Curve Progression and Clinical Outcomes in Pregnant Females with Adolescent Idiopathic Scoliosis: A Systematic Review and Meta-Analysis.

BACKGROUND: Prior reviews investigating the impact of pregnancy on adolescent idiopathic scoliosis (AIS) have reached different conclusions and a meta-analysis of curve progression among pregnant females with AIS and its effects on clinical outcomes has not previously been performed. METHODS: A comprehensive search of major bibliographic databases (PubMed, Embase, and Scopus) was conducted for articles pertaining to spinal curve progression during pregnancy among patients with AIS. Patient demographics, scoliotic curve outcomes, and patient-reported quality of life measures were extracted. RESULTS: Ten studies, including 857 patients with a mean age of 28.7 years, were included. Before pregnancy, 42.1% had undergone spinal fusion and 59.0% had a thoracic curve. Based on pre-pregnancy and post-pregnancy radiographs, the curve increased from 33.9° to 38.5° and meta-analysis revealed a curve progression of 3.6° (range=-5.85--1.25, p=0.003), primarily arising from loss of correction in the unfused group (Unfused=-5.0, p=0.040; Fused=-3.0, p=0.070). At the same time, 45.9% patients reported increased low back pain and many reported a negative body self-image and limitations in sexual function. However, five studies noted that pregnancy and number of pregnancies were not associated with curve progression, and multiple studies identified similar quality of life-related changes in non-pregnant patients with AIS. CONCLUSIONS: Among unfused pregnant females with AIS, the spinal curvature increased significantly by 5.0° from before to after pregnancy. However, these changes may be independent of pregnancy status and occur with time. Such curve progression can contribute to a negative body self-image, low back pain, and functional limitations irrespective of pregnancy state.

Dysregulation of ceramide metabolism causes phytoceramide-dependent induction of the unfolded protein response.

The unfolded protein response (UPR) detects and mitigates the harmful effects of dysregulated endoplasmic reticulum (ER) function. The UPR has been best characterized as a protein quality control response, and the sole UPR sensor in yeast, Ire1, is known to detect misfolded ER proteins. However, recent work suggests the UPR can also sense diverse defects within the ER membrane, including increased fatty acid saturation and altered phospholipid abundance. These and other lipid-related stimuli have been referred to as lipid bilayer stress and may be sensed independently through Ire1's transmembrane domain. Here, we show that the loss of Isc1, a phospholipase that catabolizes complex ceramides, causes UPR induction, even in the absence of exogenous stress. A series of chemical and genetic approaches identified a requirement for very long-chain fatty acid (VLCFA)-containing phytoceramides for UPR induction. In parallel, comprehensive lipidomics analyses identified large increases in the abundance of specific VLCFA-containing phytoceramides in the isc1Δ mutant. We failed to identify evidence of an accompanying defect in protein quality control or ER-associated protein degradation. These results extend our understanding of lipid bilayer stress in the UPR and provide a foundation for mechanistic investigation of this fascinating intersection between ceramide metabolism, membrane homeostasis, and the UPR.

PEComa With MITF Overexpression: Clinicopathologic and Molecular Analysis of a Series of 36 Cases.

Perivascular epithelioid cell neoplasms (PEComas) are tumors of uncertain cell lineage that occur across a wide age range, at a variety of anatomic sites, and with a female predominance. Most PEComas are associated with dysregulation of the mTOR pathway, most commonly through inactivating mutations of TSC2 or TSC1. However, a small subset of PEComas are instead associated with TFE3 gene fusions. MITF is closely related to TFE3 and is frequently overexpressed in PEComas, often in a mutually exclusive manner with TFE3. Here we report the clinical, histopathologic, and molecular features of MITF-overexpressing PEComas in a series of 36 cases. The clinical and morphologic features were comparable to conventional PEComa, although the immunohistochemical profile was notable for the relatively limited expression of melanocytic markers, a surprising finding given that MITF is the master regulator of melanocytic differentiation. At the molecular level, 20 cases (56%) showed supernumerary copies of the MITF gene, suggesting a potential explanation for MITF overexpression. A putative genetic driver event within the mTOR pathway was identified in 11 of 15 cases (73%) analyzed by DNA or RNA sequencing. Interestingly, the malignant PEComas showed 2 distinguishing molecular features: they were associated with a complex chromosomal copy number profile, and they tended to show additional genetic changes, most commonly inactivating events involving TP53, RB1, and ATRX. These results elucidate key features of PEComas showing MITF overexpression, begin to explain the molecular basis for MITF overexpression in some PEComas and identify potential molecular correlates for malignancy that may be applicable to the broader PEComa family.

