Comparison of Length of Stay and Discharge Disposition after Short-Segment Lumbar Fusion Surgery at Tertiary Care and Non-Tertiary Care Hospitals: A Propensity Score Matched Analysis.

STUDY DESIGN: A retrospective study. OBJECTIVE: To compare the perioperative and postoperative outcomes among lumbar fusion patients treated at an orthopaedic specialty hospital (OSH), a hybrid community hospital (HCH), and a conventional community hospital in comparison to a tertiary care hospital (TCH). SUMMARY OF BACKGROUND DATA: In spine surgery, strategies to reduce length of stay (LOS) include a myriad of pre-, intra-, and postoperative strategies that require a multidisciplinary infrastructure. The sum of these efforts has led to the creation of orthopedic specialty hospitals and protocols that have been adopted by community hospitals as well. There is a notable lack of information regarding the results of these efforts across different healthcare institution models. METHODS: This was a retrospective study of patients undergoing elective one or two-level lumbar fusion between 2017 and 2022 at a large urban TCH, an OSH, a HCH, and a conventional CH. Data was collected on patient characteristics, demographics, comorbidities, BMI, smoking status, surgical type, surgical levels, surgery duration, hospital length of stay, readmissions, reoperations, and discharge status within a year. Patients across the four surgical settings were matched based on age, BMI, CCI, type of procedure, and number of levels fused. RESULTS: A total of 1435 patients met the inclusion criteria. Length of hospital stay was significantly longer at TCH compared to OSH, HCH, and CH by an average of 1-2 days (P<0.001). 90-day readmissions were higher at TCH compared to OSH (P=0.001). TCH patients also were less likely to be discharged home than OSH and HCH patients (P=0.001 and P=0.016, respectively). No significant differences were noted in 1-year reoperation rates across all hospital models. CONCLUSION: Shorter lengths of stays and more home discharges at the orthopaedic specialty hospital and community hospital settings did not compromise surgical quality or postoperative outcomes.

Calcium-sensing receptor (CaSR) modulates ocular surface chloride transport and its inhibition promotes ocular surface hydration.

PURPOSE: Ocular surface hydration is critical for eye health and its impairment can lead to dry eye disease. Extracellular calcium-sensing receptor (CaSR) is regulator of ion transport in epithelial cells expressing cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel. CFTR is also a major ion channel in ocular surface epithelia, however the roles of CaSR in ocular surface are not well studied. This study aims to investigate expression and functional roles of CaSR in ocular surface. METHODS: CaSR immunostaining was performed in mouse and human cornea and conjunctiva. Ocular surface potential difference (OSPD) and tear fluid volume measurements were performed in mice with topically applied cinacalcet (CaSR activator) and NPS-2143 (CaSR inhibitor). RESULTS: CaSR is expressed in corneal and conjunctival epithelia of mice and humans. Topically administered CaSR activator cinacalcet inhibits cAMP agonist forskolin-induced Cl- secretion and CFTR activity up to 90 %. CaSR inhibitor NPS-2143 stimulates CFTR-mediated Cl- secretion in mouse ocular surface, after which cAMP agonist forskolin had minimal additional secretory effects. Single dose NPS-2143 treatment (as an eye drop) increases tear fluid volume in mice by ∼60 % compared to vehicle treatment. NPS-2143 effect on tear volume lasts at least 8 h after single dose. CONCLUSIONS: CaSR is a key regulator of ocular surface ion transport and CaSR inhibition promotes Cl- and tear secretion in the ocular surface. If they are found to be effective in in dry eye models, CaSR inhibitors (currently in clinical development) can potentially be repurposed as novel prosecretory treatments for dry eye disease.

Enhancing pediatric access to cell and gene therapies.

Increasing numbers of cell and gene therapies (CGTs) are emerging to treat and cure pediatric diseases. However, small market sizes limit the potential return on investment within the traditional biopharmaceutical drug development model, leading to a market failure. In this Perspective, we discuss major factors contributing to this failure, including high manufacturing costs, regulatory challenges, and licensing practices that do not incorporate pediatric development milestones, as well as potential solutions. We propose the creation of a new entity, the Pediatric Advanced Medicines Biotech, to lead late-stage development and commercialize pediatric CGTs outside the traditional biopharmaceutical model in the United States-where organized efforts to solve this problem have been lacking. The Pediatric Advanced Medicines Biotech would partner with the academic ecosystem, manufacture products in academic good manufacturing practice facilities and work closely with regulatory bodies, to ferry CGTs across the drug development 'valley of death' and, ultimately, increase access to lifesaving treatments for children in need.

