The harms of promoting the lab leak hypothesis for SARS-CoV-2 origins without evidence.

Science is humanity's best insurance against threats from nature, but it is a fragile enterprise that must be nourished and protected. The preponderance of scientific evidence indicates a natural origin for SARS-CoV-2. Yet, the theory that SARS-CoV-2 was engineered in and escaped from a lab dominates media attention, even in the absence of strong evidence. We discuss how the resulting anti-science movement puts the research community, scientific research, and pandemic preparedness at risk.

Comparison of the Clinical Manifestations of Acute Coronary Syndrome Between Diabetic and Non-diabetic Patients: A Systematic Review and Meta-Analysis.

The presentation of acute coronary syndrome (ACS) in patients with type 2 diabetes mellitus (T2DM) may differ from that of non-diabetic patients, potentially leading to delayed diagnosis and treatment. This meta-analysis aimed to compare the clinical presentation of ACS between diabetic and non-diabetic patients. A systematic search of PubMed, Excerpta Medica database (EMBASE), and Web of Science databases was conducted for observational studies published from January 2010 onwards. Studies comparing ACS symptoms between diabetic and non-diabetic patients were included. The odds ratio (OR) with 95% confidence intervals (CI) was calculated using a random-effects model. Eight studies with a total of 29,503 patients (23.03% diabetic) were included. Diabetic patients were significantly less likely to present with chest pain compared to non-diabetic patients (OR: 0.43, 95% CI: 0.30 to 0.63, p<0.001). Anxiety (OR: 2.20, 95% CI: 1.17-4.14), shortness of breath (OR: 1.49, 95% CI: 1.11-2.01), and neck pain (OR: 1.62, 95% CI: 1.03-2.54) were significantly more common in diabetic patients. Sweating/cold sweat was less common in diabetics (OR: 0.60, 95% CI: 0.34-1.07), though not statistically significant. Other symptoms showed minimal differences between groups. High heterogeneity was observed across studies for most symptoms. This meta-analysis demonstrates that diabetic patients with ACS are less likely to experience typical chest pain and more likely to present with atypical symptoms such as anxiety, shortness of breath, and neck pain. These findings emphasize the need for healthcare providers to maintain high vigilance for atypical ACS presentations in diabetic patients. Tailored diagnostic approaches, modified triage protocols, and enhanced patient education are crucial to improving the timely diagnosis and treatment of ACS in this high-risk population.

Proximity to humans is associated with antimicrobial-resistant enteric pathogens in wild bird microbiomes.

Humans are radically altering global ecology, and one of the most apparent human-induced effects is urbanization, where high-density human habitats disrupt long-established ecotones. Changes to these transitional areas between organisms, especially enhanced contact among humans and wild animals, provide new opportunities for the spread of zoonotic pathogens. This poses a serious threat to global public health, but little is known about how habitat disruption impacts cross-species pathogen spread. Here, we investigated variation in the zoonotic enteric pathogen Campylobacter jejuni. The ubiquity of C. jejuni in wild bird gut microbiomes makes it an ideal organism for understanding how host behavior and ecology influence pathogen transition and spread. We analyzed 700 C. jejuni isolate genomes from 30 bird species in eight countries using a scalable generalized linear model approach. Comparing multiple behavioral and ecological traits showed that proximity to human habitation promotes lineage diversity and is associated with antimicrobial-resistant (AMR) strains in natural populations. Specifically, wild birds from urban areas harbored up to three times more C. jejuni genotypes and AMR genes. This study provides novel methodology and much-needed quantitative evidence linking urbanization to gene pool spread and zoonoses.

Can Large Language Models (LLMs) Predict the Appropriate Treatment of Acute Hip Fractures in Older Adults? Comparing Appropriate Use Criteria With Recommendations From ChatGPT.

