Ash1 l loss-of-function results in structural birth defects and altered cortical development.

The histone methyltransferase ASH1L plays a crucial role in regulating gene expression across various organ systems during development, yet its role in brain development remains largely unexplored. Over 130 individuals with autism harbour heterozygous loss-of-function ASH1L variants, and population studies confirm it as a high-risk autism gene. Previous studies on Ash1 l deficient mice have reported autistic-like behaviours and provided insights into the underlying neuropathophysiology. In this study, we used mice with a cre-inducible deletion of Ash1 l exon 4, which results in a frame shift and premature stop codon (p.V1693Afs*2). Our investigation evaluated the impact of Ash1 l loss-of-function on survival and craniofacial skeletal development. Using a tamoxifen-inducible cre strain, we targeted Ash1 l knockout early in cortical development (Emx1-Cre-ERT2; e10.5). Immunohistochemistry was utilized to assess cortical lamination, while EdU incorporation aided in birthdating cortical neurons. Additionally, single-cell RNA sequencing was employed to compare cortical cell populations and identify genes with differential expression. At e18.5, the proportion of homozygous Ash1 l germline knockout embryos appeared normal; however, no live Ash1 l null pups were present at birth (e18.5: n = 77, P = 0.90; p0: n = 41, P = 0.00095). Notably, Ash1l-/- exhibited shortened nasal bones (n = 31, P = 0.017). In the cortical-specific knockout model, SATB2 neurons showed increased numbers (n = 6/genotype, P = 0.0001) and were distributed through the cortical plate. Birthdating revealed generation of ectopically placed deep layer neurons that express SATB2 (e13.5 injection: n = 4/genotype, P = 0.0126). Single cell RNA sequencing revealed significant differences in gene expression between control and mutant upper layer neurons, leading to distinct clustering. Pseudotime analysis indicated that the mutant cluster followed an altered cell differentiation trajectory. This study underscores the essential role of Ash1 l in postnatal survival and normal craniofacial development. In the cortex, ASH1L exerts broad effects on gene expression and is indispensable for determining the fate of upper layer cortical neurons. These findings provide valuable insights into the potential mechanisms of ASH1L neuropathology, shedding light on its significance in neurodevelopmental disorders like autism.

Development and Pilot Testing of a Programmatic System for Competency Assessment in US Anesthesiology Residency Training.

BACKGROUND: In 2018, a set of entrustable professional activities (EPAs) and procedural skills assessments were developed for anesthesiology training, but they did not assess all the Accreditation Council for Graduate Medical Education (ACGME) milestones. The aims of this study were to (1) remap the 2018 EPA and procedural skills assessments to the revised ACGME Anesthesiology Milestones 2.0, (2) develop new assessments that combined with the original assessments to create a system of assessment that addresses all level 1 to 4 milestones, and (3) provide evidence for the validity of the assessments. METHODS: Using a modified Delphi process, a panel of anesthesiology education experts remapped the original assessments developed in 2018 to the Anesthesiology Milestones 2.0 and developed new assessments to create a system that assessed all level 1 through 4 milestones. Following a 24-month pilot at 7 institutions, the number of EPA and procedural skill assessments and mean scores were computed at the end of the academic year. Milestone achievement and subcompetency data for assessments from a single institution were compared to scores assigned by the institution's clinical competency committee (CCC). RESULTS: New assessment development, 2 months of testing and feedback, and revisions resulted in 5 new EPAs, 11 nontechnical skills assessments (NTSAs), and 6 objective structured clinical examinations (OSCEs). Combined with the original 20 EPAs and procedural skills assessments, the new system of assessment addresses 99% of level 1 to 4 Anesthesiology Milestones 2.0. During the 24-month pilot, aggregate mean EPA and procedural skill scores significantly increased with year in training. System subcompetency scores correlated significantly with 15 of 23 (65.2%) corresponding CCC scores at a single institution, but 8 correlations (36.4%) were <30.0, illustrating poor correlation. CONCLUSIONS: A panel of experts developed a set of EPAs, procedural skill assessment, NTSAs, and OSCEs to form a programmatic system of assessment for anesthesiology residency training in the United States. The method used to develop and pilot test the assessments, the progression of assessment scores with time in training, and the correlation of assessment scores with CCC scoring of milestone achievement provide evidence for the validity of the assessments.

