Perioperative Infection Prophylaxis with Vancomycin is a Significant Risk Factor for Deep Surgical Site Infection in Spine Surgery.

STUDY DESIGN: Retrospective cohort. OBJECTIVE: The purpose of this study was to compare the efficacy of cefazolin versus vancomycin for perioperative infection prophylaxis. SUMMARY OF BACKGROUND DATA: The relative efficacy of cefazolin alternatives for perioperative infection prophylaxis is poorly understood. METHODS: This study was a single-center multi-surgeon retrospective review of all patients undergoing primary spine surgery from an institutional registry. Postoperative infection was defined by the combination of three criteria: irrigation and debridement within 3 months of the index procedure, clinical suspicion for infection, and positive intraoperative cultures. Microbiology records for all infections were reviewed to assess the infectious organism and organism susceptibilities. Univariate and multivariate analyses were performed. RESULTS: A total of 10,122 patients met inclusion criteria. The overall incidence of infection was 0.78%, with an incidence of 0.73% in patients who received cefazolin and 2.03% in patients who received vancomycin (OR 2.83, 95% CI 1.35-5.91, P-0.004). Use of IV vancomycin (OR 2.83, 95% CI 1.35-5.91, P=0.006), BMI (MD 1.56, 95% CI 0.32-2.79, P=0.014), presence of a fusion (OR 1.62, 95% CI 1.04-2.52, P=0.033), and operative time (MD 42.04, 95% CI 16.88-67.21, P=0.001) were significant risk factors in the univariate analysis. In the multivariate analysis, only non-cefazolin antibiotics (OR 2.48, 95% CI 1.18-5.22, P=0.017) and BMI (MD 1.56, 95% CI 0.32-2.79, P=0.026) remained significant independent risk factors. Neither IV antibiotic regimen nor topical vancomycin significantly impacted Gram type, organism type, or antibiotic resistance (P>0.05). The most common reason for antibiosis with vancomycin was a penicillin allergy (75.0%). CONCLUSIONS: Prophylactic antibiosis with IV vancomycin leads to a 2.5-times higher risk of infection compared to IV cefazolin in primary spine surgery. We recommend the routine use of IV cefazolin for infection prophylaxis, and caution against the elective use of alternative regimens like IV vancomycin unless clinically warranted.

A comparative cohort study of surgical approaches for adult spinal deformity at a minimum 2-year follow-up.

STUDY DESIGN: This study was a retrospective multi-center comparative cohort study. MATERIALS AND METHODS: A retrospective institutional database of operative adult spinal deformity patients was utilized. All fusions > 5 vertebral levels and including the sacrum/pelvis were eligible for inclusion. Revisions, 3 column osteotomies, and patients with < 2-year clinical follow-up were excluded. Patients were separated into 3 groups based on surgical approach: 1) posterior spinal fusion without interbody (PSF), 2) PSF with interbody (PSF-IB), and 3) anteroposterior (AP) fusion (anterior lumbar interbody fusion or lateral lumbar interbody fusion with posterior screw fixation). Intraoperative, radiographic, and clinical outcomes, as well as complications, were compared between groups with ANOVA and χ2 tests. RESULTS: One-hundred and thirty-eight patients were included for study (PSF, n = 37; PSF-IB, n = 44; AP, n = 57). Intraoperatively, estimated blood loss was similar between groups (p = 0.171). However, the AP group had longer operative times (547.5 min) compared to PSF (385.1) and PSF-IB (370.7) (p < 0.001). Additionally, fusion length was shorter in PSF-IB (11.4) compared to AP (13.6) and PSF (12.9) (p = 0.004). There were no differences between the groups in terms of change in alignment from preoperative to 2 years postoperative. There were no differences in clinical outcomes. While postoperative complications were largely similar between groups, operative complications were higher in the AP group (31.6%) compared to the PSF (5.4%) and PSF-IB (9.1) groups (p < 0.001). CONCLUSION: While there were differences in intraoperative outcomes (operative time and fusion length), there were no differences in postoperative clinical or radiographic outcomes. AP fusion was associated with a higher rate of operative complications.

UBX-390: A Novel Androgen Receptor Degrader for Therapeutic Intervention in Prostate Cancer.

