Bioactivation and reactivity research advances-2023 year in review.

Advances in the field of bioactivation have significantly contributed to our understanding and prediction of drug-induced liver injury (DILI). It has been established that many adverse drug reactions, including DILI, are associated with the formation and reactivity of metabolites. Modern methods allow us to detect and characterize these reactive metabolites in earlier stages of drug development, which helps anticipate and circumvent the potential for DILI. Improved in silico models and experimental techniques that better reflect in vivo environments are enhancing predictive capabilities for DILI risk. Further, studies on the mechanisms of bioactivation, including enzyme interactions and the role of individual genetic differences, have provided valuable insights for drug optimizations. Cumulatively, this progress is continually refining our approaches to drug safety evaluation and personalized medicine.Shuai Wang and Cyrus Khojasteh, on behalf of the authors.

Renal Aspergillosis Complicating Renal Allograft Transplantation: A Case Report.

Renal aspergillosis is a rare yet potentially devastating complication following renal allograft transplantation. We present the case of a 45-year-old male with a history of crescentic IgA nephropathy who underwent renal allograft transplantation from his mother. Despite initial favorable progress, he developed post-transplant renal dysfunction attributed to active antibody-mediated rejection. Subsequently, he presented with signs of systemic infection and graft dysfunction, leading to the diagnosis of renal aspergillosis. Despite aggressive management, including antifungal therapy and cessation of immunosuppression, the patient progressed to renal graft cortical necrosis, necessitating nephrectomy. This case underscores the challenges in diagnosing and managing renal aspergillosis in transplant recipients and highlights the importance of early recognition and prompt intervention to improve outcomes in such cases.

The changing epidemiology of traumatic spine injuries: a trends analysis of 26 years of patients at a major level 1 trauma center in the United States.

BACKGROUND CONTEXT: Traumatic spinal injuries (TSI) are associated with high morbidity, mortality, and resource utilization. The epidemiology of TSI varies greatly across different countries and regions and is impacted by national income levels, infrastructure, and cultural factors. Further, there may be changes over time. It is essential to investigate TSI to gain useful epidemiologic information. However, there have been no recent studies on trends for TSI in the US, despite the changing population demographics, healthcare policy, and technology. As a result, re-examination is warranted to reflect how the modern era has affected the epidemiology of US spine trauma patients and their management. PURPOSE: To determine epidemiologic trends in traumatic spine injuries over time. STUDY DESIGN/SETTING: Retrospective analysis; level 1 trauma center in the United States. PATIENT SAMPLE: A total of 21,811 patients, between the years of 1996 and 2022, who presented with traumatic spine injury. OUTCOME MEASURES: Age, sex, race, Injury Severity Score, mechanism of injury, injury diagnosis, injury level, rate of operative intervention, hospital length of stay, intensive care unit length of stay, discharge disposition, in-hospital mortality. METHODS: Data was collected from our institutional trauma registry over a 26-year period. Inclusion criteria involved at least one diagnosis of vertebral fracture, spinal cord injury, spinal subluxation, or intervertebral disc injury. Exclusion criteria consisted of patients with no diagnosed spine injury or a diagnosis of strain only. A total of 21,811 patients were included in the analysis. Descriptive statistics were tabulated and ordinary least squares linear regression was conducted for trends analysis. RESULTS: Regression analysis showed a significant upward trend in patient age (+13.83 years, ß=+0.65/year, p<.001), female sex (+2.7%, ß=+0.18%/year, p=.004), falls (+10.5%, ß=+0.82%/year, p<.001), subluxations (+12.8%, ß=+0.35%/year, p<.001), thoracic injuries (+1.5%, ß=+0.28%/year, p<.001), and discharges to subacute rehab (+15.9%, ß=+0.68%/year, p<.001). There was a significant downward trend in motor vehicle crashes (-7.8%, ß=-0.47%/year, p=.016), firearms injuries (-3.4%, ß=-0.19%/year, p<.001), sports/recreation injuries (-2.9%, ß=-0.18%/year, p<.001), spinal cord injuries (-11.25%, ß=-0.37%, p<.001), complete spinal cord injuries (-7.6%, ß=-0.24%/year, p<.001), and discharges to home (+4.5%, ß=-0.27%/year, p=.011). CONCLUSIONS: At our institution, the average spine trauma patient has trended toward older females. Falls represent an increasing proportion of the mechanism of injury, on a trajectory to become the most common cause. With time, there have been fewer spinal cord injuries and a lower proportion of complete injuries. At discharge, there has been a surge in the utilization of subacute rehabilitation facilities. Overall, there has been no significant change in injury severity, rate of operative intervention, length of stay, or mortality.