Delayed Tension Symptomatic Pneumoperitoneum After POEM Requiring Needle Decompression.

INTRODUCTION: Per-oral endoscopic myotomy (POEM) is an effective modality for the management of achalasia. Tension pneumoperitoneum is a significant complication that causes hemodynamic instability, generally within the periprocedural period. METHODS: Here, we report 2 cases of delayed tension pneumoperitoneum that was recognized and treated several hours after uncomplicated POEM. RESULTS: These cases illustrate the importance of continued vigilance for this complication outside of the immediate periprocedural period as well as the utility of computed tomography-guided aspiration in managing it. DISCUSSION: When discharging patients after POEM, caregivers should be aware of this rare complication and alert patients to return for immediate care when it happens.

Development and Pilot Testing of Entrustable Professional Activities for US Anesthesiology Residency Training.

BACKGROUND: Modern medical education requires frequent competency assessment. The Accreditation Council for Graduate Medical Education (ACGME) provides a descriptive framework of competencies and milestones but does not provide standardized instruments to assess and track trainee competency over time. Entrustable professional activities (EPAs) represent a workplace-based method to assess the achievement of competency milestones at the point-of-care that can be applied to anesthesiology training in the United States. METHODS: Experts in education and competency assessment were recruited to participate in a 6-step process using a modified Delphi method with iterative rounds to reach consensus on an entrustment scale, a list of EPAs and procedural skills, detailed definitions for each EPA, a mapping of the EPAs to the ACGME milestones, and a target level of entrustment for graduating US anesthesiology residents for each EPA and procedural skill. The defined EPAs and procedural skills were implemented using a website and mobile app. The assessment system was piloted at 7 anesthesiology residency programs. After 2 months, faculty were surveyed on their attitudes on usability and utility of the assessment system. The number of evaluations submitted per month was collected for 1 year. RESULTS: Participants in EPA development included 18 education experts from 11 different programs. The Delphi rounds produced a final list of 20 EPAs, each differentiated as simple or complex, a defined entrustment scale, mapping of the EPAs to milestones, and graduation entrustment targets. A list of 159 procedural skills was similarly developed. Results of the faculty survey demonstrated favorable ratings on all questions regarding app usability as well as the utility of the app and EPA assessments. Over the 2-month pilot period, 1636 EPA and 1427 procedure assessments were submitted. All programs continued to use the app for the remainder of the academic year resulting in 12,641 submitted assessments. CONCLUSIONS: A list of 20 anesthesiology EPAs and 159 procedural skills assessments were developed using a rigorous methodology to reach consensus among education experts. The assessments were pilot tested at 7 US anesthesiology residency programs demonstrating the feasibility of implementation using a mobile app and the ability to collect assessment data. Adoption at the pilot sites was variable; however, the use of the system was not mandatory for faculty or trainees at any site.

Histone H2A Monoubiquitination in Neurodevelopmental Disorders.

Covalent histone modifications play an essential role in gene regulation and cellular specification required for multicellular organism development. Monoubiquitination of histone H2A (H2AUb1) is a reversible transcriptionally repressive mark. Exchange of histone H2A monoubiquitination and deubiquitination reflects the succession of transcriptional profiles during development required to produce cellular diversity from pluripotent cells. Germ-line pathogenic variants in components of the H2AUb1 regulatory axis are being identified as the genetic basis of congenital neurodevelopmental disorders. Here, we review the human genetics findings coalescing on molecular mechanisms that alter the genome-wide distribution of this histone modification required for development.

Pediatric sleep-disordered breathing: an update on diagnostic testing.