The androgen receptor (AR) is an attractive target for treating prostate cancer, considering its role in the development and progression of localized and metastatic prostate cancer. The high global mortality burden of prostate cancer, despite medical treatments such as androgen deprivation or AR antagonist therapy, highlights the need to explore alternative strategies. One strategy involves the use of heterobifunctional degraders, also known as proteolysis-targeting chimeras, which are novel small-molecule therapeutics that inhibit amplified or mutated targets. Here, the study reports a novel cereblon-based AR degrader, UBX-390, and demonstrates its superior activity over established AR degraders, such as ARV-110 or ARCC-4, in prostate cancer cells under short- and long-term treatment conditions. UBX-390 suppresses chromatin binding and gene expression of AR and demonstrates substantial efficacy in the degradation of AR mutants in patients with treatment-resistant prostate cancer. UBX-390 is presented as an optimized AR degrader with remarkable potential for treating castration-resistant prostate cancer.

Hip Osteoarthritis in Patients Undergoing Surgery for Severe Adult Spinal Deformity: Prevalence and Impact on Spine Surgery Outcomes.

BACKGROUND: Hip osteoarthritis (OA) is common in patients with adult spinal deformity (ASD). Limited data exist on the prevalence of hip OA in patients with ASD, or on its impact on baseline and postoperative alignment and patient-reported outcome measures (PROMs). Therefore, this paper will assess the prevalence and impact of hip OA on alignment and PROMs. METHODS: Patients with ASD who underwent L1-pelvis or longer fusions were included. Two independent reviewers graded hip OA with the Kellgren-Lawrence (KL) classification and stratified it by severity into non-severe (KL grade 1 or 2) and severe (KL grade 3 or 4). Radiographic parameters and PROMs were compared among 3 patient groups: Hip-Spine (hip KL grade 3 or 4 bilaterally), Unilateral (UL)-Hip (hip KL grade 3 or 4 unilaterally), or Spine (hip KL grade 1 or 2 bilaterally). RESULTS: Of 520 patients with ASD who met inclusion criteria for an OA prevalence analysis, 34% (177 of 520) had severe bilateral hip OA and unilateral or bilateral hip arthroplasty had been performed in 8.7% (45 of 520). A subset of 165 patients had all data components and were examined: 68 Hip-Spine, 32 UL-Hip, and 65 Spine. Hip-Spine patients were older (67.9 ± 9.5 years, versus 59.6 ± 10.1 years for Spine and 65.8 ± 7.5 years for UL-Hip; p < 0.001) and had a higher frailty index (4.3 ± 2.6, versus 2.7 ± 2.0 for UL-Hip and 2.9 ± 2.0 for Spine; p < 0.001). At 1 year, the groups had similar lumbar lordosis, yet the Hip-Spine patients had a worse sagittal vertebral axis (SVA) measurement (45.9 ± 45.5 mm, versus 25.1 ± 37.1 mm for UL-Hip and 19.0 ± 39.3 mm for Spine; p = 0.001). Hip-Spine patients also had worse Veterans RAND-12 Physical Component Summary scores at baseline (25.7 ± 9.3, versus 28.7 ± 9.8 for UL-Hip and 31.3 ± 10.5 for Spine; p = 0.005) and 1 year postoperatively (34.5 ± 11.4, versus 40.3 ± 10.4 for UL-Hip and 40.1 ± 10.9 for Spine; p = 0.006). CONCLUSIONS: This study of operatively treated ASD revealed that 1 in 3 patients had severe hip OA bilaterally. Such patients with severe bilateral hip OA had worse baseline SVA and PROMs that persisted 1 year following ASD surgery, despite correction of lordosis. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Tissue Engineering and Regenerative Medicine in the Field of Otorhinolaryngology.

