Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor.

KRASG12C was recently identified to be potentially druggable by allele-specific covalent targeting of Cys-12 in vicinity to an inducible allosteric switch II pocket (S-IIP). Success of this approach requires active cycling of KRASG12C between its active-GTP and inactive-GDP conformations as accessibility of the S-IIP is restricted only to the GDP-bound state. This strategy proved feasible for inhibiting mutant KRAS in vitro; however, it is uncertain whether this approach would translate to in vivo. Here, we describe structure-based design and identification of ARS-1620, a covalent compound with high potency and selectivity for KRASG12C. ARS-1620 achieves rapid and sustained in vivo target occupancy to induce tumor regression. We use ARS-1620 to dissect oncogenic KRAS dependency and demonstrate that monolayer culture formats significantly underestimate KRAS dependency in vivo. This study provides in vivo evidence that mutant KRAS can be selectively targeted and reveals ARS-1620 as representing a new generation of KRASG12C-specific inhibitors with promising therapeutic potential.

Pharmacological expansion of type 2 alveolar epithelial cells promotes regenerative lower airway repair.

Type 2 alveolar epithelial cells (AEC2s) are stem cells in the adult lung that contribute to lower airway repair. Agents that promote the selective expansion of these cells might stimulate regeneration of the compromised alveolar epithelium, an etiology-defining event in several pulmonary diseases. From a high-content imaging screen of the drug repurposing library ReFRAME, we identified that dipeptidyl peptidase 4 (DPP4) inhibitors, widely used type 2 diabetes medications, selectively expand AEC2s and are broadly efficacious in several mouse models of lung damage. Mechanism of action studies revealed that the protease DPP4, in addition to processing incretin hormones, degrades IGF-1 and IL-6, essential regulators of AEC2 expansion whose levels are increased in the luminal compartment of the lung in response to drug treatment. To selectively target DPP4 in the lung with sufficient drug exposure, we developed NZ-97, a locally delivered, lung persistent DPP4 inhibitor that broadly promotes efficacy in mouse lung damage models with minimal peripheral exposure and good tolerability. This work reveals DPP4 as a central regulator of AEC2 expansion and affords a promising therapeutic approach to broadly stimulate regenerative repair in pulmonary disease.

Geriatric Dermatologic Surgery Part I: Frailty assessment and palliative treatments in the geriatric dermatology population.

Longer life expectancy and increasing keratinocyte carcinoma incidence contribute to an increase in geriatric patients presenting for dermatologic surgery. Unique considerations accompany geriatric patients including goals of care, physiologic changes in medication metabolism, cognitive decline, and frailty. Limited geriatric training in dermatology residency has created a knowledge gap and dermatologic surgeons should be familiar with challenges facing older patients to provide interventions more congruent with goals and avoid overtreatment. Frailty assessments including the Geriatric 8 and Karnofsky Performance Scale are efficient tools to identify patients who are at risk for poor outcomes and complications. When frail patients are identified, goals of care discussions can be aided using structured palliative care frameworks including the 4Ms, REMAP, and Serious Illness Conversation Guide. Most geriatric patients will tolerate standard of care treatments including invasive modalities like Mohs surgery and excision. However, for frail patients, non-standard treatments including topicals, energy-based devices, and intralesional chemotherapy may be appropriate options to limit patient morbidity while offering reasonable disease control.

Geriatric Dermatologic Surgery Part II: Peri and intraoperative considerations in the geriatric dermatologic surgery patient.

Geriatric patients compose a growing proportion of the dermatologic surgical population. Dermatologists and dermatologic surgeons should be cognizant of the unique physiologic considerations that accompany this group to deliver highly effective care. The purpose of this article is to discuss the unique preoperative, intraoperative, and postoperative considerations geriatric patients present with to provide goal-concordant care. Preoperative considerations include medication optimization and anxiolysis. Intraoperative considerations such as fall-risk assessment and prevention, sundowning, familial support, and pharmacologic interactions will be discussed. Lastly, effective methods for optimizing post-operative wound care, home care, and follow up are reviewed.

Adult versus adolescent idiopathic scoliosis surgery: a meta-analysis of clinical and radiographic outcomes.