PURPOSE OF REVIEW: Recent advances in diagnostic testing for obstructive sleep apnea in children have refined the standard tests while identifying several new tools that hold promise to radically change how we diagnose sleep apnea. RECENT FINDINGS: Studies have demonstrated that the polysomnogram may be modified to permit home assessment of sleep disturbed breathing in children to ensure more widespread access to the test. Alternately, questionnaires, nocturnal oximetry, and diagnostic urinary biomarkers have shown great promise as both sensitive and specific tools to diagnose sleep apnea in children as well as track the severity of the disease. SUMMARY: The gold standard polysomnogram has been refined to permit its application in a modified form at home and for brief examinations in children. This standard has been challenged on several fronts, including questionnaires, nocturnal oximetry, drug-induced sleep endoscopy, and noninvasive urinary biomarkers that may ultimately supplant polysomnography as the gold standard to diagnose obstructive sleep apnea syndrome in children.

Abnormal Glucose Tolerance in Women Diagnosed With Gestational Diabetes (WHO 2013) 10 Years After Index Pregnancy.

Context: It is not clear if the risk of abnormal glucose tolerance (AGT) is attenuated in the long-term in women diagnosed with gestational diabetes (GDM) using the World Health Organization (WHO) 2013 criteria and who have received appropriate treatment during pregnancy. Objective: We aimed to assess the long-term prevalence of AGT and other cardiovascular disease (CVD) risk factors in this cohort. Methods: A retrospective cohort follow-up study was conducted of 37 and 107 women diagnosed with and without GDM respectively using the WHO 2013 criteria between June 2010 and December 2010. Women were invited to attend our center, where they underwent a 75-g oral glucose tolerance test, blood and urine collection, body measurements, and electrocardiography. Main outcome measure included the development of AGT using the American Diabetes Association criteria. Results: Sixteen (43.2%) women with GDM compared to 5 (4.7%) women with normal glucose tolerance (NGT) at index pregnancy had AGT (P < .001). In the GDM group, 10 (27.0%), 7 (18.9%), and 4 (10.8%) women had impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and type 2 diabetes mellitus (T2DM), respectively. In the NGT group, 2 (1.9%), 3 (2.8%), and 1 (0.9%) woman had IFG, IGT, and T2DM, respectively. Women with AGT also had an unfavorable metabolic profile including obesity, hypertension, insulin resistance, and dyslipidemia. Conclusion: Women treated for GDM (WHO 2013 criteria) remain at increased risk for developing AGT and adverse CVD risk factors as early as a decade after diagnosis. Continued efforts are needed to accurately follow this population to address modifiable risk factors.

Assessment of Coronary Stenoses for Percutaneous Coronary Intervention: A Systematic Review and Network Meta-Analysis of Randomized Trials.

Evidence regarding the comparative efficacy of the different methods to determine the significance of coronary stenoses in the catheterization laboratory is lacking. We aimed to compare all available methods guiding the decision to perform percutaneous coronary intervention (PCI). We searched Medline, Embase, and CENTRAL until October 5, 2023. We included trials that randomized patients with greater than 30% stenoses who were considered for PCI and reported major adverse cardiovascular events (MACE). We performed a frequentist random-effects network meta-analysis and assessed the certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. We included 15 trials with 16,333 participants with a mean weighted follow-up of 34 months. The trials contained a median of 49.3% (interquartile range: 32.6%, 100%) acute coronary syndrome participants. Quantitative flow ratio (QFR) was associated with a decreased risk of MACE compared with coronary angiography (CA) (risk ratio [RR] 0.68, 95% confidence interval [CI] 0.56 to 0.82, high certainty), fractional flow reserve (FFR) (RR 0.73, 95% CI 0.58 to 0.92, moderate certainty), and instantaneous wave-free ratio (iFR) (RR 0.63, 95% CI 0.49 to 0.82, moderate certainty), and ranked first for MACE (88.1% probability of being the best). FFR (RR 0.93, 95% CI 0.82 to 1.06, moderate certainty) and iFR (RR 1.07, 95% CI 0.90 to 1.28, moderate certainty) likely did not decrease the risk of MACE compared with CA. Intravascular imaging may not be associated with a significant decrease in MACE compared with CA (RR 0.85, 95% CI 0.62 to 1.17, low certainty) when used to guide the decision to perform PCI. In conclusion, a decision to perform PCI based on QFR was associated with a decreased risk of MACE compared with CA, FFR, and iFR in a mixed stable coronary disease and acute coronary syndrome population. These hypothesis-generating findings should be validated in large, randomized, head-to-head trials.