BACKGROUND: Otorhinolaryngology is a medical specialty that focuses on the clinical study and treatments of diseases within head and neck regions, specifically including the ear, nose, and throat (ENT), but excluding eyes and brain. These anatomical structures play significant roles in a person's daily life, including eating, speaking as well as facial appearance and expression, thus greatly impacting one's overall satisfaction and quality of life. Consequently, injuries to these regions can significantly impact a person's well-being, leading to extensive research in the field of tissue engineering and regenerative medicine over many years. METHODS: This chapter provides an overview of the anatomical characteristics of otorhinolaryngologic tissues and explores the tissue engineering and regenerative medicine research in otology (ear), rhinology (nose), facial bone, larynx, and trachea. RESULTS AND CONCLUSION: The integration of tissue engineering and regenerative medicine in otorhinolaryngology holds the promise of broadening the therapeutic choices for a wide range of conditions, ultimately improving quality of a patient's life.

Nanobioactive Blood-Derived Shear-Thinning Biomaterial for Tissue Engineering Applications.

The conventional technique for successful bone grafts, involving the use of a patients own tissue (autografts), is challenged by limited availability and donor site morbidity. While allografts and xenografts offer alternatives, they come with the risk of rejection. This underscores the pressing need for tailor-made artificial bone graft materials. In this context, injectable hydrogels are emerging as a promising solution for bone regeneration, especially in complex maxillofacial reconstruction cases. These hydrogels can seamlessly adapt to irregular shapes and conservatively fill defects. Our study introduces a shear-thinning biomaterial by blending silicate nanoplatelets (SNs) enriched with human blood-derived plasma rich in growth factors (PRGF) for personalized applications. Notably, our investigations unveil that injectable hydrogel formulations comprising 7.5% PRGF yield sustained protein and growth factor release, affording precise control over critical growth factors essential for tissue regeneration. Moreover, our hydrogel exhibits exceptional biocompatibility in vitro and in vivo and demonstrates hemostatic properties. The hydrogel also presents a robust angiogenic potential and an inherent capacity to promote bone differentiation, proven through Alizarin Red staining, gene expression, and immunostaining assessments of bone-related biomarkers. Given these impressive attributes, our hydrogel stands out as a leading candidate for maxillofacial bone regeneration application. Beyond this, our findings hold immense potential in revolutionizing the field of regenerative medicine, offering an influential platform for crafting precise and effective therapeutic strategies.

Micro-current stimulation could inhibit IL-1ß-induced inflammatory responses in chondrocytes and protect knee bone cartilage from osteoarthritis.

This study aimed to evaluate the inhibitory effects of micro-current stimulation (MCS) on inflammatory responses in chondrocytes and degradation of extracellular matrix (ECM) in osteoarthritis (OA). To determine the efficacy of MCS, IL-1ß-treated chondrocytes and monosodium iodoacetate (MIA)-induced OA rat model were used. To evaluate the cytotoxicity and nitric oxide (NO) production in SW1353 cells, the presence or absence of IL-1ß treatment or various levels of MCS were applied. Immunoblot analysis was conducted to evaluate whether MCS can modulate IL-1R1/MyD88/NF-κB signaling pathway and various indicators involved in ECM degradation. Additionally, to determine whether MCS alleviates subchondral bone structure destruction caused by OA, micro-CT analysis, immunoblot analysis, and ELISA were conducted using OA rat model. 25 and 50 µA levels of MCS showed effects in cell proliferation and NO production. The MCS group with IL-1ß treatment lead to significant inhibition of protein expression levels regarding IL-1R1/MyD88/NF-κB signaling and reduction of the nucleus translocation of NF-κB. In addition, the protein expression levels of MMP-1, MMP-3, MMP-13, and IL-1ß decreased, whereas collagen II and aggrecan increased. In animal results, morphological analysis of subchondral bone using micro-CT showed that MCS induced subchondral bone regeneration and improvement, as evidenced by increased thickness and bone mineral density of the subchondral bone. Furthermore, MCS-applied groups showed decreases in the protein expression of MMP-1 and MMP-3, while increases in collagen-II and aggrecan expressions. These findings suggest that MCS has the potential to be used as a non-pharmaceutical method to alleviate OA.

What Is the Carbon Footprint of Adult Spinal Deformity Surgery?