BACKGROUND: Acute hip fractures are a public health problem affecting primarily older adults. Chat Generative Pretrained Transformer may be useful in providing appropriate clinical recommendations for beneficial treatment. OBJECTIVE: To evaluate the accuracy of Chat Generative Pretrained Transformer (ChatGPT)-4.0 by comparing its appropriateness scores for acute hip fractures with the American Academy of Orthopaedic Surgeons (AAOS) Appropriate Use Criteria given 30 patient scenarios. "Appropriateness" indicates the unexpected health benefits of treatment exceed the expected negative consequences by a wide margin. METHODS: Using the AAOS Appropriate Use Criteria as the benchmark, numerical scores from 1 to 9 assessed appropriateness. For each patient scenario, ChatGPT-4.0 was asked to assign an appropriate score for six treatments to manage acute hip fractures. RESULTS: Thirty patient scenarios were evaluated for 180 paired scores. Comparing ChatGPT-4.0 with AAOS scores, there was a positive correlation for multiple cannulated screw fixation, total hip arthroplasty, hemiarthroplasty, and long cephalomedullary nails. Statistically significant differences were observed only between scores for long cephalomedullary nails. CONCLUSION: ChatGPT-4.0 scores were not concordant with AAOS scores, overestimating the appropriateness of total hip arthroplasty, hemiarthroplasty, and long cephalomedullary nails, and underestimating the other three. ChatGPT-4.0 was inadequate in selecting an appropriate treatment deemed acceptable, most reasonable, and most likely to improve patient outcomes.

Bibliometric Patent Review of Minimally Invasive Spine Surgery.

STUDY DESIGN: This study analyzes patents associated with minimally invasive spine surgery (MISS) found on the Lens open online platform. OBJECTIVE: The goal of this research was to provide an overview of the most referenced patents in the field of MISS and to uncover patterns in the evolution and categorization of these patents. SUMMARY OF BACKGROUND DATA: MISS has rapidly progressed, with a core focus on minimizing surgical damage, preserving the natural anatomy, and enabling swift recovery, all while achieving outcomes that rival traditional open surgery. While prior studies have primarily concentrated on MISS outcomes, the analysis of MISS patents has been limited. METHODS: To conduct this study, we used the Lens platform to search for patents that included the terms "minimally invasive" and "spine" in their titles, abstracts, or claims. We then categorized these patents and identified the top 100 with the most forward citations. We further classified these patents into 4 categories: Spinal Stabilization Systems, Joint Implants or Procedures, Screw Delivery System or Method, and Access and Surgical Pathway Formation. RESULTS: Five hundred two MISS patents were identified initially, and 276 were retained following a screening process. Among the top 100 patents, the majority had active legal status. The largest category within the top 100 patents was Access and Surgical Pathway Formation, closely followed by Spinal Stabilization Systems and Joint Implants or Procedures. The smallest category was Screw Delivery System or Method. Notably, the majority of the top 100 patents had priority years falling between 2000 and 2009, indicating a moderate positive correlation between patent rank and priority year. CONCLUSIONS: Thus far, patents related to Access and Surgical Pathway Formation have laid the foundation for subsequent innovations in Spinal Stabilization Systems and Screw Technology. This study serves as a valuable resource for guiding future innovations in this rapidly evolving field.

Water-powered, electronics-free dressings that electrically stimulate wounds for rapid wound closure.

Chronic wounds affect ~2% of the U.S. population and increase risks of amputation and mortality. Unfortunately, treatments for such wounds are often expensive, complex, and only moderately effective. Electrotherapy represents a cost-effective treatment; however, its reliance on bulky equipment limits its clinical use. Here, we introduce water-powered, electronics-free dressings (WPEDs) that offer a unique solution to this issue. The WPED performs even under harsh conditions-situations wherein many present treatments fail. It uses a flexible, biocompatible magnesium-silver/silver chloride battery and a pair of stimulation electrodes; upon the addition of water, the battery creates a radial electric field. Experiments in diabetic mice confirm the WPED's ability to accelerate wound closure and promote healing by increasing epidermal thickness, modulating inflammation, and promoting angiogenesis. Across preclinical wound models, the WPED-treated group heals faster than the control with wound closure rates comparable to treatments requiring expensive biologics and/or complex electronics. The results demonstrate the WPED's potential as an effective and more practical wound treatment dressing.