Socioeconomic Disparities and the Prevalence of Antimicrobial Resistance.

BACKGROUND: The increased prevalence of antimicrobial resistant (AMR) infections is a significant global health threat, resulting in increased morbidity, mortality, and costs. The drivers of AMR are complex and potentially impacted by socioeconomic factors. We investigated the relationships between geographic and socioeconomic factors and AMR. METHODS: We collected select patient bacterial culture results from 2015 to 2020 from electronic health records (EHR) of two expansive healthcare systems within the Dallas-Fort Worth, TX (DFW) metropolitan area. Among individuals with EHR records who resided in the four most populus counties in DFW, culture data were aggregated. Case counts for each organism studied were standardized per 1,000 persons per area population. Using residential addresses, the cultures were geocoded and linked to socioeconomic index values. Spatial autocorrelation tests identified geographic clusters of high and low AMR organism prevalence and correlations with established socioeconomic indices. RESULTS: We found significant clusters of AMR organisms in areas with high levels of deprivation, as measured by the Area Deprivation Index (ADI). We found a significant spatial autocorrelation between ADI and the prevalence of AMR organisms, particularly for AmpC and MRSA with 14% and 13%, respectively, of the variability in prevalence rates being attributable to their relationship with the ADI values of the neighboring locations. CONCLUSIONS: We found that areas with a high ADI are more likely to have higher rates of AMR organisms. Interventions that improve socioeconomic factors such as poverty, unemployment, decreased access to healthcare, crowding, and sanitation in these areas of high prevalence may reduce the spread of AMR.

Choice of antiretroviral therapy has low impact on weight gain.

OBJECTIVE: Antiretroviral therapy (ART) containing integrase inhibitors (INSTIs) and/or tenofovir alafenamide (TAF) has been associated with greater weight gain. Yet few studies have delineated between exposure to "anchor" drugs (protease inhibitors [PI], non-nucleoside reverse transcriptase inhibitors [NNRTI] or INSTIs) and exposure to nucleoside reverse transcriptase inhibitors (NRTIs). DESIGN: In this cohort of antiretroviral (ARV) naïve patients who initiated ART from 2008-2022, we analyzed body mass index (BMI) gain for 8 contemporary "anchor" drugs and 3 contemporary NRTIs during the first 3 years of ART. We censored patients if they stopped, switched, or added another ARV to their regimen. METHODS: We used generalized estimating equations (GEE) to assess the association between BMI gain and choice of ART and a non-linear mixed model for the marginal coefficients of determination. We adjusted for time, baseline demographic and HIV-characteristics, and time-updated HIV and substance use related variables. RESULTS: 4,194 patients contributed 20,528 BMI measurements which were used for multivariable modeling. Most patients were black (55%) and male (77%). Median BMI gain over 3 years was +1.9 kg/m2 (IQR 0.1-4.1). ARV use accounted for only 9% of the predicted BMI change. Only efavirenz (EFV) and tenofovir disoproxil fumarate (TDF) were independently associated with (lower) weight gain while no differences between INSTIs, PIs, or rilpivirine were observed, nor between TAF and abacavir. CONCLUSIONS: The choice of initial ART had little impact on weight gain. INSTIs or TAF were not independently associated with weight change after ART initiation, but EFV and TDF were.

Risk factors for healthcare-associated candidemia in adults hospitalized with SARS-CoV-2 infection.

Analyzing data from a national deidentified electronic health record-based data set using a matched case-control study design, we found that antibiotic use and severity of illness were independent risk factors for healthcare-associated candidemia in adult patients hospitalized with SARS-CoV-2 infection. Interleukin-6 inhibitor and corticosteroid use were not independent risk factors.