INTRODUCTION: While the natural history of adolescent idiopathic scoliosis (AIS) and adult idiopathic scoliosis (AdIS) is well documented in the literature, the impact of age on postoperative outcomes remains an active area of research. We performed a systematic review and meta-analysis to compare patients undergoing surgery for AIS and AdIS with respect to: (1) postoperative Cobb correction, (2) perioperative variables, and (3) postoperative complications. METHODS: A systematic literature search was performed in accordance with preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. INCLUSION CRITERIA: studies published between 2002 and 2022, retrospective, and comparing AIS vs. AdIS patients undergoing deformity surgery. The primary outcome was postoperative Cobb correction. Secondary outcomes included estimated blood loss (EBL), operative time, total instrumented levels, length of stay (LOS), and postoperative complications. Random-effects models were performed according to the method of DerSimonian and Laird. RESULTS: Of 190 identified articles, 14 fit the inclusion criteria. A total of 1788 patients were included, 1275(71.3%) with AIS, and 513(28.7%) with AdIS. There was a significant age difference between AIS and AdIS (15.3 vs. 36.7 years, mean difference (MD) = 21.3 years, 95%CI = 14.3-28.4,p < 0.001). Mean postoperative Cobb percentage correction was reported in 5 articles and was significantly higher in AIS (68.4%) vs. AdIS (61.4%) (MD = -7.2, 95%CI = -11.6,-2.7,p = 0.001). EBL was not significantly different between AIS and AdIS (695.6 mL vs 817.7 mL,p = 0.204). Furthermore, no difference was found in operative time (MD = 37.9 min,95%CI = -10.7;86.6,p = 0.127), total instrumented level (MD = 0.88,95%CI = -0.7,2.4,p = 0.273), and LOS (MD = 0.5, 95%CI = -0.2;1.2, p = 0.188). Four articles reported postoperative complications in AIS vs AdIS, with no difference in neurological deficit, instrumentation-related complications, and medical complications. CONCLUSION: AIS patients had better radiographic correction compared to AdIS. Though no difference was found in perioperative outcomes and complications, these findings emphasize the importance of counseling patients regarding the optimal timing of surgical correction.

Melanoma Detected Through Teledermatology Versus In-Person Visits.

Background: Early detection of melanoma improves survival; however, patients face long wait times to receive dermatology care. Teledermatology (TD) is a promising tool to optimize access to care and has shown promise for the identification of malignancies but has not been well studied for melanoma. We evaluated the utility of TD as a triage tool to allow high-risk lesions of concern to be seen more expeditiously. Methods: Patient sociodemographic factors and histological characteristics of 836 melanomas biopsied between March 2020 and November 2022 in the University of Pittsburgh Medical Center health system were retrospectively evaluated, stratified by initial appointment type of TD versus in-person visit. Results: Patients first seeking care through teledermatology had shorter wait times to initial evaluation (p < 0.001) and eventual biopsy (p < 0.001), and these melanomas had higher Breslow thickness (p < 0.001), were more ulcerated (p = 0.002), invasive (p = 0.001), and of a more aggressive subtype (p = 0.007) than those initially evaluated in-person. TD was also utilized by a higher proportion of younger (p = 0.001) and non-white (p = 0.03) patients who identified their own lesion (p < 0.001). Conclusions: TD may be a strategy to improve melanoma outcomes by providing an accessible avenue of expedited care for high-risk lesions associated with worse clinical prognosticators of disease.

Descriptive and Concordance Data for Asynchronous Teledermatology Consultations for Dermatitis: A Retrospective Study.

Background: Implementation of teledermatology for assessing dermatitis patients provides comparable diagnostic and management outcomes to in-person visits, but studies on consumer to physician asynchronous teledermatology (eDerm) consults submitted by patients in large dermatitis cohorts are limited. The objective of this study was to retrospectively assess associations of eDerm consults with diagnostic accuracy, management, and follow-up in a large cohort of dermatitis patients. Methods: One thousand forty-five eDerm encounters between April 1, 2020, and October 29, 2021, recorded in the University of Pittsburgh Medical Center Health System Epic electronic medical record were reviewed. Descriptive statistics and concordance were analyzed using chi-square. Results: Asynchronous teledermatology modified/changed treatment in 97.6% of cases and had the same diagnosis between teledermatology and in-person follow-up in 78.3% of cases. Patients following up in the time line requested were more likely to follow-up in person (61.2% vs. 43.8%) than those who did not. Patients with intertriginous dermatitis (p = 0.003), preexisting conditions (p = 0.002), who required follow-ups (<0.0001), and moderate-high severity scores of 4-7 (p = 0.019) were more likely to follow up in the time line requested. Limitations: Lack of similar in-person visit data did not allow us to compare descriptive and concordance data between eDerm and clinic visits. Conclusions: eDerm offers a quick accessible solution to provide comparable dermatologic care for patients with dermatitis.