Bone cancer.

Primary bone cancers are extremely rare neoplasms, accounting for fewer than 0.2% of all cancers. The evaluation and treatment of patients with bone cancers requires a multidisciplinary team of physicians, including musculoskeletal, medical, and radiation oncologists, and surgeons and radiologists with demonstrated expertise in the management of these tumors. Long-term surveillance and follow-up are necessary for the management of treatment late effects related to surgery, radiation therapy, and chemotherapy. These guidelines discuss the management of chordoma, giant cell tumor of the bone, and osteosarcoma.

Changing epidemiology of acute appendicitis in the United States: study period 1993-2008.

BACKGROUND: Addis et al. [5] described the epidemiology of appendicitis in the United States from 1970 to 1984. He reported that while overall incidence decreased, the highest incidence of appendicitis occurred in 10- to 19-y-olds. This study examines if the incidence of appendicitis and mean age of diagnosis has changed, and whether demographics are related to the frequency of admissions and incidence rate of acute appendicitis (AA). MATERIALS AND METHODS: Study questions were assessed using the Nationwide Inpatient Sample (NIS) discharge data and US Census data from 1993-2008. Operatively managed, uncomplicated, and complex cases of AA were included. Incidental appendectomy and right hemicolectomy were excluded. Descriptive, ANOVA, χ(2), and test of proportion statistics were used to evaluate frequency of admissions, incidence rate, and demographic changes in appendicitis. RESULTS: The annual rate of AA increased from 7.62 to 9.38 per 10,000 between 1993 and 2008. The highest frequency of AA was found in the 10-19 y age group, however occurrence in this group decreased by 4.6%. Persons between ages 30 and 69 y old experienced an increase of AA by 6.3%. AA rates remained higher in males. Hispanics, Asians, and Native Americans saw a rise in the frequency of AA, while the frequencies among Whites and Blacks decreased. CONCLUSIONS: While AA is most common in persons 10- to 19-y old, the mean age at diagnosis has increased over time. Minorities are experiencing an increase in the frequency of appendicitis. The changing demographics of the US plays a role in the current epidemiology of appendicitis, but is not solely responsible for the change observed.

Clostridioides difficile toxin is infrequently detected in inflammatory bowel disease and does not associate with clinical outcomes.

INTRODUCTION: Clostridioides difficile infection (CDI) rates and outcomes can vary based on differences in testing strategy. Our aim was to assess the prevalence of toxin detection in inflammatory bowel disease (IBD) when compared to those without IBD. Secondly, the clinical outcomes of CDI in IBD were assessed using two-step testing strategies. METHODS: We included patients undergoing CDI testing from four academic centers in the United States between January 1, 2018 and June 30, 2020. First the prevalence of toxin detection was compared between individuals with IBD and those without IBD. Secondly, among patients with IBD a primary composite outcome of abdominal colectomy, admission to an intensive care unit (ICU) or death within 30 days of C. difficile testing was assessed across the three categorical groups (screen positive/toxin positive, screen positive/toxin negative and screen negative assay) resulting from the two-step testing strategy. RESULTS: When comparing individuals with a positive screening assay, patients with IBD were less likely to have toxin detected by enzyme immunoassay (EIA) as compared to the non-IBD population (22/145 (15.2%) vs. 413/1144 (36.1%), p < 0.0001). Among all patients with IBD (n = 300), twenty-five (8.3%) had a screen positive assay/toxin positive assay, 136 (45.3%) had a screen positive/toxin negative assay and 139 (46.3%) had a negative screening assay. No significant difference in the primary composite outcome was detected across the three groups (p = 0.566). CONCLUSION: When compared to those without IBD, patients with IBD have a reduced proportion of cases of C. difficile with toxin positivity. Differences in clinical outcomes among patients with IBD were not detected and limited by the infrequent detection of expressed toxin.

