efficiency in the ischemic limbs than controls. Both Flk-1+/- and MK2-/- KO mice showed decreased capillary density and capillary myocyte ratios with increased fibrosis than their corresponding wild types. Ad.Peli1 injected ischemic Flk-1+/- limb showed improved perfusion, increased capillary density, and pro-angiogenic molecules with reduced fibrosis compared to Ad.LacZ group. No significant improvement in perfusion was observed in MK2-/- ischemic limb after Ad. Peli1 injection. CONCLUSION: Deletion of Flk-1 and MK2 impairs neovascularization and perfusion following HLI. Treatment with Ad. Peli1 results in increased angiogenesis and improved perfusion in Flk-1+/- mice but fails to rectify perfusion in MK2 KO mice. Overall, Peli1 gene therapy is a promising candidate for the treatment of PAD.

Virological measures and factors associated with outcomes, and missing outcome data in HIV clinical trials: a methodological study.

BACKGROUND: To evaluate the definition of HIV virological outcomes in the literature and factors associated with outcomes and missing outcome data. METHODS: We conducted a methodological review of HIV RCTs using a search (2009-2019) of PubMed, Embase and the Cochrane Central Register of Controlled Trials.Only full-text, peer-reviewed, randomised controlled trials (RCTs) that measured virological outcomes in people living with HIV, and published in English were included.We extracted study details and outcomes. We used logistic regression to identify factors associated with a viral threshold ≤50 copies/mL and linear regression to identify factors associated with missing outcome data. RESULTS: Our search yielded 5847 articles; 180 were included. A virological outcome was the primary outcome in 73.5% of studies. 89 studies (49.4%) used virological success. The remaining used change in viral load (VL) (33 studies, 18.3%); virological failure (59 studies, 32.8%); or virological rebound (9 studies, 5.0%). 96 studies (53.3%) set the threshold at ≤50 copies/mL; and 33.1% used multiple measures.Compared with government and privately funded studies, RCTs with industry funding (adjusted OR 6.39; 95% CI 2.15 to 19.00; p<0.01) were significantly associated with higher odds of using a VL threshold of ≤50 copies/mL. Publication year, intervention type, income level and number of patients were not associated with a threshold of ≤50 copies/mL. Trials with pharmacological interventions had less missing data (ß=-11.04; 95% CI -20.02 to -1.87; p=0.02). DISCUSSION: Country source of funding was associated with VL threshold choice and studies with pharmacological interventions had less missing data, which may in part explain heterogeneous virological outcomes across studies. Multiple measures of VL were not associated with missing data. The development of formal guidelines on virological outcome reporting in RCTs is needed.

Patient engagement in preclinical laboratory research: A scoping review.

BACKGROUND: 'Patient engagement' involves meaningful collaboration between researchers and 'patient partners' to co-create research. It helps ensure that research being conducted is relevant to its ultimate end-users. Although patient engagement within clinical research has been well documented, the prevalence and effects of patient engagement in translational preclinical laboratory research remain unclear. The aim of this scoping review is to present current patient engagement activities reported in preclinical laboratory research. METHODS: MEDLINE, Embase, and grey literature were systematically searched from inception to April 2021. Studies that described or investigated patient engagement in preclinical laboratory research were included. Patient engagement activities where patients (i.e. patients, family members, caregivers or community members) provided input, or consultation on at least one element of the research process were eligible for inclusion. Study characteristics and outcomes were extracted and organized thematically. FINDINGS: 32 reports were included (30 primary studies, 1 narrative review, and 1 researcher guide). Most studies engaged patients at the education or priority setting stages (n=26). The most frequently reported benefit of patient engagement was 'providing a mutual learning opportunity'. Reported barriers to patient engagement reflected concerns around 'differences in knowledge and research experience' and how this may challenge communication and limit meaningful collaboration. INTERPRETATION: Patient engagement is feasible and beneficial for preclinical laboratory research. Future work should focus on assessing the impacts of patient engagement in this area of research. FUNDING: None.

Heterotopic Ossification Negatively Influences Range of Motion After Revision Total Knee Arthroplasty.