Molecular Detection of Tick-Borne Pathogens in Kumasi: With a First Report of Zoonotic Pathogens in Abattoir Workers.

Tick-borne pathogens continue to infect humans and animals worldwide. By adapting to the movement of livestock, ticks facilitate the spread of these infectious pathogens. Humans in close contact with animals that could be amplifying hosts are especially at risk of being infected with tick-borne pathogens. This study involved the collection of dry blood spots (DBSs) to determine tick-borne pathogens occurring in slaughtered livestock and abattoir workers in Kumasi. This study employed the use of conventional PCR, RT-PCR, and Sanger sequencing to detect and identify the tick-borne pathogens. The resulting data was analysed using Stata version 13. A total of 175 DBSs were collected from goats (76), cattle (54), and sheep (45) in the Kumasi abattoir (130, 74.29%) and Akwatia Line slaughter slab (45, 25.71%). The pathogens identified were mostly bacterial including Anaplasma capra (9.71%), Anaplasma phagocytophilum (1.14%), and Rickettsia aeschlimannii (0.57.%). The only parasite identified was Theileria ovis (9.14%). A significant association was seen between A. capra (p < 0.001) infection and female sheep sampled from the Akwatia Line slaughter slab. Again, there was a significant association between T. ovis (p < 0.001) infections and female sheep from the Kumasi abattoir. From the human DBS (63) screened, the pathogens identified were all bacterial including Coxiella burnetii (1.89%), Rickettsia africae (1.89%), and R. aeschlimannii (1.89%). This study reports the first detection of R. aeschlimannii in livestock as well as the occurrence of the above-mentioned pathogens in humans in Ghana. Animals can serve as amplifying hosts for infectious pathogens; hence, there is an increased risk of infections among the abattoir workers. Continuous surveillance effort is essential, and abattoir workers need to protect themselves from tick bites and infectious tick-borne pathogens.

Engineering a "muco-trapping" ACE2-immunoglobulin hybrid with picomolar affinity as an inhaled, pan-variant immunotherapy for COVID-19.

Soluble angiotensin-converting enzyme 2 (ACE2) can act as a decoy molecule that neutralizes severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by blocking spike (S) proteins on virions from binding ACE2 on host cells. Based on structural insights of ACE2 and S proteins, we designed a "muco-trapping" ACE2-Fc conjugate, termed ACE2-(G4S)6-Fc, comprised of the extracellular segment of ACE2 (lacking the C-terminal collectrin domain) that is linked to mucin-binding IgG1-Fc via an extended glycine-serine flexible linker. ACE2-(G4S)6-Fc exhibits substantially greater binding affinity and neutralization potency than conventional full length ACE2-Fc decoys or similar truncated ACE2-Fc decoys without flexible linkers, possessing picomolar binding affinity and strong neutralization potency against pseudovirus and live virus. ACE2-(G4S)6-Fc effectively trapped fluorescent SARS-CoV-2 virus like particles in fresh human airway mucus and was stably nebulized using a commercial vibrating mesh nebulizer. Intranasal dosing of ACE2-(G4S)6-Fc in hamsters as late as 2 days postinfection provided a 10-fold reduction in viral load in the nasal turbinate tissues by Day 4. These results strongly support further development of ACE2-(G4S)6-Fc as an inhaled immunotherapy for COVID-19, as well as other emerging viruses that bind ACE2 for cellular entry.

Supportive care interventions in metastatic bone disease: scoping review.