Navigating the future: machine learning's role in revolutionizing antimicrobial stewardship and infection prevention and control.

PURPOSE OF REVIEW: This review examines the current state and future prospects of machine learning (ML) in infection prevention and control (IPC) and antimicrobial stewardship (ASP), highlighting its potential to transform healthcare practices by enhancing the precision, efficiency, and effectiveness of interventions against infections and antimicrobial resistance. RECENT FINDINGS: ML has shown promise in improving surveillance and detection of infections, predicting infection risk, and optimizing antimicrobial use through the development of predictive analytics, natural language processing, and personalized medicine approaches. However, challenges remain, including issues related to data quality, model interpretability, ethical considerations, and integration into clinical workflows. SUMMARY: Despite these challenges, the future of ML in IPC and ASP is promising, with interdisciplinary collaboration identified as a key factor in overcoming existing barriers. ML's role in advancing personalized medicine, real-time disease monitoring, and effective IPC and ASP strategies signifies a pivotal shift towards safer, more efficient healthcare environments and improved patient care in the face of global antimicrobial resistance challenges.

Mechanism of autocatalytic activation during proteasome assembly.

Many large molecular machines are too elaborate to assemble spontaneously and are built through ordered pathways orchestrated by dedicated chaperones. During assembly of the core particle (CP) of the proteasome, where protein degradation occurs, its six active sites are simultaneously activated via cleavage of N-terminal propeptides. Such activation is autocatalytic and coupled to fusion of two half-CP intermediates, which protects cells by preventing activation until enclosure of the active sites within the CP interior. Here we uncover key mechanistic aspects of autocatalytic activation, which proceeds through alignment of the ß5 and ß2 catalytic triad residues, respectively, with these triads being misaligned before fusion. This mechanism contrasts with most other zymogens, in which catalytic centers are preformed. Our data also clarify the mechanism by which individual subunits can be added in a precise, temporally ordered manner. This work informs two decades-old mysteries in the proteasome field, with broader implications for protease biology and multisubunit complex assembly.

Visualizing chaperone-mediated multistep assembly of the human 20S proteasome.

Dedicated assembly factors orchestrate the stepwise production of many molecular machines, including the 28-subunit proteasome core particle (CP) that mediates protein degradation. Here we report cryo-electron microscopy reconstructions of seven recombinant human subcomplexes that visualize all five chaperones and the three active site propeptides across a wide swath of the assembly pathway. Comparison of these chaperone-bound intermediates and a matching mature CP reveals molecular mechanisms determining the order of successive subunit additions, as well as how proteasome subcomplexes and assembly factors structurally adapt upon progressive subunit incorporation to stabilize intermediates, facilitate the formation of subsequent intermediates and ultimately rearrange to coordinate proteolytic activation with gated access to active sites. This work establishes a methodologic approach for structural analysis of multiprotein complex assembly intermediates, illuminates specific functions of assembly factors and reveals conceptual principles underlying human proteasome biogenesis, thus providing an explanation for many previous biochemical and genetic observations.

Epidermodysplasia verruciformis-associated eccrine neoplasm: a rare entity with distinctive clinical and histopathologic features.

Most tumors are caused by inherited or acquired genetic changes. However, a subset of tumors is driven by viral infection including Kaposi sarcoma, nasopharyngeal carcinoma, and others. Human papillomavirus (HPV) is an especially common cause of epithelial cancers and hyperplasias. Epidermodysplasia verruciformis (EDV) is a rare type of HPV infection with characteristic histopathologic features and a unique spectrum of HPV subtypes. We report here a distinctive form of EDV-associated eccrine neoplasia. Seven tumors from two patients were analyzed and show highly uniform features including multiple clustered clinical lesions, multifocal epidermal origin, eccrine differentiation with close association with the acrosyringium, an anastomosing growth pattern, and a bland monotonous poroid-to-basaloid cytomorphology. Clinical follow-up for one patient has been benign to date. These tumors show strong similarity to two previously reported cases, suggesting that this type of EDV-associated eccrine neoplasia may represent a rare but reproducible form of skin adnexal tumor with distinctive clinicopathologic features.