BACKGROUND: The incidence of heterotopic ossification (HO) after total knee arthroplasty (TKA) varies and is of unclear clinical significance. This study aimed to identify the incidence of HO in patients undergoing revision TKA for either stiffness or aseptic loosening/instability and determine if the presence of HO is associated with inferior absolute range of motion (ROM) and ROM gains. METHODS: Eighty-seven patients were prospectively enrolled and separated into 2 cohorts to evaluate ROM after revision TKA (2017-2019). Group 1 (N = 40) patients were revised for stiffness, while group 2 (N = 47) patients were revised for either aseptic loosening or instability. Goniometer-measured ROM values were obtained preoperatively and at 6 weeks, 6 months, and 1 year postoperatively. Statistical analysis included a Fisher's exact test to assess for an association between preoperative HO and final ROM at 1 year after revision TKA. RESULTS: HO was identified on preoperative radiographs in 17 patients (20%). There was a significantly higher rate of preoperative HO in patients revised for stiffness compared to patients revised for instability or loosening (30% vs 11%; P = .03). Five cases of HO qualitatively identified as most clinically severe were associated with lower ROM at each time point compared to the remainder of HO cases in this study cohort (P < .02). CONCLUSION: The presence of HO is greater in patients undergoing revision TKA for stiffness. Additionally, HO severity appears to have a major effect on preoperative and postoperative ROM trajectory. This information should help guide patient expectations and highlight the need for a comprehensive, standardized classification system for HO.

Guidelines are needed for studies of pre-treatment HIV drug resistance: a methodological study.

BACKGROUND: The expansion of access to antiretroviral therapy (ART) has been accompanied by an increase in pre-treatment drug resistance (PDR). While it is critical to monitor the increasing prevalence of PDR across countries and populations to inform optimal regimen selection, the completeness of reporting is often suboptimal, limiting the interpretation and generalizability of the results. Indeed, there is no formal guidance on how studies investigating the prevalence of drug resistance should be reported. Thus, we sought to determine the completeness of reporting in studies of PDR and the factors associated with sub-optimal reporting to ascertain the need for guidelines. METHODS: As part of a systematic review on the global prevalence of PDR in key populations (men who have sex with men, sex workers, transgender people, people who inject drugs and people in prisons), we searched 10 electronic databases until January 2019. We extracted information on selected study characteristics useful for interpreting prevalence data. Data were extracted in duplicate. Analyses of variance and correlation were used to explore factors that may explain the number of items reported. RESULTS: We found 650 studies of which 387 were screened as full text and 234 were deemed eligible. The included studies were published between 1997 and 2019 and included a median of 239 (quartile 1 = 101; quartile 3 = 778) participants. Most studies originated from high-income countries (125/234; 53.0%). Of 23 relevant data items, including study design, setting, participant sociodemographic characteristics, HIV risk factors, type of resistance test conducted, definition of resistance, the mean (standard deviation) number of items reported was 13 (2.2). We found that more items were reported in studies published more recently (r = 0.20; p < 0.002) and in studies at low risk of bias (F [2231] = 8.142; p < 0.001). CONCLUSIONS: Incomplete reporting in studies on PDR makes characterising levels of PDR in subpopulations across countries challenging. Hence, guidelines are needed to define a minimum set of variables to be included in such studies.

Overexpression of Thioredoxin1 enhances functional recovery in a mouse model of hind limb ischemia.