BACKGROUND: Patients with secondary metastatic involvement of the musculoskeletal system due to primary cancers are a rapidly growing population with significant risks for health-related end-of-life morbidities. In particular, bone metastases or metastatic bone disease (MBD) imparts significant adversity to remaining quality of life. No rigorous review of clinical trials on the use of supportive care interventions for MBD has been conducted. The objective of this review was to examine the characteristics of supportive care interventions for MBD and critically appraise study designs, key findings, and quality of evidence of the research. METHODS: We searched for published clinical trials, systematic reviews and meta-analyses in PubMED, CINAHL and Google Scholar for articles published between September 2017 and September 2022. Some examples of Medical Subject Headings terms were: 'secondary neoplasm', 'metastatic bone disease', 'palliative care' and 'supportive care intervention'. Quality of published evidence was evaluated based on treatment types and study design. RESULTS: After reviewing 572 publications, 13 articles were included in the final review and evaluation including seven clinical trials, two trial protocols and four systematic reviews. Feasible interventions included enhanced palliative care consultation, palliative radiotherapy and alternative medicines. Interventions addressed primary endpoints of fatigue (N=4, 31%), pain (N=3, 23%) or cancer-related symptoms (N=3, 23%) with patient-reported outcome instruments. No interventions reported on fracture complications or endpoints, specifically. The quality of most studies was moderate to strong. CONCLUSION: Supportive care interventions for MBD are feasible and the impact is measurable via patient-reported outcome measures. While the evidence for interventions was moderate to strong, there are very few specific controlled trials for skeletal-related events and impacts of social determinants of health. Further clinical trials are needed to define supportive care interventions for MBD that demonstrate reduced risk of fracture and that mitigate the reduced quality of life when negative musculoskeletal outcomes arise.

Medical abortion in Ghana: A non-randomized, non-inferiority study of access through pharmacies compared with clinics.

OBJECTIVES: To compare self-reported clinical outcomes following medical abortion with mifepristone and misoprostol sourced from either a pharmacy or health clinic. STUDY DESIGN: We conducted a prospective, non-randomized, non-inferiority cohort study across four regions in Ghana, from high-volume pharmacies and health clinics. Participants seeking medical abortion (less than nine weeks' gestation) who met usual medical abortion eligibility criteria were recruited. Data collection included baseline surveys, follow-up phone interviews, and self-reported assessments of medical abortion outcomes. The study aimed to enroll 2000 medical abortion users (1000 from each source). RESULTS: Complete outcome data was available and analyzed from 1958 participants (of 2208 enrolled), with the adjusted risk difference of need for additional treatment to complete the abortion indicating non-inferiority of the pharmacy group compared to the clinic group [-2.3% (95% CI -5.3% to 0.7%)]. Both groups reported low rates of additional treatment (4.9%) and adhered similarly to the abortion regimen. Secondary outcomes showed no significant differences, with moderate acceptability in both groups (65.4% pharmacy, 52.3% facility). Adverse outcomes were rare: one ectopic pregnancy, one blood transfusion and no deaths or other major complications were reported. CONCLUSIONS: Accessing medical abortion pills directly from pharmacies without prior consultation from a provider demonstrated non-inferior self-reported clinical outcomes compared to seeking care from health clinics. The findings align with the growing global evidence supporting the safety and effectiveness of medical abortion self-care. IMPLICATIONS: This study contributes data which support future registration of over-the-counter use of medical abortion drugs up to nine weeks' gestation. Such measures could expand options for safe abortion care, especially in regions where unsafe abortion poses a substantial maternal health risk. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03727308).

A Comparison of Rosuvastatin Monotherapy and Rosuvastatin Plus Ezetimibe Combination Therapy in Patients With Type 2 Diabetes: A Meta-Analysis of Randomized Controlled Trials.