PKD1 mutant clones within cirrhotic livers inhibit steatohepatitis without promoting cancer.

Somatic mutations in non-malignant tissues are selected for because they confer increased clonal fitness. However, it is uncertain whether these clones can benefit organ health. Here, ultra-deep targeted sequencing of 150 liver samples from 30 chronic liver disease patients revealed recurrent somatic mutations. PKD1 mutations were observed in 30% of patients, whereas they were only detected in 1.3% of hepatocellular carcinomas (HCCs). To interrogate tumor suppressor functionality, we perturbed PKD1 in two HCC cell lines and six in vivo models, in some cases showing that PKD1 loss protected against HCC, but in most cases showing no impact. However, Pkd1 haploinsufficiency accelerated regeneration after partial hepatectomy. We tested Pkd1 in fatty liver disease, showing that Pkd1 loss was protective against steatosis and glucose intolerance. Mechanistically, Pkd1 loss selectively increased mTOR signaling without SREBP-1c activation. In summary, PKD1 mutations exert adaptive functionality on the organ level without increasing transformation risk.

The attainment of a patient acceptable symptom state in patients undergoing revision spine fusion.

INTRODUCTION: Revision lumbar fusion is most commonly due to nonunion, adjacent segment disease (ASD), or recurrent stenosis, but it is unclear if diagnosis affects patient outcomes. The primary aim of this study was to assess whether patients achieved the patient acceptable symptom state (PASS) or minimal clinically important difference (MCID) after revision lumbar fusion and assess whether this was influenced by the indication for revision. METHODS: We retrospectively identified all 1-3 level revision lumbar fusions at a single institution. Oswestry Disability Index (ODI) was collected at preoperative, three-month postoperative, and one-year postoperative time points. The MCID was calculated using a distribution-based method at each postoperative time point. PASS was set at the threshold of ≤ 22. RESULTS: We identified 197 patients: 56% with ASD, 28% with recurrent stenosis, and 15% with pseudarthrosis. The MCID for ODI was 10.05 and 10.23 at three months and one year, respectively. In total, 61% of patients with ASD, 52% of patients with nonunion, and 65% of patients with recurrent stenosis achieved our cohort-specific MCID at one year postoperatively with ASD (p = 0.78). At one year postoperatively, 33.8% of ASD patients, 47.8% of nonunion patients, and 37% of patients with recurrent stenosis achieved PASS without any difference between indication (p = 0.47). CONCLUSIONS: The majority of patients undergoing revision spine fusion experience significant postoperative improvements regardless of the indication for revision. However, a large proportion of these patients do not achieve the patient acceptable symptom state. While revision spine surgery may offer substantial benefits, these results underscore the need to manage patient expectations.

The Impact of the Preoperative Mental Health Component Summary (MCS) Score on Short-term Outcomes after Lumbar Fusion.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: The purpose of this study is to characterize the relationship between preoperative MCS and surgical outcomes after lumbar spine surgery including inpatient complications, length of stay, readmissions, and reoperations. SUMMARY OF BACKGROUND DATA: As the prevalence of mental health disorders in the United States increases, it is important to identify risks associated with poor mental health status in the surgical spine patient. The mental health component summary (MCS) of the Short Form-12 has been used extensively as an indication of a patient's mental health status and psychological well-being. METHODS: Adult patients older than or equal to 18 years who underwent primary one to three level lumbar fusion surgery at our academic medical institution from 2017 to 2021 were retrospectively identified. Preoperative MCS score was used to analyze outcomes in patients based on a cutoff (<45.6). A score >45.6 indicated better preoperative mental health and a score <45.6 indicated worse preoperative mental health. RESULTS: Patients with lower preoperative MCS scores had longer hospital stays (3.86 + 2.16 vs. 3.55 + 1.42 days, P=0.010) and were more likely to have inpatient renal complications (3.09% vs. 7.19%, P=0.006). Patients with lower preoperative MCS scores also had lower Activity Measure for Post-Acute Care (AM-PAC) scores (17.1 + 2.85 vs. 17.6 + 2.49, P=0.030). Ninety-day surgical readmissions, medical readmissions, and reoperations were not significantly different between groups (P>0.05). CONCLUSION: Our study suggests that patients with lower preoperative mental health scores (MCS < 45.6) were independently more likely to experience more renal complications and longer length of stay after primary lumbar fusion. Additionally, higher MCS scores may correlate with better postoperative mobility and daily activity scores. Nevertheless, long-term outcomes are not significantly different between patients of better or worse preoperative mental health.

Rationale and design of the KP ENRICH trial: A food is medicine intervention in low-income high-risk adults with diabetes within Kaiser Permanente.