Navigating the Uncharted: A Rare Case of Ocular Flutter and Intermittent Jaw Movements in a Case of Chronic Lymphoid Leukemia.

Although chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world, neurologic complications arising from direct leukemic involvement of the nervous system are reported in only 1% of patients with CLL. Ocular involvement in CLL, direct or indirect, is less known and exceptionally rare. This case involves a 63-year-old female with CLL undergoing chemotherapy for a year, who recently presented with unusual eye movements in the horizontal plane (ocular flutter), resting and intentional tremors in the right upper and lower limbs, and intermittent jaw movements. With no established protocol for CLL with central nervous system involvement, collecting case data becomes crucial for determining optimal treatment and diagnostic approaches early on.

ACR Appropriateness Criteria® Soft Tissue Vascular Anomalies: Vascular Malformations and Infantile Vascular Tumors (Non-CNS)-Child.

Soft tissue vascular anomalies may be composed of arterial, venous, and/or lymphatic elements, and diagnosed prenatally or later in childhood or adulthood. They are divided into categories of vascular malformations and vascular tumors. Vascular malformations are further divided into low-flow and fast-flow lesions. A low-flow lesion is most common, with a prevalence of 70%. Vascular tumors may behave in a benign, locally aggressive, borderline, or malignant manner. Infantile hemangioma is a vascular tumor that presents in the neonatal period and then regresses. The presence or multiple skin lesions in an infant can signal underlying visceral vascular anomalies, and complex anomalies may be associated with overgrowth syndromes. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

Characterization of Individuals With Hepatitis B Virus-Related Cirrhosis in a Large Integrated Health Care Organization, 2008-2019.

CONTEXT: Chronic hepatitis B (CHB), caused by hepatitis B virus (HBV), is a risk factor for cirrhosis. The management of HBV-related cirrhosis is challenging, with guidelines recommending treatment initiation and regular monitoring for those affected. OBJECTIVE: Our study characterized Kaiser Permanente Southern California patients with HBV-related cirrhosis and assessed whether they received recommended laboratory testing and imaging monitoring. DESIGN: Retrospective cohort study. SETTING AND PARTICIPANTS: We identified KPSC members aged ≥18 years with CHB (defined by 2, consecutive positive hepatitis B surface antigens ≥6 months apart) from 2008 to 2019. Of these patients, we further identified patients with potential HBV-related cirrhosis through ICD-10 code diagnosis, adjudicated via chart review. MAIN OUTCOME MEASURES: Age, race/ethnicity, laboratory tests (eg, alanine aminotransferase [ALT]), and hepatocellular carcinoma (HCC) screening (based on standard screening recommendations via imaging) were described in those with HBV-related cirrhosis versus those without. RESULTS: Among patients with CHB, we identified 65 patients with HBV-related cirrhosis over ~8 years. Diabetes was the most common comorbidity and was approximately 3 times more prevalent among patients with cirrhosis compared to patients without cirrhosis (21.5% vs. 7.1%). Of the 65 patients with cirrhosis, 72.3% (N = 47) received treatment. Generally, we observed that liver function tests (eg, ALT) were completed frequently in this population, with patients completing a median of 10 (6, 16) tests/year. All patients with cirrhosis had ≥1 ALT completed over the study period, and almost all cirrhotic patients (N = 64; 98.5%) had ≥1 HBV DNA test. However, the proportion of yearly imaging visits completed varied across the study years, between 64.0% in 2012 and 87.5% in 2009; overall, 35% (N = 23) completed annual imaging. CONCLUSIONS: Our findings suggest that among patients with HBV-related cirrhosis, at the patient-level, completed imaging orders for HCC screening were sub-optimal. However, we observed adequate disease management practices through frequent liver function tests, linkage to specialty care, image ordering, and shared EHR between KPSC providers.

Diagnosis and Management of Thoracic Myelopathy.