Type 2 diabetes mellitus is a metabolic condition where vascular inflammation and oxidative stress contribute to disease progression and associated complications. Although statins are recommended for managing dyslipidemia in diabetes, additional therapies are often required to achieve target lipid levels. This meta-analysis aimed to evaluate the efficacy of rosuvastatin monotherapy versus combination therapy with ezetimibe in patients with type 2 diabetes. A systematic literature search was conducted across multiple databases until April 2024, identifying six randomized controlled trials meeting the inclusion criteria. The meta-analysis revealed that the rosuvastatin plus ezetimibe combination resulted in significantly greater reductions in total cholesterol (mean difference, or MD: 19.49; 95% CI: 13.99 to 24.99), triglycerides (MD: 13.44; 95% CI: 2.04 to 24.85), and low-density lipoprotein cholesterol (MD: -17.68; 95% CI: 12.85 to 22.51) compared to rosuvastatin monotherapy. Conversely, rosuvastatin monotherapy achieved a greater reduction in HbA1c levels (MD: -0.11; 95% CI: -0.17 to -0.04). Subgroup analysis demonstrated that using the same dose of rosuvastatin in both groups led to more significant improvements in lipid parameters with lower heterogeneity. The findings suggest that the rosuvastatin-ezetimibe combination may be a more effective lipid-lowering strategy for patients with type 2 diabetes, though larger studies are needed to assess long-term safety and optimal dosing. Additionally, while rosuvastatin monotherapy provided modest HbA1c reductions, the clinical relevance remains uncertain, and potential risks with high-dose statins should be considered.

Effect of Pulmonary Hypertension on Survival Outcomes in Patients With Transcatheter Aortic Valve Replacement: A Systematic Review and Meta-Analysis.

The aim of this meta-analysis was to determine the effect of pulmonary hypertension (PH) on survival in patients undergoing transcatheter aortic valve replacement (TAVR). The present study was conducted according to the guidelines of Preferred Reporting of Systematic Review and Meta-Analysis (PRISMA). We conducted a comprehensive search of electronic databases including PubMed/MEDLINE, Embase, Cochrane Library, and Web of Science from January 1, 2015, to March 10, 2024. Outcomes assessed in this meta-analysis included early and late all-cause mortality and cardiovascular mortality. Total 15 studies were integrated into the pooled analysis to assess the impact of PH on outcomes among patients undergoing TAVR, comprising a total sample size of 35,732 individuals. The pooled prevalence of PH stood at 52.57% (n=18,767). Predominantly, the studies were conducted in the United States (n=6), followed by Germany (n=3), with one study each from Japan, Italy, Switzerland, Brazil, Poland, and Australia. Pooled analysis showed that risk of short-term mortality was greater in patients with PH compared to patients without PH (risk ratio (RR): 1.46, 95% CI: 1.19 to 1.80). Risk of long-term mortality was greater in patients with PH (RR: 1.42, 95% CI: 1.29 to 1.55). Risk of cardiovascular mortality was also greater in patients with PH compared to patients without PH (RR: 1.66, 95% CI: 1.36 to 2.02). We advocate for further research to address gaps in understanding different types of PH and their impacts on mortality and cardiovascular outcomes.

Comparing opioid utilization and costs for surgical management of single-level spondylolisthesis: A national claims database analysis.