BACKGROUND: Food insecurity is associated with poor glycemic control and increased risk for diabetes-related complications. The clinical benefit of addressing these challenges through a medically supportive grocery prescription (GRx) program in patients with type 2 diabetes mellitus (T2D) remains unclear. We report the aims and design of a randomized clinical trial to evaluate the effectiveness of a 6-month GRx intervention on hemoglobin A1c (HbA1c) levels among low-income adults with T2D. METHODS: The Kaiser Permanente Evaluating Nutritional Interventions in Food-Insecure High-Risk Adults (KP ENRICH) Study is a pragmatic randomized trial enrolling 1100 participants within Kaiser Permanente Northern California and Southern California, two integrated health care delivery systems serving >9 million members. Medicaid-insured adults with T2D and baseline HbA1c ≥7.5% will be randomized at a 1:1 ratio to either GRx, delivered as $100 per month for select items from among a curated list of healthful food groups in an online grocery ordering and home-delivery platform along with biweekly digital nutrition educational materials, or control, consisting of free membership and deliveries from the online grocery platform but without curated food groups or purchasing dollars. The primary outcome is 6-month change in HbA1c. Secondary outcomes include 12-month change in HbA1c, and 6- and 12-month change in medical resource utilization, food security, nutrition security, dietary habits, diabetes-related quality of life, and dietary self-efficacy. CONCLUSIONS: The results of this large randomized clinical trial of GRx will help inform future policy and health system-based initiatives to improve food and nutrition security, disease management, and health equity among patients with T2D.

How good are large language models at product risk assessment?

Product safety professionals must assess the risks to consumers associated with the foreseeable uses and misuses of products. In this study, we investigate the utility of generative artificial intelligence (AI), specifically large language models (LLMs) such as ChatGPT, across a number of tasks involved in the product risk assessment process. For a set of six consumer products, prompts were developed related to failure mode identification, the construction and population of a failure mode and effects analysis (FMEA) table, risk mitigation identification, and guidance to product designers, users, and regulators. These prompts were input into ChatGPT and the outputs were recorded. A survey was administered to product safety professionals to ascertain the quality of the outputs. We found that ChatGPT generally performed better at divergent thinking tasks such as brainstorming potential failure modes and risk mitigations. However, there were errors and inconsistencies in some of the results, and the guidance provided was perceived as overly generic, occasionally outlandish, and not reflective of the depth of knowledge held by a subject matter expert. When tested against a sample of other LLMs, similar patterns in strengths and weaknesses were demonstrated. Despite these challenges, a role for LLMs may still exist in product risk assessment to assist in ideation, while experts may shift their focus to critical review of AI-generated content.

Learning performance and GABAergic pathway link to deformed wing virus in the mushroom bodies of naturally infected honey bees.

Viral infections can be detrimental to the foraging ability of the Western honey bee Apis mellifera. The deformed wing virus (DWV) is the most common honey bee virus and has been proposed as a possible cause of learning and memory impairment. However, evidence for this phenomenon so far has come from artificially infected bees, while less is known about the implications of natural infections with the virus. Using the proboscis extension reflex (PER), we uncovered no significant association between a simple associative learning task and natural DWV loads. However, when assessed through a reversal associative learning assay, bees with higher DWV loads performed better in the reversal learning phase. DWV is able to replicate in the honey bee mushroom bodies, where the GABAergic signalling pathway has an antagonistic effect on associative learning but is crucial for reversal learning. Hence, we assessed the pattern of expression of several GABA-related genes in bees with different learning responses. Intriguingly, mushroom body expression of selected genes was positively correlated with DWV load, but only for bees with good reversal learning performance. We hypothesize that DWV might improve olfactory learning performance by enhancing the GABAergic inhibition of responses to unrewarded stimuli, which is consistent with the behavioural patterns that we observed. However, at higher disease burdens, which might be induced by an artificial infection or by a severe, natural Varroa infestation, this DWV-associated increase in GABA signalling could impair associative learning as previously reported by other studies.

Postoperative Opioid Consumption Patterns Diverge Between Propensity Matched Patients Undergoing Traumatic and Elective Cervical Spine Fusion.