Background/Objectives: While the economic cost of adult spinal deformity (ASD) surgery has been studied extensively, its environmental impact is unknown. The aim of this study is to determine the carbon footprint (CF) associated with ASD surgery. Methods: ASD patients who underwent > four levels of corrective surgery between 2017 and 2021 were included. The open group included a posterior-only, single-stage technique, while the minimally invasive surgery (MIS) group was defined as the use of lateral interbody fusion and percutaneous posterior screw fixation. The two groups were propensity-score matched to adjust for baseline demographic, surgical, and radiographic characteristics. Data on all disposables and reusable instruments, anesthetic gas, and non-gas medications used during surgery were collected from medical records. The CF of transporting, using, and disposing of each product and the footprint of energy use in operating rooms were calculated. The CF produced was evaluated using the carbon dioxide equivalent (CO2e), which is relative to the amount of CO2 with an equivalent global warming potential. Results: Of the 175 eligible patients, 15 pairs (65 ± 9 years, 47% female) were properly matched and analyzed for all variables. The average CF generated per case was 147.7 ± 37.3 kg-CO2e, of which 54% was attributable to energy used to sterilize reusable instruments, followed by anesthetic gas released into the environment (17%) and operating room air conditioning (15%). Conclusions: The CF generated during ASD surgery should be reduced using a multidisciplinary approach, taking into account that different surgical procedures have different impacts on carbon emission sources.

Impact of Alternating-Current Operation on All-Inorganic Quantum Dot Light-Emitting Diodes.

In colloidal quantum dot light-emitting diodes (QD-LEDs), replacing organic hole transport layers (HTLs) with their inorganic counterparts is expected to yield distinct advantages due to their inherent material robustness. However, despite the promising characteristics of all-inorganic QD-LEDs, some challenges persist in achieving stable operation; for example, the electron overflow toward the inorganic HTL and charge accumulation within working devices return a temporal inconsistency in device characteristics. To address these challenges, we propose an operational approach that employs an alternating-current (AC) in all-inorganic QD-LEDs. We carry out comprehensive studies on the optoelectrical characteristics of all-inorganic QD-LEDs under direct-current (DC) or AC operation and demonstrate that AC operation can facilitate efficient charge carrier recombination within the QD emissive layer, leading to improved device efficiency and temporally invariant optoelectronic characteristics. Leveraging the intrinsic material robustness of inorganic charge transport layers (CTLs), our current study suggests a promising pathway toward enhancing the performance and stability of QD-LEDs, particularly for futuristic display applications.

The Society for Cardiovascular Magnetic Resonance Registry at 150,000.

BACKGROUND: Cardiovascular magnetic resonance (CMR) is increasingly utilized to evaluate expanding cardiovascular conditions. The Society for Cardiovascular Magnetic Resonance (SCMR) Registry is a central repository for real-world clinical data to support cardiovascular research, including those relating to outcomes, quality improvement, and machine learning. The SCMR Registry is built on a regulatory-compliant, cloud-based infrastructure that houses searchable content and Digital Imaging and Communications in Medicine images. The goal of this study is to summarize the status of the SCMR Registry at 150,000 exams. METHODS: The processes for data security, data submission, and research access are outlined. We interrogated the Registry and presented a summary of its contents. RESULTS: Data were compiled from 154,458 CMR scans across 20 United States sites, containing 299,622,066 total images (∼100 terabytes of storage). Across reported values, the human subjects had an average age of 58 years (range 1 month to >90 years old), were 44% (63,070/145,275) female, 72% (69,766/98,008) Caucasian, and had a mortality rate of 8% (9,962/132,979). The most common indication was cardiomyopathy (35,369/131,581, 27%), and most frequently used current procedural terminology code was 75561 (57,195/162,901, 35%). Macrocyclic gadolinium-based contrast agents represented 89% (83,089/93,884) of contrast utilization after 2015. Short-axis cines were performed in 99% (76,859/77,871) of tagged scans, short-axis late gadolinium enhancement (LGE) in 66% (51,591/77,871), and stress perfusion sequences in 30% (23,241/77,871). Mortality data demonstrated increased mortality in patients with left ventricular ejection fraction <35%, the presence of wall motion abnormalities, stress perfusion defects, and infarct LGE, compared to those without these markers. There were 456,678 patient-years of all-cause mortality follow-up, with a median follow-up time of 3.6 years. CONCLUSION: The vision of the SCMR Registry is to promote evidence-based utilization of CMR through a collaborative effort by providing a web mechanism for centers to securely upload de-identified data and images for research, education, and quality control. The Registry quantifies changing practice over time and supports large-scale real-world multicenter observational studies of prognostic utility.