Economics of appendicitis: cost trend analysis of laparoscopic versus open appendectomy from 1998 to 2008.

BACKGROUND: Laparoscopic appendectomy (LA) has become more acceptable for the treatment of appendicitis over the last decade; however, its cost benefit compared to open appendectomy (OA) remains under debate. The purpose of this study is to evaluate the utilization of LA and its cost effectiveness based on total hospital charges stratified by complexity of disease and complications compared to OA. MATERIAL AND METHODS: Nationwide Inpatient Sample data from 1998 to 2008 with the principal diagnosis of appendicitis were included. Appendicitis cases were divided by simple and complex (peritonitis or abscess) and subdivided by OA, LA, and lap converted to open (CONV). Total charges (2008 value), length of stay (LOS), and complications were assessed by disease presentation and operative approach. RESULTS: Between 1998 and 2008, 1,561,518 (54.3%) OA, 1,231,643 (42.8%) LA, and 84,662 (2.9%) CONV appendectomies were performed. LA had shorter LOS (2 d) than OA (3 d) and CONV (5 d) (P<0.001). CONV (7.4%) cases had more complications than OA (3.7%) and LA (2.6%). LA ($19,978) and CONV ($28,103) are costlier than OA ($15,714) based on normalized cost for simple and complex diseases (P<0.001). CONCLUSIONS: LA is more prevalent but its cost is higher in both simple and complex cases. Cost and complications increase if the case is converted to open. OA remains the most cost effective approach for patients with acute appendicitis.

Urban ecological systems: scientific foundations and a decade of progress.

Urban ecological studies, including focus on cities, suburbs, and exurbs, while having deep roots in the early to mid 20th century, have burgeoned in the last several decades. We use the state factor approach to highlight the role of important aspects of climate, substrate, organisms, relief, and time in differentiating urban from non-urban areas, and for determining heterogeneity within spatially extensive metropolitan areas. In addition to reviewing key findings relevant to each state factor, we note the emergence of tentative "urban syndromes" concerning soils, streams, wildlife and plants, and homogenization of certain ecosystem functions, such as soil organic carbon dynamics. We note the utility of the ecosystem approach, the human ecosystem framework, and watersheds as integrative tools to tie information about multiple state factors together. The organismal component of urban complexes includes the social organization of the human population, and we review key modes by which human populations within urban areas are differentiated, and how such differentiation affects environmentally relevant actions. Emerging syntheses in land change science and ecological urban design are also summarized. The multifaceted frameworks and the growing urban knowledge base do however identify some pressing research needs.

Transcatheter Aortic Valve Replacement With the LOTUS Edge System: Early European Experience.

OBJECTIVES: The aim of this study was to evaluate the short-term safety and efficacy of transcatheter aortic valve replacement (TAVR) with the LOTUS Edge system. BACKGROUND: The LOTUS Edge system was commercially re-released in April 2019. The authors report the first European experience with this device. METHODS: A multicenter, single-arm, retrospective registry was initiated to evaluate short-term clinical outcomes. Included cases are the first experience with this device and new implantation technique in Europe. Clinical, echocardiographic, and computed tomographic data were analyzed. Endpoints were defined according to Valve Academic Research Consortium-2 and were site reported. RESULTS: Between April and November 2019, 286 consecutive patients undergoing TAVR with the LOTUS Edge system at 18 European centers were included. The mean age and Society of Thoracic Surgeons score were 81.2 ± 6.9 years and 5.2 ± 5.4%, respectively. Nearly one-half of all patients (47.9%) were considered to have complex anatomy. Thirty-day major adverse events included death (2.4% [n = 7]) and stroke (3.5% [n = 10]). After TAVR, the mean aortic valve area was 1.9 ± 0.9 cm2, and the mean transvalvular gradient was 11.9 ± 5.7 mm Hg. None or trace paravalvular leak (PVL) occurred in 84.4% and moderate PVL in 2.0%. There were no cases of severe PVL. New permanent pacemaker (PPM) implantation was required in 25.9% among all patients and 30.8% among PPM-naive patients. CONCLUSIONS: Early experience with the LOTUS Edge system demonstrated satisfactory short-term safety and efficacy, favorable hemodynamic data, and very low rates of PVL in an anatomically complex cohort. New PPM implantation remained high. Further study will evaluate if increasing operator experience with the device and new implantation technique can reduce the incidence of PPM implantation.