BACKGROUND CONTEXT: Prolonged opioid therapy following spine surgery is an ongoing postoperative concern. While prior studies have investigated postoperative opioid use patterns in the elective cervical surgery patient population, to our knowledge, opioid use patterns in patients undergoing surgery for traumatic cervical spine injuries have not been elucidated. PURPOSE: The purpose of this study was to compare opioid use and prescription patterns in the postoperative pain management of patients undergoing traumatic and elective cervical spine fusion surgery. STUDY DESIGN: Retrospective cohort study PATIENT SAMPLE: Adult patients with traumatic cervical injuries who underwent primary anterior cervical discectomy and fusion (ACDF) or posterior cervical decompression and fusion (PCDF) during their initial hospital admission. The propensity matched, control group consisted of adult elective cervical fusion patients who underwent primary ACDF or PCDF. OUTCOME MEASURES: Demographic data, surgical characteristics, spinal disease diagnosis, location of cervical injury, procedure type, operative levels fused, and Prescription Drug Monitoring Program (PDMP) data. PDMP data included the number of opioid prescriptions filled, preoperative opioid use, postoperative opioid use, and use of perioperative benzodiazepines, muscle relaxants, or gabapentin. Opioid consumption data was collected in morphine milligram equivalents (MME) and standardized per day. METHODS: A 1:1 propensity match was performed to match traumatic injury patients undergoing cervical fusion surgery with elective cervical fusion patients. Traumatic injury patients were matched based on age, sex, CCI, procedure type, and cervical levels fused. Pre- and postoperative opioid, benzodiazepine, muscle relaxant, and gabapentin use were assessed for the traumatic injury and elective patients. T- or Mann-Whitney U tests were used to compare continuous data and Chi-Squared or Fisher's Exact were used to compare categorical data. Multivariate stepwise regression using MME per day 0 - 30 days following surgery as the dependent outcome was performed to further evaluate associations with postoperative opioid use. RESULTS: A total of 48 patients underwent fusion surgery for a traumatic cervical spine injury and 48 elective cervical fusion with complete PDMP data were assessed. Elective patients were found to fill more prescriptions (3.19 vs. 0.65, p=0.023) and take more morphine milligram equivalents (MME) per day (0.60 vs. 0.04, p=0.014) within one year prior to surgery in comparison to traumatic patients. Elective patients were also more likely to use opioids (29.2% vs. 10.4%, p=0.040) and take more MMEs per day (0.70 vs. 0.05, p=0.004) within 30 days prior to surgery. Within 30 days postoperatively, elective patients used opioids more frequently (89.6% vs. 52.1%, p<0.001) and took more MMEs per day (3.73 vs. 1.71, p<0.001) than traumatic injury patients. Multivariate stepwise regression demonstrated preoperative opioid use (Estimate: 1.87, p=0.013) to be correlated with higher postoperative MME per day within 30 days of surgery. Surgery after traumatic injury was correlated with lower postoperative MME use per day within 30 days of surgery (Estimate:-1.63 p=0.022). CONCLUSION: Cervical fusion patients with a history of traumatic spine injury consume fewer opioids in the early postoperative period in comparison to elective cervical fusion patients, however both cohorts consumed a similar amount after the initial 30-day postoperative period. Preoperative opioid use was also a risk factor for higher consumption in the short-term postoperative period. These results may aid physicians in further understanding patients' postoperative care needs based on presenting injury characteristics and highlights the need for enhanced follow-up care for traumatic cervical spine injury patients after fusion surgery.

The Impact of Outpatient Physical Therapy on Patient-Reported Outcomes after Lumbar Fusion: Perspective from A Bundled Care Dataset.

OBJECTIVE/BACKGROUND: As value-based care grows in popularity across the United States, more payers have turned toward bundled payment models for surgical procedures. Though episode costs in spine are highly variable, physical therapy (PT) has been identified as a driver of 90-day cost. The goal of this study is to assess the impact of postoperative PT on patient-reported outcomes and cost after lumbar fusion surgery using bundled insurance data. METHODS: Bundled payment information of lumbar fusion episodes-of-care (EOC) from 2019 to 2021 was reviewed at a single, urban, tertiary care center. EOC comprised a 210-day period surrounding the date of the procedure, beginning 30 days preoperatively and ending 180 days postoperatively. Patients were grouped into physical therapy (PT) and no physical therapy (no PT) groups based on the presence of physical therapy claims. RESULTS: Bivariate analysis of surgical outcomes revealed similar overall complication rates (p=0.413), 30-day readmissions (p=0.366) and 90-day readmissions (p=0.774). Patients that did not participate in postoperative PT had significantly better preoperative PCS (p=0.003), six-month postoperative PCS (p=0.001), and six-month ΔPCS (p=0.026) compared to patients who participated in postoperative PT. At one-year follow-up, patients who did not participate in PT had less leg pain (p=0.041) than those who did participate in PT. CONCLUSIONS: Our study finds that PT after lumbar fusion is not associated with significant improvement in ODI, PCS, MCS, or VAS pain scores. Additionally, the number of PT sessions a patient attends has no correlation with improvement in these outcomes.