Innominate artery occlusion: a case study.

Aim of the study: The aim of this case report is to evaluate carotid duplex and hemodynamic patterns in an asymptomatic male patient with innominate artery occlusion. Innominate artery occlusion is a rare clinical entity that can lead to a range of cerebrovascular symptoms, including arm claudication, subclavian steal syndrome, and stroke. The case report emphasizes key learning points in diagnosing innominate artery occlusion using imaging and physiological methods. Case description: A 64-year-old asymptomatic male patient with a history of carotid bruit, hypertension, coronary artery bypass grafting, aortic aneurysm, hyperlipidemia, mild aortic stenosis, long-term tobacco use, and a body mass index of 24 was referred for a carotid ultrasound. Conclusions: Innominate artery occlusion is a rare condition requiring a comprehensive assessment of collateralization before any intervention is attempted. Considering waveform features such as transient end-diastolic flow reversal and tardus parvus, along with brachial pressures and transcranial Doppler, can assist in evaluating the extent of disease.

Visualizing chaperone-mediated multistep assembly of the human 20S proteasome.

Dedicated assembly factors orchestrate stepwise production of many molecular machines, including the 28-subunit proteasome core particle (CP) that mediates protein degradation. Here, we report cryo-EM reconstructions of seven recombinant human subcomplexes that visualize all five chaperones and the three active site propeptides across a wide swath of the assembly pathway. Comparison of these chaperone-bound intermediates and a matching mature CP reveals molecular mechanisms determining the order of successive subunit additions, and how proteasome subcomplexes and assembly factors structurally adapt upon progressive subunit incorporation to stabilize intermediates, facilitate the formation of subsequent intermediates, and ultimately rearrange to coordinate proteolytic activation with gated access to active sites. The structural findings reported here explain many previous biochemical and genetic observations. This work establishes a methodologic approach for structural analysis of multiprotein complex assembly intermediates, illuminates specific functions of assembly factors, and reveals conceptual principles underlying human proteasome biogenesis.

Structure and Funding of Clinical Informatics Fellowships: A National Survey of Program Directors.

BACKGROUND: In 2011, the American Board of Medical Specialties established clinical informatics (CI) as a subspecialty in medicine, jointly administered by the American Board of Pathology and the American Board of Preventive Medicine. Subsequently, many institutions created CI fellowship training programs to meet the growing need for informaticists. Although many programs share similar features, there is considerable variation in program funding and administrative structures. OBJECTIVES: The aim of our study was to characterize CI fellowship program features, including governance structures, funding sources, and expenses. METHODS: We created a cross-sectional online REDCap survey with 44 items requesting information on program administration, fellows, administrative support, funding sources, and expenses. We surveyed program directors of programs accredited by the Accreditation Council for Graduate Medical Education between 2014 and 2021. RESULTS: We invited 54 program directors, of which 41 (76%) completed the survey. The average administrative support received was $27,732/year. Most programs (85.4%) were accredited to have two or more fellows per year. Programs were administratively housed under six departments: Internal Medicine (17; 41.5%), Pediatrics (7; 17.1%), Pathology (6; 14.6%), Family Medicine (6; 14.6%), Emergency Medicine (4; 9.8%), and Anesthesiology (1; 2.4%). Funding sources for CI fellowship program directors included: hospital or health systems (28.3%), clinical departments (28.3%), graduate medical education office (13.2%), biomedical informatics department (9.4%), hospital information technology (9.4%), research and grants (7.5%), and other sources (3.8%) that included philanthropy and external entities. CONCLUSION: CI fellowships have been established in leading academic and community health care systems across the country. Due to their unique training requirements, these programs require significant resources for education, administration, and recruitment. There continues to be considerable heterogeneity in funding models between programs. Our survey findings reinforce the need for reformed federal funding models for informatics practice and training.

Arthroscopic Treatment Is a Safe and Effective Alternative to Open Treatment for Acute Septic Arthritis of the Native Knee: A Systematic Review.