Comparison of Metabarcoding and Microscopy Methodologies to Analyze Diatom Communities in Five Estuaries Along the Southern Coast of the Korean Peninsula.

The study of microalgal communities is critical for understanding aquatic ecosystems. These communities primarily comprise diatoms (Heterokontophyta), with two methods commonly used to study them: Microscopy and metabarcoding. However, these two methods often deliver different results; thus, their suitability for analyzing diatom communities is frequently debated and evaluated. This study used these two methods to analyze the diatom communities in identical water samples and compare the results. The taxonomy of the species constituting the diatom communities was confirmed, and both methods showed that species belonging to the orders Bacillariales and Naviculales (class Bacillariophyceae) are the most diverse. In the lower taxonomic levels (family, genus, and species), microscopy tended to show a bias toward detecting diatom species (Nitzschia frustulum, Nitzschia inconspicua, Nitzschia intermedia, Navicula gregaria, Navicula perminuta, Navicula recens, Navicula sp.) belonging to the Bacillariaceae and Naviculaceae families. The results of the two methods differed in identifying diatom species in the communities and analyzing their structural characteristics. These results are consistent with the fact that diatoms belonging to the genera Nitzschia and Navicula are abundant in the communities; furthermore, only the Illumina MiSeq data showed the abundance of the Melosira and Entomoneis genera. The results obtained from microscopy were superior to those of Illumina MiSeq regarding species-level identification. Based on the results obtained via microscopy and Illumina MiSeq, it was revealed that neither method is perfect and that each has clear strengths and weaknesses. Therefore, to analyze diatom communities effectively and accurately, these two methods should be combined.

Heterogeneity in the Definitions of Proximal Junctional Kyphosis and Failure in Spinal Deformity Literature: A Tower of Babel.

STUDY DESIGN: Systematic review. OBJECTIVE: To describe the various definitions of PJK and PJF used in spinal deformity literature and their utility over time. SUMMARY OF BACKGROUND DATA: Proximal junctional kyphosis or failure (PJK/PJF) is among the most common complication after long-segment fusions, but there is no consensus on their definitions. This presents challenges in understanding risk factors, management, and prevention strategies. METHODS: A systematic literature review was performed on studies specifying a definition of PJK and/or PJF. PJK definitions were categorized as radiographic vs non-radiographic and data was collected on PJK criteria including threshold for proximal junctional angle (PJA), change in PJA, vertebra selection for PJA measurement, and follow-up timepoints. PJF definitions were categorized as structural failure, need for revision, symptomatic failure, and radiographic (angular). RESULTS: 359 studies defining PJK and/or PJF were identified. While 56% of studies used the definition PJA>10° and PJA change from baseline>10°, the remainder expressed significant heterogeneity with respect to criteria for magnitude of PJA and degree of PJA change. The most common vertebrae assessed were UIV/UIV+2 (74%) and most common minimum follow-up (mFU) listed was 2 years (60%). Mean FUs for studies varied considerably even in studies with the same mFU, from 2.1-8.9 years (2-year mFU) and 1.1-4.0 years (1-year mFU). PJF definitions were most commonly structural (58%) or defined as a need for revision (48%), with a much less common use of PJA thresholds (23%). CONCLUSIONS: The challenges faced in preventing proximal junctional complications are mired in the heterogenous groundwork by which PJK and PJF are defined. Most definitions of PJK use radiographic thresholds without consideration of clinical relevance and variations in individual alignment. Conversely, definitions of PJF are based on clinical criteria, which are often subjective. Future research should focus on understanding the mechanisms of PJK/PJF, as only then will we be able to accurately define and prevent these complications.

Tumor necrosis factor-α-treated human adipose-derived stem cells enhance inherent radiation tolerance and alleviate in vivo radiation-induced capsular contracture.