Thoracic myelopathy can be a challenging condition to diagnose and treat. Successful outcomes depend on early recondition of the pathology and appropriate surgical referral in cases of progressive neurologic deterioration. The thoracic cord is tethered in kyphosis by the dentate ligaments and contains a tenuous blood supply. These conditions make the thoracic cord particularly susceptible to external compression and ischemic damage. Careful preoperative planning with specific attention to the location and source of thoracic stenosis is critical to successful decompression and complication avoidance. The purpose of this discussion is to outline the common sources of thoracic myelopathy and current recommendations regarding diagnosis and management. The review concludes with an overview of the most up-to-date literature regarding clinical outcomes.

Superinfections of the Spine: A Single-Institution Experience.

Background/Objectives: A superinfection occurs when a new, secondary organism colonizes an existing infection. Spine infections are associated with high patient morbidity and sometimes require multiple irrigations and debridements (I&Ds). When multiple I&Ds are required, the risk of complications increases. The purpose of this study was to report our experience with spine superinfections and determine which patients are typically affected. Methods: A retrospective case series of spine superinfections and a retrospective case-control analysis were conducted. Data were collected manually from electronic medical records. Spine I&Ds were identified. Groups were created for patients who had multiple I&Ds for (1) a recurrence of the same causative organism or (2) a superinfection with a novel organism. Preoperative demographic, clinical, and microbiologic data were compared between these two outcomes. A case series of superinfections with descriptive data was constructed. Lastly, two illustrative cases were provided in a narrative format. Results: A total of 92 patients were included in this analysis. Superinfections occurred after 6 out of the 92 (7%) initial I&Ds and were responsible for 6 out of the 24 (25%) repeat I&Ds. The preoperative erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) of the patients with a superinfection were significantly lower than those in the control group (p = 0.022 and p = 0.032). Otherwise, the observed differences in the preoperative variables were not statistically different. In the six cases of superinfection, the presence of high-risk comorbidities, a history of substance abuse, or a lack of social support were commonly observed. The superinfecting organisms included Candida, Pseudomonas, Serratia, Klebsiella, Enterobacter, and Staphylococcus species. Conclusions: Superinfections are a devastating complication requiring reoperation after initial spine I&D. Awareness of the possibility of superinfection and common patient archetypes can be helpful for clinicians and care teams. Future work is needed to examine how to identify, help predict, and prevent spine superinfections.

Risk Factors Associated with Thromboembolic Complications After total Hip Arthroplasty: An Analysis of 1,129 Pulmonary Emboli.

INTRODUCTION: Venous thromboembolism (VTE) remains a dangerous complication after total hip arthroplasty (THA), despite advances in chemoprophylactic measures. This study aimed to identify risk factors of developing pulmonary embolism (PE) and deep vein thrombosis (DVT) after THA using a modern cohort of patients reflecting contemporary practices. METHODS: The Premier Healthcare Database was queried for primary, elective THAs from January 1st, 2015, to December 31st, 2021. Patients who developed PE or DVT within 90 days of THA were compared with patients who did not develop any postoperative VTE. Differences in patient demographics, comorbidities, hospital factors, perioperative medications, chemoprophylactic agents, and allogeneic blood transfusion were compared between cohorts. Multivariable logistic regression models were used to identify independent risk factors of PE and DVT. In total, 544,298 THAs were identified, of which 1,129 (0.21%) developed a PE and 1,799 (0.33%) developed a DVT. RESULTS: Patients diagnosed with a PE had significantly higher rates of in-hospital death (2.6% vs 0.1%, P < 0.001) compared with those without a PE. Age (adjusted odds ratio: 1.02 per year, 95% confidence interval [CI]: 1.01 to 1.03) and Black race (aOR: 1.52, 95% CI: 1.24 to 1.87) were associated with an increased risk of PE. Comorbidities associated with increased risk of PE included chronic pulmonary disease (aOR: 1.58, 95% CI: 1.36 to 1.84), pulmonary hypertension (aOR: 2.06, 95% CI: 1.39 to 3.04), and history of VTE (aOR: 2.38, 95% CI: 1.98 to 2.86). Allogeneic blood transfusion (aOR: 2.40, 95% CI: 1.88 to 3.06) was also associated with an increased risk of PE while dexamethasone utilization was associated with a reduced risk (aOR: 0.83, 95% CI: 0.73 to 0.95). DISCUSSION: Increasing age; Black race; allogeneic blood transfusion; and comorbidities, including chronic pulmonary disease, pulmonary hypertension, and history of VTE, were independent risk factors of PE after THA. Given the increased mortality associated with PE, patients should be carefully evaluated for these factors and managed with an appropriate chemoprophylactic regimen.