Robot-Assisted Versus Laparoscopic Distal Pancreatectomy in Patients with Resectable Pancreatic Cancer: An International, Retrospective, Cohort Study.

BACKGROUND: Robot-assisted distal pancreatectomy (RDP) is increasingly used as an alternative to laparoscopic distal pancreatectomy (LDP) in patients with resectable pancreatic cancer but comparative multicenter studies confirming the safety and efficacy of RDP are lacking. METHODS: An international, multicenter, retrospective, cohort study, including consecutive patients undergoing RDP and LDP for resectable pancreatic cancer in 33 experienced centers from 11 countries (2010-2019). The primary outcome was R0-resection. Secondary outcomes included lymph node yield, major complications, conversion rate, and overall survival. RESULTS: In total, 542 patients after minimally invasive distal pancreatectomy were included: 103 RDP (19%) and 439 LDP (81%). The R0-resection rate was comparable (75.7% RDP vs. 69.3% LDP, p = 0.404). RDP was associated with longer operative time (290 vs. 240 min, p < 0.001), more vascular resections (7.6% vs. 2.7%, p = 0.030), lower conversion rate (4.9% vs. 17.3%, p = 0.001), more major complications (26.2% vs. 16.3%, p = 0.019), improved lymph node yield (18 vs. 16, p = 0.021), and longer hospital stay (10 vs. 8 days, p = 0.001). The 90-day mortality (1.9% vs. 0.7%, p = 0.268) and overall survival (median 28 vs. 31 months, p = 0.599) did not differ significantly between RDP and LDP, respectively. CONCLUSIONS: In selected patients with resectable pancreatic cancer, RDP and LDP provide a comparable R0-resection rate and overall survival in experienced centers. Although the lymph node yield and conversion rate appeared favorable after RDP, LDP was associated with shorter operating time, less major complications, and shorter hospital stay. The specific benefits associated with each approach should be confirmed by multicenter, randomized trials.

Generalized pustular psoriasis: Quality and readability of online health information.

Generalized pustular psoriasis (GPP) is a multisystem disease with potentially life-threatening adverse effects. As patients increasingly seek health information online, and as the landscape for GPP changes, the quality of online health information (OHI) becomes progressively more important. This paper is the first of its kind to examine the quality, comprehensiveness and readability of online health information for GPP. Similar to pre-existing studies evaluating OHI, this paper examines 5 key search terms for GPP- 3 medical and 2 laymen. For each search term, the results were evaluated based on HONcode accreditation, an enhanced DISCERN analysis and a number of readability indices. Of the 500 websites evaluated, 84 (16.8%) were HONcode-accredited. Mean DISCERN scores of all websites were 74.9% and 38.6% for website reliability and treatment sections, respectively, demonstrating key gaps in comprehensiveness and reliability of GPP-specific OHI. Additionally, only 4/100 websites (4%) analysed for readability were written at the NIH-recommended sixth-grade level. Academic websites were significantly more difficult to read than governmental websites. This further exacerbates the patient information gap, particularly for patients with low health literacy, who may already be at higher risk of not receiving timely medical care.

High-frequency spinal cord stimulation (10 kHz) alters sensory function and nerve fiber density in painful diabetic neuropathy: a pilot prospective open-label study.

OBJECTIVE: Spinal cord stimulation at 10 kHz has provided effective pain relief and improved function in painful diabetic peripheral neuropathy. This study aims to confirm the clinical outcomes for 10-kHz spinal cord stimulation treatment of painful diabetic peripheral neuropathy and explore its impact on objective quantitative measures of nerve pathology and function. METHODS: This single-academic center, prospective, open-label, observational study examined the pain relief success of 10-kHz spinal cord stimulation in patients >18 years of age with diabetic peripheral neuropathy. Patients underwent skin biopsies to measure intra-epidermal nerve fiber densities and corneal confocal microscopy measurements before implantation and at the 3-, 6-, and 12-month follow-up visits. Numerical rating scale for pain, visual analog scale, neuropathy pain scale, Short Form-36, and Neuropen (pin prick and monofilament) assessments were also conducted. RESULTS: Eight patients met the criteria and were enrolled in the study. A successful trial was achieved in 7 subjects, and 6 completed the study. Significant pain relief (P < .001) was achieved at all follow-up visits. Neurological assessments showed reduced numbers of "absent" responses and increased "normal" responses from baseline to 12 months. Both proximal and distal intra-epidermal nerve fiber densities were higher at 12 months than at baseline (P < .01). Confocal microscopy measurements showed a steady increase in nerve density from baseline (188.8% increase at 12 months; P = .029). CONCLUSIONS: We observed pain relief and improvements in sensory function after stimulation that were accompanied by increases in lower-limb intra-epidermal nerve fiber density and corneal nerve density. Further evaluation with a blinded and controlled study is needed to confirm the preliminary findings in this study.