INTRODUCTION: Post-mastectomy radiotherapy plays a crucial role in breast cancer treatment but can lead to an inflammatory response causing soft tissue damage, particularly radiation-induced capsular contracture (RICC), impacting breast reconstruction outcomes. Adipose-derived stem cells (ADSCs), known for their regenerative potential via paracrine capacity, exhibit inherent radiotolerance. The influence of tumor necrosis factor-alpha (TNF-α) on ADSCs has been reported to enhance the paracrine effect of ADSCs, promoting wound healing by modulating inflammatory responses. OBJECTIVE: This study investigates the potential of TNF-α-treated human ADSCs (T-hASCs) on silicone implants to alleviate RICC, hypothesizing to enhance suppressive effects on RICC by modulating inflammatory responses in a radiation-exposed environment. METHODS: In vitro, T-hASCs were cultured on various surfaces to assess viability after exposure to radiation up to 20 Gy. In vivo, T-hASC and non-TNF-α-treated hASC (C-hASCs)-coated membranes were implanted in mice before radiation exposure, and an evaluation of the RICC mitigation took place 4 and 8 weeks after implantation. In addition, the growth factors released from T-hASCs were assessed. RESULTS: In vitro, hASCs displayed significant radiotolerance, maintaining consistent viability after exposure to 10 Gy. TNF-α treatment further enhanced radiation tolerance, as evidenced by significantly higher viability than C-hASCs at 20 Gy. In vivo, T-hASC-coated implants effectively suppressed RICC, reducing capsule thickness. T-hASCs exhibited remarkable modulation of the inflammatory response, suppressing M1 macrophage polarization while enhancing M2 polarization. The elevated secretion of vascular endothelial growth factor from T-hASCs is believed to induce macrophage polarization, potentially reducing RICC. CONCLUSION: This study establishes T-hASCs as a promising strategy for ameliorating the adverse effects experienced by breast reconstruction patients after mastectomy and radiation therapy. The observed radiotolerance, anti-fibrotic effects, and immune modulation suggest the possibility of enhancing patient outcomes and quality of life. Further research and clinical trials are warranted for broader clinical uses.

Clinical practice recommendations for the use of next-generation sequencing in patients with solid cancer: a joint report from KSMO and KSP.

In recent years, next-generation sequencing (NGS)-based genetic testing has become crucial in cancer care. While its primary objective is to identify actionable genetic alterations to guide treatment decisions, its scope has broadened to encompass aiding in pathological diagnosis and exploring resistance mechanisms. With the ongoing expansion in NGS application and reliance, a compelling necessity arises for expert consensus on its application in solid cancers. To address this demand, the forthcoming recommendations not only provide pragmatic guidance for the clinical use of NGS but also systematically classify actionable genes based on specific cancer types. Additionally, these recommendations will incorporate expert perspectives on crucial biomarkers, ensuring informed decisions regarding circulating tumor DNA panel testing.

Clinical phenotype of pulmonary vascular disease requiring treatment in extremely preterm infants.

BACKGROUND: Pulmonary vascular disease (PVD) and pulmonary hypertension (PH) is a significant disorder affecting prognosis of extremely preterm infants. However, there is still a lack of a consensus on the definition and optimal treatments of PH, and there is also a lack of research comparing these conditions with persistent pulmonary hypertension of newborn (PPHN), early PH, and late PH. To investigate PH in extremely preterm infants, this study compared the baseline characteristics, short-term outcomes, and treatment duration, categorized by the timing of requiring PH treatment. METHODS: This study retrospectively analyzed extremely preterm infants admitted to a single tertiary center. Between 2018 and 2022, infants with clinical or echocardiographic diagnosis of PH who required treatment were divided into three groups based on the timing of treatment initiation: initial 3 days (extremely early-period), from day 4 to day 27 (early-period), and after day 28 (late-period). The study compared the outcomes, including mortality rates, bronchopulmonary dysplasia (BPD) severity, PH treatment duration, and oxygen therapy duration, among the three groups. RESULTS: Among the 157 infants, 67 (42.7%) were treated for PH during their stay. Of these, 39 (57.3%) were treatment in extremely early, 21 (31.3%) in early, and seven (11.4%) in late periods. No significant differences were observed in maternal factors, neonatal factors, or morbidity between the three groups. However, infants who received extremely early-period treatment had a higher mortality rate, but shorter duration of noninvasive respiratory support, oxygen therapy, and PH medication use. On the other hand, the late-period treatment group received longer durations of respiratory support and treatment. CONCLUSIONS: This study revealed differences in mortality rates, respiratory outcomes, and treatment duration between the three groups, suggesting varying pathophysiologies over time in extremely preterm infants.