A cross-sectional study to assess the under-nutrition amongst the elderly population in a rural area of district Gautam Buddha Nagar, Uttar Pradesh.

Background: Ageing is a universal process. It is influenced by a person's genetic makeup, lifestyle, and environmental factors. Nutrition plays a significant role in modulation of ageing. In developing countries like India, the health and nutritional status of the elderly population is not satisfactory. Objectives: The current study was done to assess undernutrition amongst the elderly population and to find the various associations with sociodemographic factors and social determinants. Materials and Methods: This cross-sectional study was done from February 2023 to July 2023 in rural area of District Gautam Buddha Nagar, Uttar Pradesh. The elderly participants who were 60 years of age and more and who met the inclusion criteria were selected by simple random sampling technique for the study. Undernutrition was assessed by Mini Nutritional Assessment Tool (MNA). Result: Out of the total of 400 elderly persons, 18% were found to be undernourished and 38% were at risk of undernutrition. The association between undernutrition and age group, gender, occupation, family type, living arrangements that is staying with family or not, financial dependence, any co-morbid illness, smoking, and physical activity was found to be significant. Conclusion: The present findings reveal that undernutrition is not an uncommon problem in the elderly, and further studies are needed in this regard.

A Second-Generation Oral SARS-CoV-2 Main Protease Inhibitor Clinical Candidate for the Treatment of COVID-19.

Despite the record-breaking discovery, development and approval of vaccines and antiviral therapeutics such as Paxlovid, coronavirus disease 2019 (COVID-19) remained the fourth leading cause of death in the world and third highest in the United States in 2022. Here, we report the discovery and characterization of PF-07817883, a second-generation, orally bioavailable, SARS-CoV-2 main protease inhibitor with improved metabolic stability versus nirmatrelvir, the antiviral component of the ritonavir-boosted therapy Paxlovid. We demonstrate the in vitro pan-human coronavirus antiviral activity and off-target selectivity profile of PF-07817883. PF-07817883 also demonstrated oral efficacy in a mouse-adapted SARS-CoV-2 model at plasma concentrations equivalent to nirmatrelvir. The preclinical in vivo pharmacokinetics and metabolism studies in human matrices are suggestive of improved oral pharmacokinetics for PF-07817883 in humans, relative to nirmatrelvir. In vitro inhibition/induction studies against major human drug metabolizing enzymes/transporters suggest a low potential for perpetrator drug-drug interactions upon single-agent use of PF-07817883.

Pancreatic Enzyme Use Reduces Pancreatitis Frequency in Children With Acute Recurrent or Chronic Pancreatitis: A Report From INSPPIRE.

INTRODUCTION: Among children who suffer from acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP), acute pancreatitis (AP) episodes are painful, often require hospitalization, and contribute to disease complications and progression. Despite this recognition, there are currently no interventions to prevent AP episodes. In this retrospective cohort study, we assessed the impact of pancreatic enzyme therapy (PERT) use on clinical outcomes among children with pancreatic-sufficient ARP or CP. METHODS: Children with pancreatic-sufficient ARP or CP in the INSPPIRE-2 cohort were included. Clinical outcomes were compared for those receiving vs not receiving PERT, as well as frequency of AP before and after PERT. Logistic regression was used to study the association between development of AP episodes after starting PERT and response predictors. RESULTS: Among 356 pancreatic-sufficient participants, 270 (76%) had ARP, and 60 (17%) received PERT. Among those on PERT, 42% did not have a subsequent AP episode, during a mean 2.1 years of follow-up. Children with a SPINK1 mutation ( P = 0.005) and those with ARP (compared with CP, P = 0.008) were less likely to have an AP episode after starting PERT. After initiation of PERT, the mean AP annual incidence rate decreased from 3.14 down to 0.71 ( P < 0.001). DISCUSSION: In a retrospective analysis, use of PERT was associated with a reduction in the incidence rate of AP among children with pancreatic-sufficient ARP or CP. These results support the need for a clinical trial to evaluate the efficacy of PERT to improve clinical outcomes among children with ARP or CP.