Riluzole for Degenerative Cervical Myelopathy: A Secondary Analysis of the CSM-PROTECT Trial.

Importance: The modified Japanese Orthopaedic Association (mJOA) scale is the most common scale used to represent outcomes of degenerative cervical myelopathy (DCM); however, it lacks consideration for neck pain scores and neglects the multidimensional aspect of recovery after surgery. Objective: To use a global statistical approach that incorporates assessments of multiple outcomes to reassess the efficacy of riluzole in patients undergoing spinal surgery for DCM. Design, Setting, and Participants: This was a secondary analysis of prespecified secondary end points within the Efficacy of Riluzole in Surgical Treatment for Cervical Spondylotic Myelopathy (CSM-PROTECT) trial, a multicenter, double-blind, phase 3 randomized clinical trial conducted from January 2012 to May 2017. Adult surgical patients with DCM with moderate to severe myelopathy (mJOA scale score of 8-14) were randomized to receive either riluzole or placebo. The present study was conducted from July to December 2023. Intervention: Riluzole (50 mg twice daily) or placebo for a total of 6 weeks, including 2 weeks prior to surgery and 4 weeks following surgery. Main Outcomes and Measures: The primary outcome measure was a difference in clinical improvement from baseline to 1-year follow-up, assessed using a global statistical test (GST). The 36-Item Short Form Health Survey Physical Component Score (SF-36 PCS), arm and neck pain numeric rating scale (NRS) scores, American Spinal Injury Association (ASIA) motor score, and Nurick grade were combined into a single summary statistic known as the global treatment effect (GTE). Results: Overall, 290 patients (riluzole group, 141; placebo group, 149; mean [SD] age, 59 [10.1] years; 161 [56%] male) were included. Riluzole showed a significantly higher probability of global improvement compared with placebo at 1-year follow-up (GTE, 0.08; 95% CI, 0.00-0.16; P = .02). A similar favorable global response was seen at 35 days and 6 months (GTE for both, 0.07; 95% CI, -0.01 to 0.15; P = .04), although the results were not statistically significant. Riluzole-treated patients had at least a 54% likelihood of achieving better outcomes at 1 year compared with the placebo group. The ASIA motor score and neck and arm pain NRS combination at 1 year provided the best-fit parsimonious model for detecting a benefit of riluzole (GTE, 0.11; 95% CI, 0.02-0.16; P = .007). Conclusions and Relevance: In this secondary analysis of the CSM-PROTECT trial using a global outcome technique, riluzole was associated with improved clinical outcomes in patients with DCM. The GST offered probability-based results capable of representing diverse outcome scales and should be considered in future studies assessing spine surgery outcomes.

Does Paraspinal Muscle Mass Predict Lumbar Lordosis before and after Decompression for Degenerative Spinal Stenosis?

STUDY DESIGN: Retrospective Cohort Study. OBJECTIVE: The purpose of this study was to determine if muscle mass and quality of the lumbar paraspinal muscles was associated with improvements in lumbar lordosis and other sagittal parameters after isolated posterior lumbar decompression surgery for lumbar spinal stenosis. SUMMARY OF BACKGROUND DATA: Over time, either due to degenerative changes or other spinal conditions, individuals may develop sagittal imbalance. In patients with lumbar spinal stenosis, sagittal imbalance can further exacerbate symptoms of pain and radiculopathy. Sarcopenia of paraspinal muscles has been implicated in previous spine research as a variable with influence on surgical outcomes. METHODS: Sagittal parameters were measured on preoperative and postoperative lateral lumbar radiographs and included lumbar lordosis (LL), sacral slope (SS), and pelvic tilt (PT). Preoperative MRI images were evaluated at the base of the L4 vertebral body to assess muscles mass of the psoas muscle and paravertebral muscles (PVM) and Goutallier grade of the PVM. Patients were divided into 3 muscle size groups based on PVM normalized for body size (PVM/BMI): Group A (smallest), Group B, and Group C (largest). RESULTS: Patients in Group C had greater LL preoperatively (51.5° vs. 47.9° vs. 43.2, P=0.005) and postoperatively (52.2° vs. 48.9° vs. 45.7°, P=0.043). There was no significant difference in the ∆LL values between groups (P>0.05). Patients in Group C had larger SS preoperatively (35.2° vs. 32.1° vs. 30.0°, P=0.010) and postoperatively (36.1° vs. 33.0° vs. 31.7°, P=0.030). Regression analysis showed that PVM/BMI was a significant predictor of LL preoperatively (P=0.039) and postoperatively (P=0.031), as well as SS preoperatively (P=0.001) and postoperatively (P<0.001). CONCLUSION: Muscle mass of the paravertebral muscles significantly impacts lumbar lordosis and sacral slope in patients with lumbar spinal stenosis before and after posterior lumbar decompression. These findings highlight a need to address risk factors for poor muscle quality in patients with sagittal imbalance.