PURPOSE: To compare complication rates, reoperation rates, and subjective outcomes after arthroscopic and open irrigation and debridement for treatment of native knee septic arthritis. METHODS: Following The Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, a systematic review of the Embase, Cochrane, and PubMed databases was performed. Comparative studies reporting clinical outcomes after arthroscopic versus open treatment for septic arthritis of the native knee in human adults were included. Excluded were case series with <10 patients, inclusion of patients <18 years old, studies on non-native joints, abstract-only publications, and studies without stratification of the involved joint. Two reviewers in duplicate independently performed search and data extraction. The quality of the included studies was assessed with the Methodological Index for Non-Randomized Studies instrument. The mean score among the included studies was 18.2 (range 16-23). RESULTS: Eleven studies were included, comprising 2,343 knees treated arthroscopically, and 1,595 treated with arthrotomy. Studies reported no differences in erythrocyte sedimentation rate, C-reactive protein, peripheral white blood cells, or symptom chronicity between groups. Nine studies (81.8%) attempted to control for potentially confounding variables in their analyses, and 4 studies (36.4%) reported significant differences in patient characteristics. Reoperation rates ranged from 0% to 50% for arthroscopy and 6% to 71% for arthrotomy. Complication rates ranged from 0% to 39.4% arthroscopically and 0% to 49% for arthrotomy. Superior patient-reported outcomes were achieved after arthroscopy in 2 studies that analyzed subjective outcomes. CONCLUSIONS: Arthroscopic management of native knee septic arthritis is a safe and effective alternative to open treatment and is associated with comparable complication rates, reoperation rates, hospitalization lengths, readmission rates, and superior patient-reported outcomes compared with open irrigation and debridement. LEVEL OF EVIDENCE: Level IV, systematic review of Level I, III, and IV studies.

Management Principles and Current Debates Surrounding Common Pediatric Elbow Fractures.

Elbow fractures are among the most common fractures sustained in pediatric patients. A specific set of pediatric elbow fractures (olecranon, radial neck, and lateral condyle fractures) comprises the ones that occur most often. It is important to review commonly accepted principles in the evaluation and treatment of these injuries as well as highlight some debates that exist within the literature regarding the optimal management of these injuries. Although management of pediatric olecranon, radial neck, and lateral condyle fractures has been well described, controversy persists among orthopaedic surgeons regarding the surgical indications and preferred fixation techniques for these injuries.

Melanotic PEComa: A Rare But Distinctive Subtype Analyzed in a Series of 7 Cases.

Perivascular epithelioid cell neoplasms (PEComas) are tumors of uncertain cell lineage that show a strong female predominance. Their hallmark is the presence of combined smooth muscle and melanocytic differentiation. In most cases, melanocytic differentiation is detectable only by immunohistochemistry, but there are rare reports of PEComa with extensive melanin accumulation (so-called "melanotic PEComa"). Here we report a clinicopathologic series of 7 melanotic PEComas that occurred across a wide patient age range of 21 to 82 years (median: 41 y) and with a wide anatomic distribution, including 2 cases in the pelvis and 1 case each in the gallbladder, cervix, eyelid, epidural space, and femur. All tumors were heavily pigmented and, like conventional PEComas, were composed of variably sized neoplastic cells with voluminous granular, or less commonly clear, cytoplasm with prominent nucleoli. All tumors expressed HMB45 by immunohistochemistry, and 6 of 7 showed nuclear TFE3 expression. Where tested, tumors were uniformly negative for Mart-1/Melan-A, S100, desmin, and smooth muscle actin. Molecular analysis identified TFE3 gene rearrangement in 5 of 7 cases, 4 of which were demonstrated by fluorescence in situ hybridization and one by whole-exome RNA sequencing which revealed a SFPQ::TFE3 fusion. The one tumor negative for TFE3 by immunohistochemistry was found instead to harbor a SFPQ::TFEB fusion, the first reported example to our knowledge of TFEB fusion in a PEComa. Clinical follow-up was available for 6 of 7 patients (median: 2.5 y: range: 0.75 to 7 y). The patient whose tumor harbored SFPQ::TFEB died of metastatic disease 9 months after diagnosis. The other tumors behaved in an indolent fashion: 4 patients were alive without evidence of disease at the most recent follow-up and 1 patient died of an unrelated cancer 4 years after diagnosis of the melanotic PEComa. Our results expand the morphologic and molecular spectrum of melanotic PEComa, and awareness of this rare but distinctive subtype is important to ensure accurate diagnosis within the broader family of heavily pigmented neoplasms.