Introduction: The rise in degenerative lumbar spondylolisthesis (DLS) cases has led to a significant increase in fusion surgeries, which incur substantial hospitalization costs and often necessitate chronic opioid use for pain management. Recent evidence suggests that single-level low-grade DLS outcomes are comparable whether a fusion procedure or decompression alone is performed, sparking debate over the cost-effectiveness of these procedures, particularly with the advent of minimally invasive techniques reducing the morbidity of fusion. This study aims to compare chronic opioid utilization and associated costs between decompression alone and decompression with instrumented fusion for single-level degenerative lumbar spondylolisthesis. Material and methods: Using data from the PearlDiver database, a retrospective database analysis was conducted. We analyzed records of Medicare and Medicaid patients undergoing lumbar fusion or decompression from 2010 to 2022. Patient cohorts were divided into decompression alone (DA) and decompression with instrumented fusion (DIF). Chronic opioid use, pain clinic visits, and total costs were compared between the two groups at 90 days, 1 year, and 2 years post-surgery. Theory: Does DIF offer a more cost-effective approach to managing DLS in terms of chronic opioid use in single-level DLS patients. Results: The study revealed comparable chronic opioid use and pain clinic visits between DA and DIF groups at 90 days and 1 year. However, total costs associated with opioid prescriptions as well as surgical aftercare were significantly higher in the DIF group at 90 days (p < 0.05), 1 year (p < 0.05), and 2 years (p < 0.05) post-surgery compared to the DA group. Conclusions: This study highlights the higher costs associated with DIF up to 2 years post-surgery despite comparable symptom improvement when compared to DA and DIF at the 1-year interval. DA emerges as a more financially favorable option, challenging the notion of fusion's cost-offsetting benefits. While further investigation is needed to understand underlying cost drivers and optimize outcomes, our findings emphasize the necessity of integrating clinical and economic factors in the management of single-level DLS.

Modelling the potential impact of global hepatitis B vaccination on the burden of chronic hepatitis B in the United States.

About 80% of persons with chronic hepatitis B virus (HBV) infection in the United States are non-US-born. Despite improvements in infant hepatitis B vaccination globally since 2000, work remains to attain the World Health Organization's (WHO) global 2030 goal of 90% vaccination. We explore the impacts on the United States of global progress in hepatitis B vaccination since 2000 and of achieving WHO hepatitis B vaccination goals. We simulated immigrants with HBV infection arriving to the United States from 2000 to 2070 using models of the 10 countries from which the largest numbers of individuals with HBV infection were born. We estimated costs in the United States among these cohorts using a disease simulation model. We simulated three scenarios: a scenario with no progress in infant vaccination for hepatitis B since 2000 (baseline), current (2020) progress and achieving WHO 2030 goals for hepatitis B vaccination. We estimate current hepatitis B vaccination progress since the 2000 baseline in these 10 countries will lead to 468,686 fewer HBV infections, avoid 35,582 hepatitis B-related deaths and save $4.2 billion in the United States through 2070. Achieving the WHO 2030 90% hepatitis B infant vaccination targets could lead to an additional 16,762 fewer HBV infections, 989 fewer hepatitis B-related deaths and save $143 million through 2070. Global hepatitis B vaccination since 2000 reduced prevalence of HBV infection in the United States. Achieving the WHO 2030 infant vaccination goals globally could lead to over one hundred million dollars in additional savings.

Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity.

Isocitrate dehydrogenase 1 (IDH1) is the most commonly mutated metabolic gene across human cancers. Mutant IDH1 (mIDH1) generates the oncometabolite (R)-2-hydroxyglutarate, disrupting enzymes involved in epigenetics and other processes. A hallmark of IDH1-mutant solid tumors is T cell exclusion, whereas mIDH1 inhibition in preclinical models restores antitumor immunity. Here, we define a cell-autonomous mechanism of mIDH1-driven immune evasion. IDH1-mutant solid tumors show selective hypermethylation and silencing of the cytoplasmic double-stranded DNA (dsDNA) sensor CGAS, compromising innate immune signaling. mIDH1 inhibition restores DNA demethylation, derepressing CGAS and transposable element (TE) subclasses. dsDNA produced by TE-reverse transcriptase (TE-RT) activates cGAS, triggering viral mimicry and stimulating antitumor immunity. In summary, we demonstrate that mIDH1 epigenetically suppresses innate immunity and link endogenous RT activity to the mechanism of action of a US Food and Drug Administration-approved oncology drug.

Mitigation of Fetal Radiation Injury from Mid-Gestation Total-body Irradiation by Maternal Administration of Mitochondrial-Targeted GS-Nitroxide JP4-039.