Lateral to Medial Joint Space Ratio is Predictive of Survivorship After Primary Hip Arthroscopy.

PURPOSE: To assess whether preoperative joint space measures would be predictive of survivorship in patients undergoing hip arthroscopy (HA) for femoroacetabular impingement (FAI). METHODS: Data on consecutive patients who underwent hip arthroscopy between February 2008 and February 2018 were retrospectively reviewed. To be eligible for final analysis, patients were required to have preoperative radiographs for joint space measurements and data indicating conversion to a total hip arthroplasty (THA), hip resurfacing, or neither; at a minimum of 2 years after primary hip arthroscopy. Survivorship following HA was defined as remaining conversion free and served as the primary outcome. A multivariate logistic regression analysis and receiver operator curve (ROC) were used to evaluate the correlation between joint space measurements and survivorship following HA. RESULTS: A total of 1,885 primary arthroscopy cases were included in this study. The multivariate regression analysis found preoperative lateral-to-medial joint space ratio (L/M ratio) to be the strongest predictive factor of survivorship after primary hip arthroscopy (OR = 2.084, CI95% = 1.239-3.503; P = .006). The ROC curve for the model demonstrated acceptable discrimination with an area under the curve (AUC) of 0.792. Patients with an L/M ratio ≥0.75 had a survivorship rate of 91.7% compared to a rate of 75% for patients with an L/M ratio <0.75 (OR: 3.68). CONCLUSIONS: This study found that, of the factors evaluated in this study, the most significant factor in predicting survivorship at 2 years after undergoing primary hip arthroscopy was a larger lateral-to-medial joint space ratio. This may suggest an initiation of primary arthritis at the edge-loading area of the lateral acetabulum. LEVEL OF EVIDENCE: III, retrospective comparative observation study.

Osteolysis Following the Use of Polyetheretherketone Suture Anchors in Hand and Wrist Surgery: A Preliminary Study.

PURPOSE: The objective of this study was to investigate and describe the presence of osteolysis after implantation of polyetheretherketone (PEEK) suture anchors in the hand and wrist. METHODS: Patients who underwent hand or wrist surgery using PEEK suture anchor(s) at a large academic institution from January 2019 to January 2021 were identified. Patients without accessible intraoperative fluoroscopic imaging were excluded. Patient demographics, type of procedure, and suture anchor material were recorded. The suture anchor tunnel size was measured on sequential radiographs and recorded as percentage change. Descriptive statistics were used to summarize findings. RESULTS: A total of 26 PEEK suture anchors in 14 patients were included, with an average follow-up of 12.0 months (range, 1.5-24.1 months). Twenty-seven percent of the anchors (7/26) demonstrated osteolysis at final follow-up, as defined by enlargement of tunnel size by >30%. In all anchors, the tunnel size increased by 19.1% on average (range, -7.7% to 56.1%) by final follow-up. CONCLUSIONS: Polyetheretherketone suture anchors may be associated with the development of osteolysis in hand and wrist surgery. The clinical implications of osteolysis in the smaller bones of the hand and wrist remain unclear. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV.

Spinal Cord Stimulator (SCS) Placement: Examining Outcomes Between the Open and Percutaneous Approach.