Rational design of proteasome inhibitors based on the structure of the endogenous inhibitor PI31/Fub1.

Proteasome inhibitors are widely used anticancer drugs. The three clinically approved agents are modified small peptides that preferentially target one of the proteasome's three active sites (ß5) at physiologic concentrations. In addition to these drugs, there is also an endogenous proteasome inhibitor, PI31/Fub1, that enters the proteasome's interior to simultaneously yet specifically inhibit all three active sites. Here, we have used PI31's evolutionarily optimized inhibitory mechanisms to develop a suite of potent and specific ß2 inhibitors. The lead compound strongly inhibited growth of multiple myeloma cells as a standalone agent, indicating the compound's cell permeability and establishing ß2 as a potential therapeutic target in multiple myeloma. The lead compound also showed strong synergy with the existing ß5 inhibitor bortezomib; such combination therapies might help with existing challenges of resistance and severe side effects. These results represent an effective method for rational structure-guided development of proteasome inhibitors.

Limited Clinical Utility of Routine Mycobacterial Cultures for the Management of Diabetic Foot Infections.

Mycobacterial infections of the foot and ankle are uncommon. In a cohort of 2340 patients with diabetic foot infection (DFI) in a region with increased prevalence of mycobacterial disease, we identified no clinically significant positive cultures over a 3-year period. Routine mycobacterial culture of DFIs is of limited clinical utility.

Armillaria altimontana in North America: Biology and Ecology.

Armillaria altimontana is a fungus (Basidiomycota, Agaricomycetes, Agaricales, and Physalacriaceae) that is generally considered as a weak/opportunistic pathogen or saprophyte on many tree hosts. It widely occurs across the northwestern USA to southern British Columbia, Canada, but relatively little is known about its ecological role in the diverse forest ecosystems where it occurs. This review summarizes the biology and ecology of A. altimontana, including its identification, life cycle, distribution, host associations, and bioclimatic models under climate change.

3D printed hybrid scaffolds for bone regeneration using calcium methoxyethoxide as a calcium source.

Introduction: Hybrids consist of inorganic and organic co-networks that are indistinguishable above the nanoscale, which can lead to unprecedented combinations of properties, such as high toughness and controlled degradation. Methods: We present 3D printed bioactive hybrid scaffolds for bone regeneration, produced by incorporating calcium into our "Bouncy Bioglass", using calcium methoxyethoxide (CME) as the calcium precursor. SiO2-CaOCME/PTHF/PCL-diCOOH hybrid "inks" for additive manufacturing (Direct Ink Writing) were optimised for synergy of mechanical properties and open interconnected pore channels. Results and Discussion: Adding calcium improved printability. Changing calcium content (5, 10, 20, 30, and 40 mol.%) of the SiO2-CaOCME/PTHF/PCL-diCOOH hybrids affected printability and mechanical properties of the lattice-like scaffolds. Hybrids containing 30 mol.% calcium in the inorganic network (70S30CCME-CL) printed with 500 µm channels and 100 µm strut size achieved the highest strength (0.90 ± 0.23 MPa) and modulus of toughness (0.22 ± 0.04 MPa). These values were higher than Ca-free SiO2/PTHF/PCL-diCOOH hybrids (0.36 ± 0.14 MPa strength and 0.06 ± 0.01 MPa toughness modulus). Over a period of 90 days of immersion in simulated body fluid (SBF), the 70S30CCME-CL hybrids also kept a stable strain to failure (~30 %) and formed hydroxycarbonate apatite within three days. The extracts released by the 70S30CCME-CL hybrids in growth medium did not cause cytotoxic effects on human bone marrow stromal cells over 24 h of culture.