Circulating microRNAs May Be Predictive of Degenerative Cervical Myelopathy.

STUDY DESIGN: Basic Science. OBJECTIVE: The objective of this study was to identify a unique serum profile of circulating miRNAs and inflammatory markers in patients with degenerative cervical myelopathy (DCM) compared to healthy controls (HC). SUMMARY OF BACKGROUND DATA: Currently, DCM is diagnosed with a combination of history, physical examination, and close correlation to advanced imaging. To date, no serum marker has been identified to be diagnostic of this condition. METHODS: Whole venous blood was collected from patients with DCM as well as healthy age- and sex-matched controls. miRNA was extracted from venous blood and a screening analysis was initially conducted to identify miRNA dysregulation in DCM patients. RT-qPCR was used to analyze the expression of 2 specific miRNAs based on screening analysis and literature review. Bioinformatics analysis was used to identify gene networks and potential targets of the miRNA. In addition, the serum inflammatory profile of DCM and HC groups was differentiated using a pro-inflammatory panel. RESULTS: Thirty-six patients were enrolled in the DCM group (36.1% male, 61.5±9.5 y) while 35 patients were enrolled in the HC group (31.4% male, 57.5±8.9 y). Of the 15 total miRNAs differentially expressed between DCM and HC groups, two were selected for further analysis: miR-223-3p (upregulated) and miR-451a (downregulated). Functional gene network analysis revealed the highest-ranking gene network was involved in neurological disease, while the most overexpressed miRNA in this network (miR-233-3p) was noted to have over 100 targets including CDKN1B and the insulin receptor. Serum cytokine analysis showed significant upregulation of several pro-inflammatory cytokines in the DCM cohort compared to the HC group. CONCLUSION: DCM patients demonstrated a set of unique circulating miRNAs in addition to a different serum inflammatory profile compared to HC. These miRNAs may potentially serve as targets for future therapeutic intervention or diagnostic/prognostic testing.

A case of spontaneous abdominal hemoperitoneum secondary to ruptured splenosis.

We present a case of spontaneous abdominal hemoperitoneum secondary to ruptured splenosis in a 35-year-old patient with a history of splenectomy secondary to trauma 23 years prior. Computed tomography imaging demonstrated a large amorphous mass-like structure in the mesentery of the left hemiabdomen with active extravasation and hemoperitoneum. The patient also had a separate focus of hyper-enhancing mass adjacent to the bladder representing a mass versus splenule. The patient's radiographic and clinical presentation prompted management with exploratory laparotomy, hematoma evacuation, and resection of two splenules. With only a few cases of spontaneous abdominal hemoperitoneum from splenosis reported, this case describes successful management with surgical intervention.

Preoperative Electrodiagnostic Study Findings Differ Between Patients With Double-crush Syndrome and Carpal Tunnel Syndrome: A Propensity Matched Analysis.

INTRODUCTION: Double-crush syndrome (DCS) represents a condition that involves peripheral nerve compression in combination with spinal nerve root impingement. The purpose of this study was to compare electrodiagnostic study (EDS) results in patients undergoing carpal tunnel release (CTR) for carpal tunnel syndrome with those undergoing both CTR and anterior cervical diskectomy and fusion for DCS. METHODS: Patients receiving an isolated CTR were compared with those undergoing CTR and anterior cervical diskectomy and fusion within two years of CTR. The latter group was defined as our DCS cohort. Electrodiagnostic study results were collected which included sensory and motor nerve conduction data as well as electromyogram (EMG) findings. All electrodiagnostic studies were done before CTR in both sets of patients. RESULTS: Fifty-four patients with DCS and 137 CTR-only patients were included. Patients with DCS were found to have decreased sensory onset latency (3.51 vs 4.01; P = 0.015) and peak latency (4.25 vs 5.17; P = 0.004) compared with the CTR-only patients. Patients with DCS had slower wrist motor velocity (30.5 vs 47.7; P = 0.012), decreased elbow motor latency (9.62 vs 10.6; P = 0.015), and faster elbow motor velocity (56.0 vs 49.4; P = 0.031). EMG results showed that patients with DCS were more likely to have positive findings in the biceps (31.9% vs 1.96%; P < 0.001) and triceps (24.4% vs 2.97%; P < 0.001), but not abductor pollicis brevis (APB) (45.7% vs 37.9%; P = 0.459). CONCLUSION: We identified changes on EDS between patients with and without DCS. In patients with DCS, sensory nerve studies showed shorter peak and onset latency than in CTR-only patients. Interestingly, DCS and CTR-only patients had different patterns of wrist and elbow motor nerve conduction. Providers observing positive EMG findings proximal to the APB should raise their suspicion for possible cervical radiculopathy and when present with carpal tunnel syndrome-like symptoms, should also consider DCS in their diagnostic differential.