BACKGROUND: Spinal cord stimulator (SCS) placement has been gaining traction as an approach to modulate pain levels for several different chronic pain conditions. This procedure can be performed via a percutaneous or open approach. Data regarding SCS complications are relatively limited. OBJECTIVE: The purpose of this study was to leverage a large national database to examine outcomes between the percutaneous and open SCS placement approaches. Outcomes in this study include length of stay (LOS), complication rates, reoperation rates, and 1-year readmission rates. MATERIALS AND METHODS: Inclusion criteria for the current study is SCS placement between 2015 and 2020, with receipt of an SCS using either a percutaneous approach or an open laminectomy based approach. Encounters included were limited to true SCS placement, such that trial placements were not included in the study. Univariate statistics and multivariable logistic regression was performed to compare outcomes between cohorts. RESULTS: Total SCS case volumes were 9935 between the percutaneous (n = 4477, 45.1%) and open (n = 5458, 54.9%) approach. Patients receiving the percutaneous approach were found to have a mean decrease in LOS of 9.91 hours when compared to those receiving the open approach. The percutaneous approach was significantly associated with the need for reoperation within one year compared to the open approach (odds ratio [OR]: 0.663, p < 0.001), as well as with the need for readmission within 30 days (51.2% vs 40.2%, OR: 0.759, p < 0.001). CONCLUSION: The open approach, when compared to the percutaneous approach, had a longer mean LOS, lower outpatient discharge rates, and higher odds of experiencing an operative complication in comparison to the percutaneous approach. The percutaneous approach had relatively increased odds of thirty-day readmission, although no significant difference in one-year readmission or removal was demonstrated.

The Association of Psychiatric Comorbidities With Short-Term and Long-Term Outcomes Following Spinal Cord Stimulator Placement.

BACKGROUND: Outcomes after spinal cord stimulator (SCS) placement are affected by psychologic comorbidities. It is part of routine practice to do psychologic assessments prior to SCS trials to assess for the presence of maladaptive behavioral patterns. However, few studies have sought to quantify the effect of psychiatric comorbidities on complications, reoperation, and readmission rates. The purpose of this study was to assess the association of psychiatric comorbidities with postprocedural outcomes after SCS implantation. MATERIALS AND METHODS: Inclusion criteria included SCS placement between 2015 and 2020 (percutaneous approach or an open laminectomy-based approach) using Healthcare Corporation of America National Database. Data on psychiatric comorbidities present at the time of SCS implantation surgery were collected. Outcomes of interest included complication rates (defined as lead migration, fracture, malfunction, battery failure, postoperative pain, infection, dural puncture, or neurological injury), reoperation rates (defined as either revision or explant [ie, removal]), and readmission rates within 30-day and 1-year time after SCS implantation. We measured the association between psychiatric comorbidities and outcomes using multivariable regression and reported odds ratio (OR) and respective 95% confidence intervals. RESULTS: A total of 12,751 cases were included. The most common psychiatric comorbidities were major depressive disorder (16.1%) and anxiety disorder (13.4%). In unadjusted univariate analysis, patients with any psychiatric comorbidity had heightened rates of any complication (27.1% vs 19.4%), infection (5.9% vs 1.9%), lead displacement (2.2% vs 1.3%), surgical pain (2.1% vs 1.2%), explant (14.7% vs 8.8%), and readmission rates at one year (54.2% vs 33.8%) (all p < 0.001). In multivariable logistic regression, with each additional psychiatric comorbidity, a patient had increased odds of experiencing any complication (OR = 1.5, 95% CI = 1.36-1.57, p < 0.001), requiring a reoperation (OR = 1.5, 95% CI = 1.37-1.6, p < 0.001), and requiring readmission (OR = 1.7, 99% CI = 1.6-1.8, p < 0.001). CONCLUSIONS: The presence of psychiatric comorbidities was found to be associated with postoperative complication rates, reoperation, and readmission rates after SCS placement. Furthermore, each consecutive increase in psychiatric comorbidity burden was associated with increased odds of complications, reoperation, and readmission. Future studies might consider examining the role of presurgical mental health screening (ie, patient selection, psychologic testing) and treatment in optimizing outcomes for patients with psychiatric comorbidities.

Breastfeeding Outcome and Complications in Females With Breast Implants: A Systematic Review and Meta-Analysis.