Victims of a radiation terrorist event will include pregnant women and unborn fetuses. Mitochondrial dysfunction and oxidative stress are key pathogenic factors of fetal radiation injury. The goal of this preclinical study is to investigate the efficacy of mitigating fetal radiation injury by maternal administration of the mitochondrial-targeted gramicidin S (GS)-nitroxide radiation mitigator JP4-039. Pregnant female C57BL/6NTac mice received 3 Gy total-body irradiation (TBI) at mid-gestation embryonic day 13.5 (E13.5). Using novel time-and-motion-resolved 4D in utero magnetic resonance imaging (4D-uMRI), we found TBI caused extensive injury to the fetal brain that included cerebral hemorrhage, loss of cerebral tissue, and hydrocephalus with excessive accumulation of cerebrospinal fluid (CSF). Histopathology of the fetal mouse brain showed broken cerebral vessels and elevated apoptosis. Further use of novel 4D Oxy-wavelet MRI capable of probing in vivo mitochondrial function in intact brain revealed a significant reduction of mitochondrial function in the fetal brain after 3 Gy TBI. This was validated by ex vivo Oroboros mitochondrial respirometry. One day after TBI (E14.5) maternal administration of JP4-039, which passes through the placenta, significantly reduced fetal brain radiation injury and improved fetal brain mitochondrial respiration. Treatment also preserved cerebral brain tissue integrity and reduced cerebral hemorrhage and cell death. JP4-039 administration following irradiation resulted in increased survival of pups. These findings indicate that JP4-039 can be deployed as a safe and effective mitigator of fetal radiation injury from mid-gestational in utero ionizing radiation exposure.

Genetic and epigenetic instability as an underlying driver of progression and aggressive behavior in IDH-mutant astrocytoma.

In recent years, the classification of adult-type diffuse gliomas has undergone a revolution, wherein specific molecular features now represent defining diagnostic criteria of IDH-wild-type glioblastomas, IDH-mutant astrocytomas, and IDH-mutant 1p/19q-codeleted oligodendrogliomas. With the introduction of the 2021 WHO CNS classification, additional molecular alterations are now integrated into the grading of these tumors, given equal weight to traditional histologic features. However, there remains a great deal of heterogeneity in patient outcome even within these established tumor subclassifications that is unexplained by currently codified molecular alterations, particularly in the IDH-mutant astrocytoma category. There is also significant intercellular genetic and epigenetic heterogeneity and plasticity with resulting phenotypic heterogeneity, making these tumors remarkably adaptable and robust, and presenting a significant barrier to the design of effective therapeutics. Herein, we review the mechanisms and consequences of genetic and epigenetic instability, including chromosomal instability (CIN), microsatellite instability (MSI)/mismatch repair (MMR) deficits, and epigenetic instability, in the underlying biology, tumorigenesis, and progression of IDH-mutant astrocytomas. We also discuss the contribution of recent high-resolution transcriptomics studies toward defining tumor heterogeneity with single-cell resolution. While intratumoral heterogeneity is a well-known feature of diffuse gliomas, the contribution of these various processes has only recently been considered as a potential driver of tumor aggressiveness. CIN has an independent, adverse effect on patient survival, similar to the effect of histologic grade and homozygous CDKN2A deletion, while MMR mutation is only associated with poor overall survival in univariate analysis but is highly correlated with higher histologic/molecular grade and other aggressive features. These forms of genomic instability, which may significantly affect the natural progression of these tumors, response to therapy, and ultimately clinical outcome for patients, are potentially measurable features which could aid in diagnosis, grading, prognosis, and development of personalized therapeutics.

Association of clonal hematopoiesis and mosaic chromosomal alterations with solid malignancy incidence and mortality.