Acute Kidney Injury, Systemic Inflammation and Long-term Cognitive Function: ASSESS-AKI.

BACKGROUND: Cognitive dysfunction is a well-known complication of chronic kidney disease, but it is less known whether cognitive decline occurs in survivors after acute kidney injury (AKI). We hypothesized that an episode of AKI is associated with poorer cognitive function, mediated, at least in part, by persistent systemic inflammation. METHODS: ASSESS-AKI enrolled patients surviving three months after hospitalization with and without AKI matched based on demographics, comorbidities, and baseline kidney function. A subset underwent cognitive testing using the modified mini-mental status examination (3MS) at 3, 12, and 36 months. We examined the association of AKI with 3MS scores using mixed linear models and assessed the proportion of risk mediated by systemic inflammatory biomarkers. RESULTS: Among 1538 participants in ASSESS-AKI, 1420 (92%) completed the 3MS assessment at 3 months and had a corresponding matched participant. Participants with AKI had lower 3MS scores at three years (difference -1.1 (95% CI: -2.0, -0.3) P=0.009) compared to participants without AKI. A higher proportion of AKI participants had a clinically meaningful (≥ 5 point) reduction in 3MS scores at three years compared to participants without AKI (14% vs. 10%, P=0.04). In mediation analyses, plasma soluble tumor necrosis factor receptor-1 (sTNFR-1) at three months after AKI mediated 35% (P=0.02) of the AKI related risk for 3MS scores at three years. CONCLUSIONS: AKI was associated with lower 3MS scores and sTNFR-1 concentrations appeared to mediate a significant proportion of the risk of long-term cognitive impairment. Further work is needed to determine if AKI is causal or a marker for cognitive impairment.

Ubiquitin-specific protease 7 inhibitors reveal a differentiated mechanism of p53-driven anti-cancer activity.

The USP7 deubiquitinase regulates proteins involved in the cell cycle, DNA repair, and epigenetics and has been implicated in cancer progression. USP7 inhibition has been pursued for the development of anti-cancer therapies. Here, we describe the discovery of potent and specific USP7 inhibitors exemplified by FX1-5303. FX1-5303 was used as a chemical probe to study the USP7-mediated regulation of p53 signaling in cells. It demonstrates mechanistic differences compared to MDM2 antagonists, a related class of anti-tumor agents that act along the same pathway. FX1-5303 synergizes with the clinically approved BCL2 inhibitor venetoclax in acute myeloid leukemia (AML) cell lines and ex vivo patient samples and leads to strong tumor growth inhibition in in vivo mouse xenograft models of multiple myeloma and AML. This work introduces new USP7 inhibitors, differentiates their mechanism of action from MDM2 inhibition, and identifies specific opportunities for their use in the treatment of AML.

Substituted 4-methylcoumarin inhibitors of SLC26A3 (DRA) for treatment of constipation and hyperoxaluria.

SLC26A3, also known as downregulated in adenoma (DRA), is an anion (Cl-, HCO3- and oxalate) exchanger in the luminal membrane of intestinal epithelial cells. Loss of DRA function in mice and humans causes congenital chloride-losing diarrhea and reduces urinary excretion of oxalate, a major constituent of kidney stones. Thus, inhibition of DRA is a potential treatment approach for constipation and calcium oxalate kidney stones. High-throughput screening previously identified 4,8-dimethylcoumarins (4a-4c) as DRA inhibitors, with lead candidate 4b having an IC50 of 40-50 nM for DRA inhibition. Here, we explored the effects of varying substituents at the 8-position, and replacing 8-methyl by 5-methyl (4e-4h). A focused library of 17 substituted compounds (4d-4t) was synthesized with good yield and purity. Compounds were tested for DRA inhibition potency using Fischer rat thyroid cells stably expressing DRA and a halide-sensitive YFP. Structure-activity analysis revealed that 8-bromo- (4m-4p) and 8-fluoro-coumarins (4q-4t) were slightly less potent than the corresponding 8-chloro analogs, demonstrating that the size of methyl or chloro substituents at the coumarin 8 position affects the potency. An analog containing 8-chlorocoumarin (4k) had ∼2-fold improved potency (IC50 25 nM) compared with the original lead candidate 4b. 5,8-Dimethylcoumarins were active against DRA, but with much lower potency than 4,8-disubstituted coumarins. In mice, orally administered 4k at 10 mg kg-1 reduced constipation and normalized stool water content in a loperamide-induced constipation model with comparable efficacy to 4b. Pharmacokinetic analysis of orally administered 4k at 10 mg kg-1 in mice indicated serum levels of >10 µM for at least six hours after single dose. This study expands SAR knowledge of 4,8-disubstituted coumarin inhibitors of DRA as novel drug candidates for constipation and kidney stones.