Polydispersity-mediated high efficacy of an in-situ aqueous nanosuspension of PPEF.3HCl in methicillin resistant Staphylococcus aureus sepsis model.

Recently, World Health Organization declared antimicrobial resistance as the third greatest threat to human health. Absence of known cross-resistance, new class, new target, and a new mode of action are few major strategies being undertaken by researches to combat multidrug resistant pathogen. PPEF.3HCl, a bisbenzimidazole was developed as highly potent antibacterial agent against ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens, targeting topoisomerase IA. The present work encompasses a radical on-site generation of In-situ nanosuspension of PPEF.3HCl with enhanced efficacy against methicillin resistant S. aureus in septicemia model. We have generated instantaneously a PPEF.3HCl nanosuspension (IsPPEF.3HCl-NS) by mixing optimized monophasic PPEF.3HCl preconcentrate in propylene glycol into an aqueous medium comprising tween 80 as stabilizer. The IsPPEF.3HCl-NS showed precipitation efficiency of > 90 %, average particle size < 500 nm, retained upto 5 h, a negative zeta potential and bi/trimodal particle size distribution. Differential scanning calorimetry, X-ray diffraction confirmed partial amorphization and transmission electron microscopy revealed spherical particles. IsPPEF.3HCl-NS was non-hemolytic and exhibited good stability in serum. More significantly, it exhibited a âˆ¼ 1.6-fold increase in macrophage uptake compared to free PPEF.3HCl in the RAW 264.7 macrophage cell line. Confocal microscopy revealed accumulation of IsPPEF.3HCl-NS within the lysosomal compartment and cell cytosol, proposing high efficacy. In terms of antimicrobial efficacy, IsPPEF.3HCl-NS outperforms free PPEF.3HCl against clinical methicillin sensitive and resistant S. aureus strains. In a pivotal experiment, IsPPEF.3HCl-NS exhibited over 83 % survival at 8 mg/kg.bw and an impressive reduction of âˆ¼ 4-5 log-fold in bacterial load, primarily in the kidney, liver and spleen of septicemia mice. IsPPEF.3HCl-NS prepared by the In-situ approach, coupled with enhanced intramacrophage delivery and superior efficacy, positions IsPPEF.3HCl-NS as a pioneering and highly promising formulation in the battle against antimicrobial resistance.

Association of hematological ratios with psoriasis: a nationwide retrospective cohort study.

BACKGROUND: Psoriasis is a common skin disorder linked to systemic inflammation and immune dysregulation. It is believed to involve activated T cells and neutrophils. Recent research has highlighted the potential role of hematological ratios, such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), eosinophil-to-lymphocyte ratio (ELR), eosinophil-to-neutrophil ratio (ENR), and eosinophil-to-monocyte ratio (EMR), as markers for inflammatory skin diseases, including psoriasis. OBJECTIVES: We aimed to investigate hematological ratios between children and adults, patients and controls, and patients with moderate-to-severe and mild psoriasis. MATERIALS AND METHODS: This national retrospective cohort study included over 16,000 psoriasis patients in Israel. Patients with comorbidities influencing blood counts were excluded. Ratios were calculated from blood counts taken within 30 days of diagnosis. Multivariable logistic regression, including age, gender, ethnicity, smoking status, and socioeconomic status, was performed. RESULTS: Findings revealed age-specific variations in blood counts, hematological ratios, and differences between mild and moderate-severe patients and patients versus controls. Moderate-severe psoriasis patients had elevated neutrophil and eosinophil counts (4.57 vs. 4.25, P < 0.001, and 0.24 vs. 0.22, P = 0.047, respectively), as well as increased NLR (2.46 vs. 2.29, P < 0.001). Multivariable logistic regression analysis confirmed the significance of neutrophil and platelet counts as well as NLR and PLR in predicting psoriasis severity. LIMITATIONS: This was a retrospective study without subjective data on disease severity. CONCLUSION: This study highlights hematologic ratios' diagnostic and prognostic potential in psoriasis.

An Updated Estimate of Total Hip and Total Knee Arthroplasty Inpatient Case Volume During the 2020 COVID-19 Pandemic in the United States.