HLA-DPB1*05:01 and HLA-A*11:01 Is Associated with Adverse Drug Reactions to Isoniazid and Rifampin for Treatment of Latent Tuberculosis Infection in South Korea.

Background: Screening and treating healthcare workers (HCWs) for latent tuberculosis infection (LTBI) are essential for tuberculosis (TB) infection control. Adverse drug reactions (ADRs) to anti-TB drugs present challenges to patient safety and treatment completion. Objective: This study investigated the association between human leukocyte antigen (HLA) alleles and the risk of ADRs, especially drug hypersensitivity (DHS) and hepatotoxicity, in HCWs with LTBI receiving isoniazid (INH) and rifampin (RIF) therapy. Methods: Korean HCWs with LTBI who received a 3 month INH and RIF regimen were included in this study. HLA genotyping was performed on HCWs who experienced ADRs during treatment, as well as the control group consisted of individuals who did not develop ADRs. Results: Of the 67 patients, 29 (43.2%) experienced ADRs during INH and RIF therapy. The HLA-A*11:01 allele was more frequent in patients with DHS without hepatotoxicity (DSH+/H-) compared to the control group (DHS-/H-) (4/9, 44.4% vs. 3/38, 7.9%; odd ratio [OR], 8.554; 95% confidence interval [CI], 1.415-59.869; p = 0.018). Conversely, HLA-DPB1*05:01 was associated with an increased risk of hepatotoxicity regardless of DHS (10/20, 50% vs. 5/38, 13.2%; OR, 5.323; 95% CI, 1.493-21.518; p = 0.011). In the DHS with hepatotoxicity group (DHS+/H+), HLA-DPB1*05:01 was present in a higher proportion (3/5, 60% vs. 5/38, 13.2%; OR, 8.912; 95% CI, 1.110-92.993; p = 0.037), whereas HLA-A*11:01 was not observed in this group. Conclusions: The HLA-A*11:01 allele was associated with an increased risk of DHS without hepatotoxicity, whereas the HLA-DPB1*05:01 allele was associated with an increased risk of hepatotoxicity.

Structure-Guided Engineering of Thermodynamically Enhanced SaCas9 for Improved Gene Suppression.

Proteins with multiple domains play pivotal roles in various biological processes, necessitating a thorough understanding of their structural stability and functional interplay. Here, a structure-guided protein engineering approach is proposed to develop thermostable Cas9 (CRISPR-associated protein 9) variant for CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) interference applications. By employing thermodynamic analysis, combining distance mapping and molecular dynamics simulations, deletable domains are identified to enhance stability while preserving the DNA recognition function of Cas9. The resulting engineered Cas9, termed small and dead form Cas9, exhibits improved thermostability and maintains target DNA recognition function. Cryo-electron microscopy analysis reveals structural integrity with reduced atomic density in the deleted domain. Fusion with functional elements enables intracellular delivery and nuclear localization, demonstrating efficient gene suppression in diverse cell types. Direct delivery in the mouse brain shows enhanced knockdown efficiency, highlighting the potential of structure-guided engineering to develop functional CRISPR systems tailored for specific applications. This study underscores the significance of integrating computational and experimental approaches for protein engineering, offering insights into designing tailored molecular tools for precise biological interventions.

Return to sporting activities following long fusions to the pelvis in adult spinal deformity.