Antibody responses in Klebsiella pneumoniae bloodstream infection: a cohort study.

Background: Klebsiella pneumonia (Kpn) is the fourth leading cause of infection-related deaths globally, yet little is known about human antibody responses to invasive Kpn. In this study, we sought to determine whether the O-specific polysaccharide (OPS) antigen, a vaccine candidate, is immunogenic in humans with Kpn bloodstream infection (BSI). We also sought to define the cross-reactivity of human antibody responses among structurally related Kpn OPS subtypes and to assess the impact of capsule production on OPS-targeted antibody binding and function. Methods: We measured plasma antibody responses to OPS (and MrkA, a fimbrial protein) in a cohort of patients with Kpn BSI and compared these with controls, including a cohort of healthy individuals and a cohort of individuals with Enterococcus BSI. We performed flow cytometry to measure the impact of Kpn capsule production on whole cell antibody binding and complement deposition, utilizing patient isolates with variable levels of capsule production and isogenic capsule-deficient strains derived from these isolates. Findings: We enrolled 69 patients with Kpn BSI. Common OPS serotypes accounted for 57/69 (83%) of infections. OPS was highly immunogenic in patients with Kpn BSI, and peak OPS-IgG antibody responses in patients were 10 to 30-fold higher than antibody levels detected in healthy controls, depending on the serotype. There was significant cross-reactivity among structurally similar OPS subtypes, including the O1v1/O1v2, O2v1/O2v2 and O3/O3b subtypes. Physiological amounts of capsule produced by both hyperencapsulated and non-hyperencapsulated Kpn significantly inhibited OPS-targeted antibody binding and function. Interpretation: OPS was highly immunogenic in patients with Kpn BSI, supporting its potential as a candidate vaccine antigen. The strong cross-reactivity observed between similar OPS subtypes in humans with Kpn BSI suggests that it may not be necessary to include all subtypes in an OPS-based vaccine. However, these observations are tempered by the fact that capsule production, even in non-highly encapsulated strains, has the potential to interfere with OPS antibody binding. This may limit the effectiveness of vaccines that exclusively target OPS. Funding: National Institute of Allergy and Infectious Diseases at the National Institutes of Health. Research in Context: Evidence before this study: Despite the potential of O-specific polysaccharide (OPS) as a vaccine antigen against Klebsiella pneumoniae (Kpn), the immunogenicity of OPS in humans remains largely unstudied, creating a significant knowledge gap with regard to vaccine development. A search of PubMed for publications up to March 18, 2024, using the terms " Klebsiella pneumoniae " and "O-specific polysaccharide" or "O-antigen" or "lipopolysaccharide" revealed no prior studies addressing OPS antibody responses in humans with Kpn bloodstream infections (BSI). One prior study 1 evaluated antibody response to a single lipopolysaccharide (which contains one subtype of OPS) in humans with invasive Kpn infection; however, in this study OPS typing of the infecting strains and target antigen were not described. Added value of this study: Our investigation into OPS immunogenicity in a human cohort marks a significant advance. Analyzing plasma antibody responses in 69 patients with Kpn BSI, we found OPS to be broadly immunogenic across all the types and subtypes examined, and there was significant cross-reactivity among structurally related OPS antigens. We also demonstrated that Kpn capsule production inhibit OPS antibody binding and the activation of complement on the bacterial surface, even in classical Kpn strains expressing lower levels of capsule.Implications of all the available evidence: While the immunogenicity and broad cross-reactivity of OPS in humans with Kpn BSI suggests it is a promising vaccine candidate, the obstruction of OPS antibody binding and engagement by physiologic levels of Kpn capsule underscores the potential limitations of an exclusively OPS-antigen based vaccine for Kpn. Our study provides insights for the strategic development of vaccines aimed at combating Kpn infections, an important antimicrobial resistant pathogen.