Background: Inpatient total hip arthroplasty (THA) and total knee arthroplasty (TKA) practices were dramatically affected in the United States in 2020 as elective surgeries were paused in response to the COVID-19 pandemic. This study sought to provide an updated estimate of inpatient total joint arthroplasty (TJA) case volumes in the United States in 2020. Methods: A retrospective cohort study was performed by identifying all adult patients who underwent primary, elective TJA from January 1st, 2017 to December 31st, 2020, using the National Inpatient Sample. Monthly and annual case volumes were reported with descriptive statistics. Baseline case volumes were established by taking the average number of monthly cases performed in 2017, 2018, and 2019. These monthly averages were compared to 2020 values. Results: From 2017 to 2019, the average case volume was 1,056,669 cases per year (41.0% THA, 59.0% TKA) and 88,055 cases per month. In 2020, 535,441 cases were identified (45.4% THA, 54.6% TKA), corresponding to a 49.3% reduction from the 2017-2019 annual average. Monthly cases decreased to 4515 in April during the "first wave" of COVID-19, corresponding to a 94.8% decrease from prior years. In June, cases rebounded to 55,520 before decreasing again in July to 50,100 during the "second wave" of COVID-19. During the "third wave," COVID-19 cases decreased month-over-month from October through December (56.5% decrease). Conclusions: This updated estimate identified a 49.3% decrease in inpatient TJA cases in 2020 compared to prior years. This is similar to the 46.5-47.7% decrease in case volume previously reported.

An objective comparative study of non-surgical cleansing techniques and cleanser types in bacterial burden management.

Cleansing is a vital component of effective wound hygiene and biofilm management, often accomplished through vigorous mechanical action or through soaking with moistened gauze. In the present study, a quantitative comparison of the effectiveness of different cleansing techniques and solutions in removing bacteria was conducted on 71 chronic wounds using bacterial fluorescence imaging as a real-time diagnostic for moderate to high bacterial loads. Vigorous gauze cleansing for 30 s proved most effective by reducing bacterial fluorescence by 33.99%, surpassing 10-min soaking in bacterial reduction (13.24%). Among different cleansers, no statistically significant differences in effectiveness were observed, but povidone-iodine showed the strongest trend towards bacterial reduction. Sub-analysis highlighted the superiority of antiseptic cleansers over saline and gentle soap (-33.30% vs. -1.80% bacterial reduction respectively). Five percent acetic acid was also shown to be more effective in removing specific bacterial strains (Pseudomonas aeruginosa). Findings from studies like this contribute to refining wound hygiene guidelines and clinical algorithms for bacterial and biofilm management.

Mechanisms of Nitrosamine Mutagenicity and Their Relationship to Rodent Carcinogenic Potency.

A thorough literature review was undertaken to understand how the pathways of N-nitrosamine transformation relate to mutagenic potential and carcinogenic potency in rodents. Empirical and computational evidence indicates that a common radical intermediate is created by CYP-mediated hydrogen abstraction at the α-carbon; it is responsible for both activation, leading to the formation of DNA-reactive diazonium species, and deactivation by denitrosation. There are competing sites of CYP metabolism (e.g., ß-carbon), and other reactive species can form following initial bioactivation, although these alternative pathways tend to decrease rather than enhance carcinogenic potency. The activation pathway, oxidative dealkylation, is a common reaction in drug metabolism and evidence indicates that the carbonyl byproduct, e.g., formaldehyde, does not contribute to the toxic properties of N-nitrosamines. Nitric oxide (NO), a side product of denitrosation, can similarly be discounted as an enhancer of N-nitrosamine toxicity based on carcinogenicity data for substances that act as NO-donors. However, not all N-nitrosamines are potent rodent carcinogens. In a significant number of cases, there is a potency overlap with non-N-nitrosamine carcinogens that are not in the Cohort of Concern (CoC; high-potency rodent carcinogens comprising aflatoxin-like-, N-nitroso-, and alkyl-azoxy compounds), while other N-nitrosamines are devoid of carcinogenic potential. In this context, mutagenicity is a useful surrogate for carcinogenicity, as proposed in the ICH M7 (R2) (2023) guidance. Thus, in the safety assessment and control of N-nitrosamines in medicines, it is important to understand those complementary attributes of mechanisms of mutagenicity and structure-activity relationships that translate to elevated potency versus those which are associated with a reduction in, or absence of, carcinogenic potency.