Breast augmentation is a commonly performed cosmetic procedure. We set out to determine whether there was any effect on breastfeeding in females after breast implants. The aim of this study was to perform a systematic review and meta-analysis of the current evidence on breastfeeding outcome and complications in females with breast augmentation. A systematic review was performed utilizing MEDLINE, EMBASE, and all evidence-based medicine reviews from their respective inception dates to November 7, 2022, to assess outcomes of breastfeeding in females with breast implants (PROSPERO ID: CRD42022357909). This review was in accordance with both the Cochrane Handbook for Systematic Review of Interventions and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Eleven studies (4 prospective and 7 retrospective) in total were included in the review. A total of 8197 out of 9965 (82.25%) patients were successfully able to breastfeed after breast implants. Of 5 studies that included a control group, 343,793 of 388,695 (88.45%) women without breast implants successfully breastfed. A meta-analysis of 5 comparative studies showed a significant reduction of breastfeeding in females with breast implants, n = 393,686, pooled odds ratio = 0.45 (95% CI, 0.38 to 0.53). Complications described included pain, mastitis, insufficient or excessive lactation, and nipple inversion. There may be impairment in ability to breastfeed for females who receive breast implants when compared with those without. Additional studies on the topic are needed to further clarify the relationship.

Mycobacterium tuberculosis EspK Has Active but Distinct Roles in the Secretion of EsxA and EspB.

The Mycobacterium tuberculosis type-7 protein secretion system ESX-1 is a major driver of its virulence. While the functions of most ESX-1 components are characterized, many others remain poorly defined. In this study, we examined the role of EspK, an ESX-1-associated protein that is thought to be dispensable for ESX-1 activity in members of the Mycobacterium tuberculosis complex. We show that EspK is needed for the timely and optimal secretion of EsxA and absolutely essential for EspB secretion in M. tuberculosis Erdman. We demonstrate that only the EsxA secretion defect can be alleviated in EspK-deficient M. tuberculosis by culturing it in media containing detergents like Tween 80 or tyloxapol. Subcellular fractionation experiments reveal EspK is exported by M. tuberculosis in an ESX-1-independent manner and localized to its cell wall. We also show a conserved W-X-G motif in EspK is important for its interaction with EspB and enabling its secretion. The same motif, however, is not important for EspK localization in the cell wall. Finally, we show EspB in EspK-deficient M. tuberculosis tends to adopt higher-order oligomeric conformations, more so than EspB in wild-type M. tuberculosis. These results suggest EspK interacts with EspB and prevents it from assembling prematurely into macromolecular complexes that are presumably too large to pass through the membrane-spanning ESX-1 translocon assembly. Collectively, our findings indicate M. tuberculosis EspK has a far more active role in ESX-1-mediated secretion than was previously appreciated and underscores the complex nature of this secretion apparatus. IMPORTANCE Mycobacterium tuberculosis uses its ESX-1 system to secrete EsxA and EspB into a host to cause disease. We show that EspK, a protein whose role in the ESX-1 machinery was thought to be nonessential, is needed by M. tuberculosis for optimal EsxA and EspB secretion. Culturing EspK-deficient M. tuberculosis with detergents alleviates EsxA but not EspB secretion defects. We also show that EspK, which is exported by M. tuberculosis in an ESX-1-independent manner to the cell wall, interacts with and prevents EspB from assembling into large structures inside the M. tuberculosis cell that are nonsecretable. Collectively, our observations demonstrate EspK is an active component of the ESX-1 secretion machinery of the tubercle bacillus.

The Inverse Relationship Between Labral Size and Acetabular Coverage: Does It Protect the Cartilage in the Dysplastic Hip?

PURPOSE: The aims of this study were to confirm the relationship between osseous coverage and labral size and to investigate the severity of intra-articular damage in borderline dysplastic hips in correlation to labral size. METHODS: Patients treated with primary hip arthroscopy for symptomatic labral tears between 2010 and 2018 were considered for this study. Patients were included if they had preoperative radiographic measures and intraoperative assessments of the labra and cartilage. The study group was divided into borderline dysplastic and nondysplastic groups via 3 measurements: lateral center edge angle (LCEA), acetabular index (Ax), and anterior center edge angle (ACEA). Undercoverage was defined as LCEA ≤ 25°, Ax ≥ 10°, and ACEA ≤ 20°. The labrum was measured in four quadrants: anterosuperior (AS), anteroinferior (AI), posterosuperior (PS), and posteroinferior (PI). Additionally, to assess cartilage damage in borderline dysplastic hips, hips with average labral size in the top quartile were compared to hips with average labral size in the bottom quartile. RESULTS: A total of 1765 hips (1589 patients) were included in the study. The mean LCEA, Ax, and ACEA between the borderline dysplastic and nondysplastic groups were significantly different (P < .001). According to the Ax classification, there was significant evidence that borderline dysplastic hips had larger labra (P < .05). Among the dysplastic group, there was significantly more cartilage damage according to the Outerbridge classifications along both the acetabulum and femoral head in hips with labra in the upper quartile (P =.011 and .005, respectively). CONCLUSION: An inverse relationship may exist between acetabular depth and labral size. Additionally, specifically in borderline dysplastic hips, a relatively large labrum correlates with worse intra-articular damage compared to borderline dysplastic hips with a relatively small labrum. Larger labral size may indicate a higher degree of instability in patients with borderline dysplasia. LEVEL OF EVIDENCE: Level III, case-control study.