BACKGROUND: There is keen interest in finding nonsurgical treatments for peripheral vascular disease (PVD). Previously, we demonstrated that selective activation of Thioredoxin1 (Trx1), a 12-kDa cytosolic protein, initiates redox-dependent signaling and promotes neovascularization after ischemic heart disease. Therefore, Trx1 might possess immense potential to not only treat murine hind limb ischemia (HLI) through effective angiogenesis but also provide PVD patients with nonsurgical therapy to enhance neovascularization and improve blood perfusion. METHODS: To determine whether activation of Trx1 increases blood perfusion in HLI, two different strategies were used-gene therapy and transgenic model system. In adenoviral-mediated gene therapy, 8- to 12-wk-old mice were divided into two groups: (1) control Adeno-LacZ (Ad-LacZ) and (2) Adeno-Thiroedoxin1 (Ad-Trx1). The mice underwent surgical intervention to induce right HLI followed by injection with Ad-LacZ or Ad-Trx1, respectively. In the second strategy, we used wild-type and transgenic mice overexpressing Trx1 (Trx1Tg/+). All the animals underwent Doppler imaging for the assessment of limb perfusion followed by immunohistochemistry and Western blot analysis. RESULTS: Significant increases in perfusion ratio were observed in all the Trx1 overexpressed groups compared with their corresponding controls. Expressions of heme oxygenase-1, vascular endothelial growth factor, and the vascular endothelial growth factor receptors Flk-1 and Flt-1 were increased in Trx1 overexpressed mice compared with their respective controls. Blood perfusion in the ischemic limb gradually improved and significantly recovered in Trx1Tg/+ and Ad-Trx1 groups compared with their corresponding controls. The capillary and arteriolar density in the ischemic zone were found to be higher in Trx1Tg/+ group compared with wild type. CONCLUSIONS: The overall outcomes of our study demonstrate that Trx1 enhances blood perfusion and increases angiogenic protein expression in a rodent HLI model. These results suggest that Trx1 is a potential target for clinical trials and drug therapy for the treatment of PVD.

RNA polymerase 1-driven transcription as a mediator of BDNF-induced neurite outgrowth.

Neurite outgrowth is essential for development of the nervous system. Neurotrophins including BDNF are among extracellular signals that regulate neurite outgrowth. The ERK1/2 pathway contributes to intracellular signaling networks transducing the pro-neuritic effects of BDNF. In the nucleolus, RNA polymerase-1 (Pol1)-mediated transcription regulates ribosomal biogenesis, enabling cellular protein synthesis and growth. Hence, we tested the possibility that Pol1 is an effector for pro-neuritic signals such as BDNF. We report that Pol1-mediated nucleolar transcription was increased by BDNF in an ERK1/2-dependent manner in rat forebrain neurons. Conversely, in cultured hippocampal neurons, knockdown of a Pol1 coactivator, transcription initiation factor 1A (TIF1A), attenuated BDNF- or ERK1/2-induced neurite outgrowth. Also, upon overexpression, a constitutively active mutant of TIF1A strongly promoted neurite outgrowth, including increases in total neurite length and branching. Finally, overexpression of wild-type TIF1A enhanced the pro-neuritic effects of ERK1/2 activation. These observations indicate that the Pol1-mediated nucleolar transcription regulates neurite outgrowth and serves as a major pro-neuritic effector of the BDNF-activated ERK1/2 pathway. Thus, development of the nervous system appears critically dependent on the nucleolus.

Significance of comprehensive surgical staging in noninvasive papillary serous carcinoma of the endometrium.

OBJECTIVE: To evaluate the biological behavior of noninvasive papillary serous carcinoma of the endometrium. METHODS; From 1990 to 2001, all women with noninvasive uterine papillary serous carcinoma (UPSC) at three Southern California hospitals were identified from tumor registry databases. Data for analysis were collected from hospital charts, office records, and tumor registry files. RESULTS: Of the 100 patients diagnosed with UPSC, 16 had noninvasive lesions. Twelve underwent a comprehensive surgical staging procedure with omental resection. Six of these 12 women were found to have disease beyond the uterine corpus, including 4 with adnexal involvement, 3 with omental disease, 2 with cervical extension, 1 with pelvic lymph node involvement, and 3 with positive washings. Three women were found to have positive cytology and metastases in more than one location. Of the 12 patients, 1 of the 6 with stage IA disease had distant recurrence and 4 of the 6 with stage II-IV disease recurred. Of the remaining 4 patients who underwent a staging procedure without pathologic omental assessment, 1 was found to have cervical extension. In these 4 women, 1 with stage IA disease recurred. CONCLUSION: The typical patterns of spread and prognostic factors for endometrioid carcinoma of the uterus do not apply to UPSC. In our series, omental assessment was necessary to detect the 25% of patients with stage IVB disease due to omental involvement. Thus, women with noninvasive UPSC should undergo a comprehensive staging procedure including omental sampling to determine the extent of disease.