Giant clear cell hidradenoma of the knee.

Hidradenomas, also referred to as nodular hidradenomas or clear cell hidradenomas (CCH), are benign cutaneous eccrine tumors usually 2-3 cm in dimension. Hidradenomas are relatively common; however, giant forms are rare. We report a case of an 8.0 x 6.0 x 3.0 cm clear cell hidradenoma of the left knee in a 43-year-old man. The tumor was mobile, located above the patellar tendon and was without bony involvement on imaging studies. Grossly, the resected tumor was unencapsulated and tan, with a solid and cystic cut surface showing papillary excrescences on the cyst wall. Microscopically, the tumor cells showed an infiltrative growth pattern at the periphery, however, the tumor cytology was bland and no necrosis or mitoses were identified. The overlying dermis contained hemosiderin pigment deposition and infiltration with eosinophils. Immunohistochemically, tumor cells were positive for cytokeratin, CAM5.2, p53, carcino-embryonic antigen (CEA) and epithelial membrane antigen (EMA), and negative for CD10 and Ki-67. The cytological features of hidradenomas can present diagnostic challenges, as other 'clear cell' tumors such as metastatic renal cell carcinoma should be considered. Immunohistochemical studies and differential diagnoses are discussed.

Isolated Diastolic Hypertension in the UK Biobank: Comparison of ACC/AHA and ESC/NICE Guideline Definitions.

The 2017 American College of Cardiology/American Heart Association guideline defines hypertension as a blood pressure ≥130/80 mm Hg, whereas the 2018 European Society of Cardiology (ESC) and 2019 National Institute for Health and Care Excellence (NICE) guidelines use a ≥140/90 mm Hg threshold. Our objective was to study the associations between isolated diastolic hypertension (IDH), diagnosed using these 2 blood pressure thresholds, and cardiovascular disease (CVD) in a large cohort of UK adults. We analyzed data from UK Biobank, which enrolled participants between 2006 and 2010 with follow-up through March 2019. We excluded persons with systolic hypertension or baseline CVD. We defined incident CVD as a composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. We used Cox regression to quantify associations between IDH and CVD, as well as the individual outcomes included in the composite outcome. We studied 151 831 participants with normal systolic blood pressure (mean age 54 years, 40% male). Overall, 24.5% had IDH by the American College of Cardiology/American Heart Association definition compared with 6% by the ESC/NICE definition. Compared with normal diastolic blood pressure, IDH by the American College of Cardiology/American Heart Association definition was not significantly associated with CVD risk (hazard ratio, 1.08 [95% CI, 0.98-1.18]) whereas IDH by the ESC/NICE definition was significantly associated with a modest increase in CVD (hazard ratio, 1.15 [95% CI, 1.04-1.29]). Similar results were found by sex and among participants not taking baseline antihypertensives. Furthermore, neither IDH definition was associated with the individual outcomes of nonfatal myocardial infarction or stroke. In conclusion, the proportion of UK Biobank participants with IDH was significantly higher by the American College of Cardiology/American Heart Association definition compared with the ESC/NICE definitions; however, only the ESC/NICE definition was statistically associated with increased CVD risk.