Best Practice Guidelines for Propensity Score Methods in Medical Research: Consideration on Theory, Implementation, and Reporting. A Review.

Rigorous and reproducible methodology of controlling for bias is essential for high-quality, evidence-based studies. Propensity score matching (PSM) is a valuable way to control for bias and achieve pseudo-randomization in retrospective observation studies. The purpose of this review is to 1) provide a clear conceptual framework for PSM, 2) recommend how to best report its use in studies, and 3) offer some practical examples of implementation. First, this article covers the concepts behind PSM, discusses its pros and cons, and compares it with other methods of controlling for bias, namely, hard/exact matching and regression analysis. Second, recommendations are given for what to report in a manuscript when PSM is used. Finally, a worked example is provided, which can also serve as a template for the reader's own studies. A study's conclusions are only as strong as its methods. PSM is an invaluable tool for producing rigorous and reproducible results in observational studies. The goal of this article is to give practicing clinical physicians not only a better understanding of PSM and its implications but the ability to implement it for their own studies. STUDY DESIGN: Review.

A SNP in the Cache 1 Signaling Domain of Diguanylate Cyclase STM1987 Leads to Increased In Vivo Fitness of Invasive Salmonella Strains.

Nontyphoidal Salmonella (NTS) strains are associated with gastroenteritis worldwide but are also the leading cause of bacterial bloodstream infections in sub-Saharan Africa. The invasive NTS (iNTS) strains that cause bloodstream infections differ from standard gastroenteritis-causing strains by >700 single-nucleotide polymorphisms (SNPs). These SNPs are known to alter metabolic pathways and biofilm formation and to contribute to serum resistance and are thought to signify iNTS strains becoming human adapted, similar to typhoid fever-causing Salmonella strains. Identifying SNPs that contribute to invasion or increased virulence has been more elusive. In this study, we identified a SNP in the cache 1 signaling domain of diguanylate cyclase STM1987 in the invasive Salmonella enterica serovar Typhimurium type strain D23580. This SNP was conserved in 118 other iNTS strains analyzed and was comparatively absent in global S Typhimurium isolates associated with gastroenteritis. STM1987 catalyzes the formation of bis-(3',5')-cyclic dimeric GMP (c-di-GMP) and is proposed to stimulate production of cellulose independent of the master biofilm regulator CsgD. We show that the amino acid change in STM1987 leads to a 10-fold drop in cellulose production and increased fitness in a mouse model of acute infection. Reduced cellulose production due to the SNP led to enhanced survival in both murine and human macrophage cell lines. In contrast, loss of CsgD-dependent cellulose production did not lead to any measurable change in in vivo fitness. We hypothesize that the SNP in stm1987 represents a pathoadaptive mutation for iNTS strains.

Aberrant mitochondrial function in patient-derived neural cells from CDKL5 deficiency disorder and Rett syndrome.

The X-linked neurodevelopmental diseases CDKL5 deficiency disorder (CDD) and Rett syndrome (RTT) are associated with intellectual disability, infantile spasms and seizures. Although mitochondrial dysfunction has been suggested in RTT, less is understood about mitochondrial function in CDD. A comparison of bioenergetics and mitochondrial function between isogenic wild-type and mutant neural progenitor cell (NPC) lines revealed increased oxygen consumption in CDD mutant lines, which is associated with altered mitochondrial function and structure. Transcriptomic analysis revealed differential expression of genes related to mitochondrial and REDOX function in NPCs expressing the mutant CDKL5. Furthermore, a similar increase in oxygen consumption specific to RTT patient-derived isogenic mutant NPCs was observed, though the pattern of mitochondrial functional alterations was distinct from CDKL5 mutant-expressing NPCs. We propose that aberrant neural bioenergetics is a common feature between CDD and RTT disorders. The observed changes in oxidative stress and mitochondrial function may facilitate the development of therapeutic agents for CDD and related disorders.