BACKGROUND: Understanding the impact of clonal hematopoiesis of indeterminate potential (CHIP) and mosaic chromosomal alterations (mCAs) on solid tumor risk and mortality can shed light on novel cancer pathways. METHODS: The authors analyzed whole genome sequencing data from the Trans-Omics for Precision Medicine Women's Health Initiative study (n = 10,866). They investigated the presence of CHIP and mCA and their association with the development and mortality of breast, lung, and colorectal cancers. RESULTS: CHIP was associated with higher risk of breast (hazard ratio [HR], 1.30; 95% confidence interval [CI], 1.03-1.64; p = .02) but not colorectal (p = .77) or lung cancer (p = .32). CHIP carriers who developed colorectal cancer also had a greater risk for advanced-stage (p = .01), but this was not seen in breast or lung cancer. CHIP was associated with increased colorectal cancer mortality both with (HR, 3.99; 95% CI, 2.41-6.62; p < .001) and without adjustment (HR, 2.50; 95% CI, 1.32-4.72; p = .004) for advanced-stage and a borderline higher breast cancer mortality (HR, 1.53; 95% CI, 0.98-2.41; p = .06). Conversely, mCA (cell fraction [CF] >3%) did not correlate with cancer risk. With higher CFs (mCA >5%), autosomal mCA was associated with increased breast cancer risk (HR, 1.39; 95% CI, 1.06-1.83; p = .01). There was no association of mCA (>3%) with breast, colorectal, or lung mortality except higher colon cancer mortality (HR, 2.19; 95% CI, 1.11-4.3; p = .02) with mCA >5%. CONCLUSIONS: CHIP and mCA (CF >5%) were associated with higher breast cancer risk and colorectal cancer mortality individually. These data could inform on novel pathways that impact cancer risk and lead to better risk stratification.

Comparison of biportal endoscopic and microscopic tubular paraspinal approach for foraminal and extraforaminal lumbar disc herniation.

OBJECTIVE: Foraminal and extraforaminal lumbar disc herniation (FELDH) is an important pathological condition that can lead to lumbar radiculopathy. The paraspinal muscle-splitting approach introduced by Reulen and Wiltse is a reasonable surgical technique. Minimally invasive procedures using a tubular retractor system have also been introduced. However, surgical treatment is considered more challenging for FELDH than for central or subarticular lumbar disc herniations (LDHs). Some researchers have proposed uniportal extraforaminal endoscopic lumbar discectomy through a posterolateral approach as an alternative for FELDH, but heterogeneous clinical results have been reported. Recently, the biportal endoscopic (BE) paraspinal approach has been suggested as an alternative. The aim of this study was to compare the clinical outcomes of BE and microscopic tubular (MT) paraspinal approaches for decompressive foraminotomy and lumbar discectomy (paraLD) in patients with FELDH. METHODS: Ninety-one consecutive patients with unilateral lumbar radiculopathy and FELDH underwent paraLD. Demographic and perioperative data were collected. Clinical outcomes were evaluated using the visual analog scale (VAS) for back and leg pain, the Oswestry Disability Index (ODI) for spinal disability, and the modified Macnab criteria for patient satisfaction. Postoperative complications and reoperation rates were also evaluated. RESULTS: In total, 76 patients were included in the final analysis. Among them, 43 underwent BE paraLD (group A) and the remaining 33 underwent MT paraLD (group B). The demographic and preoperative data were not statistically different between the groups. All patients showed significant improvements in VAS back, VAS leg, and ODI scores compared with baseline values (p < 0.05). The improvement in VAS back scores was significantly better in group A than in group B on postoperative day 2 (p < 0.001). However, all clinical parameters were comparable between the two groups after postoperative year 1 (p > 0.05). According to the modified Macnab criteria, 86.1% and 72.7% of the patients had excellent or good outcomes in groups A and B, respectively. No intergroup differences were observed (p = 0.367). In addition, there were no differences in the total operation time or amount of surgical drainage. Postoperative complications were not significantly different between the two groups (p = 0.301); however, reoperation rates were significantly higher in group B (p = 0.035). CONCLUSIONS: BE paraLD is an effective treatment for FELDH and is an alternative to MT paraLD. In particular, BE paraLD has advantages of early improvement in postoperative back pain and low reoperation rates.