BACKGROUND CONTEXT: Returning to recreational sporting activities after adult spinal deformity (ASD) correction may significantly impact the patient's perceived quality of life. PURPOSE: This study sought to characterize participation in sporting activities before and after ASD surgery, and to identify factors associated with impaired return to sports. STUDY DESIGN: Cross-sectional survey and retrospective review of prospectively collected data. PATIENT SAMPLE: Patients who underwent posterior-only thoracolumbar ASD surgery between 2016 and 2021 with ≥1 year follow-up and ≥3 levels of fusion to the pelvis were included. OUTCOME MEASURES: Preoperative and postoperative participation in sports, timing of return to these activities, and reasons for limited sports participation postoperatively were assessed. METHODS: A survey was used to evaluate outcome measures. Differences in demographic, surgical, and perioperative variables between patients who reported improved, unchanged, or worsened activity tolerance were evaluated. RESULTS: Ninety-five patients were included (mean age: 64.3±10.1 years; BMI: 27.3±6.1 kg/m2; median levels fused: 7). The survey was completed at an average of 43.5±15.9 months after surgery. Sixty-eight (72%) patients participated in sports preoperatively. The most common sports were swimming (n=33, 34.7%), yoga (n=23, 24.2%), weightlifting (n=20, 21.1%), elliptical (n=19, 20.0%), and golf (n=11, 11.6%). Fifty-seven (83.8%) returned to at least one sport postoperatively, most commonly 6-12 months after surgery (45%). Elliptical had the highest rate of equal or improved participation (53%). Patients generally returned below their preoperative level to all other sports. Reasons for reduced sporting activities included physical limitation (51.4%), fear (20.0%), pain (17.1%), and surgeon advice (8.6%). There were no differences in the demographic, surgical, or perioperative characteristics between those who returned to sports at the same or better level compared with those who returned at a lower level. CONCLUSIONS: About 84% of patients successfully resumed sporting activities after undergoing fusion to the sacrum/pelvis for ASD. However, this return is typically at a lower level of participation than their preoperative participation, particularly in higher demand sports. Understanding trends in sporting activity may be valuable for counseling patients and setting expectations.

Functional Hierarchy of the Human Neocortex from Cradle to Grave.

Recent evidence indicates that the organization of the human neocortex is underpinned by smooth spatial gradients of functional connectivity (FC). These gradients provide crucial insight into the relationship between the brain's topographic organization and the texture of human cognition. However, no studies to date have charted how intrinsic FC gradient architecture develops across the entire human lifespan. In this work, we model developmental trajectories of the three primary gradients of FC using a large, high-quality, and temporally-dense functional MRI dataset spanning from birth to 100 years of age. The gradient axes, denoted as sensorimotor-association (SA), visual-somatosensory (VS), and modulation-representation (MR), encode crucial hierarchical organizing principles of the brain in development and aging. By tracking their evolution throughout the human lifespan, we provide the first ever comprehensive low-dimensional normative reference of global FC hierarchical architecture. We observe significant age-related changes in global network features, with global markers of hierarchical organization increasing from birth to early adulthood and decreasing thereafter. During infancy and early childhood, FC organization is shaped by primary sensory processing, dense short-range connectivity, and immature association and control hierarchies. Functional differentiation of transmodal systems supported by long-range coupling drives a convergence toward adult-like FC organization during late childhood, while adolescence and early adulthood are marked by the expansion and refinement of SA and MR hierarchies. While gradient topographies remain stable during late adulthood and aging, we observe decreases in global gradient measures of FC differentiation and complexity from 30 to 100 years. Examining cortical microstructure gradients alongside our functional gradients, we observed that structure-function gradient coupling undergoes differential lifespan trajectories across multiple gradient axes.

Parathyroid-on-a-chip simulating parathyroid hormone secretion in response to calcium concentration.

The parathyroid gland is an endocrine organ that plays a crucial role in regulating calcium levels in blood serum through the secretion of parathyroid hormone (PTH). Hypoparathyroidism is a chronic disease that can occur due to parathyroid defects, but due to the difficulty of creating animal models of this disease or obtaining human normal parathyroid cells, the evaluation of parathyroid functionality for drug development is limited. Although parathyroid-like cells that secrete PTH have recently been reported, their functionality may be overestimated using traditional culture methods that lack in vivo similarities, particularly vascularization. To overcome these limitations, we obtained parathyroid organoids from tonsil-derived mesenchymal stem cells (TMSCs) and fabricated a parathyroid-on-a-chip, capable of simulating PTH secretion based on calcium concentration. This chip exhibited differences in PTH secretion according to calcium concentration and secreted PTH within the range of normal serum levels. In addition, branches of organoids, which are difficult to observe in animal models, were observed in this chip. This could serve as a guideline for successful engraftment in implantation therapies in the future.