Spread of squamous cell carcinoma from the thumb to the small finger via the flexor tendon sheaths.

We report the development of metastatic squamous cell carcinoma at the tip of the small finger following the development of a thumb distal phalanx squamous cell carcinoma caused by chronic osteomyelitis. The spread of hand infections from the flexor tendons of the thumb to the small finger through a tendon sheath connection at the wrist is a well-described phenomenon. The evidence from this case suggests that the spread of the squamous cell carcinoma from the tip of the thumb to the tip of the small finger occurred in a similar fashion. This information is important in understanding how malignant tumors spread in the hand and wrist, and it might influence the management of such tumors.

Safe angle for suture anchor insertion during acetabular labral repair.

PURPOSE: The purpose of this study was to define a safe angle for suture anchor insertion during acetabular labral repair that will facilitate anchor placement within bone and prevent penetration into the hip joint. METHODS: Nine acetabuli were harvested. Anatomic measurements were performed at the anterosuperior quadrant. Electronic calipers were used to measure acetabular bone. "Safe angle" measurements were obtained with suture anchor drills and a protractor. Comparisons between groups were calculated with a 1-way analysis of variance. The Tukey post-hoc analysis was completed for all significant analysis of variance results. RESULTS: Labral insertion point distances and acetabular bone widths at the labral insertion did not statistically differ. Mean "danger angles" ranged from 17.0 degrees to 23.8 degrees. Safe angle measurements ranged from 20.1 degrees to 27.6 degrees. CONCLUSIONS: The extracapsular labral insertion, located between 2.3 and 2.6 mm from the rim of the anterosuperior acetabulum, is offered as a starting point for insertion of anchors sized less than 3.0 mm. The danger angle and safe angle of anchor insertion serve as guidelines that may improve fixation in bone and lessen intra-articular penetration. A target angle of 10 degrees is recommended. CLINICAL RELEVANCE: The danger angle and safe angle may be referenced intraoperatively, during imaging and suture anchor insertion, to assure anchor placement within bone and prevent intra-articular penetration. A target angle of 10 degrees is safe and easily remembered.

LMWF-5A for the Treatment of Severe Osteoarthritis of the Knee: Integrated Analysis of Safety and Efficacy.

The low-molecular-weight fraction of 5% human serum albumin (LMWF-5A) is being developed to treat the signs and symptoms of severe osteoarthritis of the knee. This study was a post hoc pooled analysis of 3 randomized placebo-controlled trials of a single intra-articular injection of LMWF-5A, focusing on the subset of patients with severe osteoarthritis of the knee (Kellgren-Lawrence grade 4). Patients were randomized 1:1 to receive a single 4-mL intra-articular knee injection of either LMWF-5A or saline. Safety was assessed as the incidence and severity of adverse events. Efficacy was assessed as the change from baseline to week 12 on the Western Ontario and McMaster Universities Osteoarthritis Index pain (primary outcome), stiffness, and physical function subscores and on patient global assessment scores and was presented as the least squares mean difference and 95% confidence interval. The proportion of responders was defined with the Outcome Measures in Rheumatology-Osteoarthritis Research Society International criteria for scenario D and examined with Pearson's chi-square test. For 417 patients with severe osteoarthritis of the knee, treatment with LMWF-5A resulted in a significant decrease in pain at 12 weeks compared with saline (mean difference, -0.19; 95% confidence interval, -0.34 to -0.04; P=.016), with improvements in function (mean difference, -0.15; 95% confidence interval, -0.31 to 0.01) and patient global assessment (mean difference, -0.30; 95% confidence interval, -0.49 to -0.12) and higher responder rates (64.25% vs 50.90%, P=.006). No drug-related serious adverse events and no deaths occurred, and the incidence and severity of adverse events were similar across treatment groups. This pooled analysis supports the use of LMWF-5A as a safe therapeutic agent for relief of the signs and symptoms of severe osteoarthritis of the knee. [Orthopedics. 2018; 41(1):e77-e83.].