Characteristics of Very Young Patients Undergoing Total Hip Arthroplasty: A Contemporary Assessment.

Background: This study aims to compare indications, patient characteristics, hospital factors, and complication rates between total hip arthroplasty (THA) patients aged 30 years or younger and those older than 30 years using a large national database. Methods: The Premier Healthcare Database was utilized to identify primary THA patients from 2015 to 2021 who were aged ≤30 or >30 years. Patient demographics, hospital factors, and primary indications were compared for each cohort. Rates of complications and readmissions were assessed for each cohort by primary indication. Differences were assessed through univariate analysis. Results: Overall, 539,173 primary THA patients were identified (age ≤30: 1849; >30: 537,234). Compared to the >30 cohort, the ≤30 cohort was more likely to be male (56.5% vs 44.9%, P < .001) and non-White (34.0% vs 14.2%, P < .001). The most common indications for THA in the ≤30 cohort were osteonecrosis (49.3%), osteoarthritis (17.8%), and congenital hip deformities (16.0%), and in the >30 cohort, they were osteoarthritis (77.0%), other arthritis (11.3%), and osteonecrosis (5.4%). Patients aged ≤30 years had lower rates of respiratory failure (0.16% vs 0.57%, P < .001), acute renal failure (0.32% vs 1.72%, P < .001), and urinary tract infection (0.38% vs 1.11%, P = .003) than those aged >30 years, but higher rates of wound dehiscence (0.59% vs 0.29%, P = .015) and transfusion (3.68% vs 2.21%, P < .001). There were no differences in 90-day readmission rates (P = .811) or 90-day in-hospital death (P = .173) between cohorts. Conclusions: Younger patients undergoing THA differed significantly in indication, patient characteristics, and hospital factors compared to the older population on univariate analysis. Despite differences in indications, the cohorts did not differ markedly with regard to complication rates in this study.

The Utility of the Validated Intraoperative Bleeding Scale in Thoracolumbar Spine Surgery: A Single-Center Prospective Study.

STUDY DESIGN: Prospective, single-center study. OBJECTIVE: To evaluate the clinical relevance of the validated intraoperative bleeding severity scale (VIBe) in thoracolumbar spine surgery. METHODS: Adult patients aged 18 through 88 undergoing elective decompression, instrumentation, and fusion of the thoracolumbar spine were prospectively enrolled after informed consent was provided and written consent was obtained. Validated intraoperative bleeding severity scores were recorded intraoperatively. Univariate analysis consisted of Student T-tests, Pearson's χ2 Tests, Fisher's Exact Tests, linear regression, and binary logistic regression. Multivariable regression was conducted to adjust for baseline characteristics and potential confounding variables. RESULTS: A total of N = 121 patients were enrolled and included in the analysis. After adjusting for confounders, VIBe scores were correlated with an increased likelihood of intraoperative blood transfusion (ß = 2.46, P = .012), postoperative blood transfusion (ß = 2.36, P = .015), any transfusion (ß = 2.49, P < .001), total transfusion volume (ß = 180.8, P = .020), and estimated blood loss (EBL) (ß = 409, P < .001). Validated intraoperative bleeding severity scores had no significant association with length of hospital stay, 30-day readmission, 30-day reoperation, 30-day emergency department visit, change in pre- to post-op hemoglobin and hematocrit, total drain output, or length of surgery. CONCLUSION: The VIBe scale is associated with perioperative transfusion rates and EBL in patients undergoing thoracolumbar spine surgery. Overall, the VIBe scale has clinically relevant meaning in spine surgery, and shows potential utility in clinical research. LEVEL OF EVIDENCE: Level II.

Laminoplasty in Motion: Evolving Techniques and Complications.

Cervical laminoplasty is an increasingly popular surgical option for the treatment of cervical spondylotic myelopathy (CSM) and ossification of the posterior longitudinal ligament (OPLL). Over the past few decades, there have been substantial developments in both surgical technique and hardware options. As the field of cervical surgery rapidly evolves, there is a timely need to reassess the evolving complications associated with newer techniques. This review aims to synthesize the available literature on cervical laminoplasty and associated mechanical complications pertaining to different laminoplasty hinge fixation options.