Higher Rate of SBP Recurrence with Secondary SBP Prophylaxis Compared to No Prophylaxis in Two National Cirrhosis Cohorts.

BACKGROUND: Spontaneous bacterial peritonitis (SBP) bacteriology has changed over time. Reappraisal of primary SBP prophylaxis showed an increased rate of resistance in patients on primary prophylaxis with resultant discontinuation of this prophylaxis throughout the VA. We aimed to re-evaluate the risk-benefit ratio of secondary SBP prophylaxis (SecSBPPr). METHODS: Using validated ICD 9/10 codes, we utilized the VA Corporate Data Warehouse and the Non-VA National TriNetX database to identify patients in two different large US systems who survived their first SBP diagnosis (with chart review from two VA centers) between 2009-2019. We evaluated the prevalence of SecSBPPr and compared outcomes between those started on SecSBPPr versus not. RESULTS: We identified 4673 Veterans who survived their index SBP episode; 54.3% of whom were prescribed SecSBPPr. Multivariable analysis showed higher SBP recurrence risk in those on vs. off SecSBPPr(HR-1.63[1.40-1.91], p<0.001). This was accompanied by higher fluroquinolone-resistance odds in SecSBPPr patients (OR=4.32[1.36-15.83], p=0.03). In TriNetX we identified 6708 patients who survived their index SBP episode; 48.6% were on SecSBPPr. Multivariable analysis similarly showed SecSBPPr increased SBP recurrence risk (HR-1.68[1.33-1.80], p<0.001). Both datasets showed higher SBP recurrence trends over time in SecSBPPr patients. Results remained consistent at 6-month and 2-year timepoints. CONCLUSION: In two national data sets of >11,000 patients with SBP we found that SecSBPPr was prescribed in roughly half of patients. When initiated, SecSBPPr, compared to no prophylaxis after SBP, increased the risk of SBP recurrence in multivariable analysis by 63-68%, and this trend worsened over time. SecSBPPr should be reconsidered in cirrhosis.

Impact of Prior Inotuzumab Ozogamicin Treatment on Brexucabtagene Autoleucel outcomes in Adults with B-cell ALL.

The effect of prior inotuzumab ozogamicin (InO) treatment on brexucabtagene autoleucel (brexu-cel) outcomes remains unclear in adults with acute lymphoblastic leukemia (ALL), particularly the influence off previous InO response and the timing of administration. We conducted a retrospective multicenter analysis of 189 patients with relapsed/refractory (r/r) ALL treated with brexu-cel. Over half of the patients received InO before brexu-cel (InO-exposed). InO-exposed patients were more heavily pretreated (p= 0.02) and frequently had active marrow disease pre-apheresis (p= 0.03). Response rate and toxicity profile following brexu-cel were comparable for InO-exposed and InO-naïve; however, consolidation therapy post brexu-cel response was utilized at a higher rate in InO-naïve patients (p= 0.005). With a median follow up of 11.4 months, InO-exposed patients had inferior progression-free survival (PFS) (p=0.013) and overall survival (OS) (p=0.006) in univariate analyses; however, prior InO exposure did not influence PFS (HR 1.20, 95%CI, 0.71-2.03) in multivariate models. When InO-exposed patients were stratified according to prior InO response, InO responders had superior PFS (p=0.002) and OS (p<0.0001) relative to InO-refractory. The timing of administering InO did not affect brexu-cel outcomes, with comparable PFS (p=0.51) and OS (p=0.86) for patients receiving InO as bridging therapy or pre-apheresis. In conclusion, while InO exposure was associated with inferior survival outcomes following brexu-cel in unadjusted analyses, these associations were no longer significant in multivariate analyses, suggesting it is unlikely that InO negatively impacts brexu-cel efficacy. Our data instead imply that InO-exposed recipients of brexu-cel tend to be higher-risk patients with intrinsic adverse leukemia biology.

Association between oral health and cognitive impairment in older adults: Insights from a Six-year prospective cohort study.

OBJECTIVE: This study aims to investigate the relationships between four baseline oral conditions (periodontal status, dental caries, tooth wear, and dentition) and repeated global cognition or domain-specific cognition (memory, executive function, attention, and verbal fluency) in non-demented older adults over time. METHODS: This prospective cohort study (2011-2019) enrolled 516 non-demented community-dwelling older adults (age ≥ 65) to explore the association between oral health and cognitive function. Global and domain-specific cognition were assessed biennially (four repeats) using a battery of neuropsychological tests. The baseline oral health conditions were examined, including periodontal status, dental caries, tooth wear, and dentition. The association of these oral conditions with cognition was evaluated by generalized linear mixed models. Stratified analyses were performed by important covariates. RESULTS: Over time, dental caries was associated with poor memory in two different logical memory tests (ß^= -0.06 and ß^= -0.04). Incomplete dentition with less than 28 teeth was associated with poor performance in attention (ß^= -0.05) and verbal fluency (ß^= -0.03). These associations became more evident in those with an elevated inflammatory marker (IL-6, ß^= -0.11 to -0.08). In contrast, tooth wear was associated with better memory in two different logical memory tests (ß^= 0.33 and ß^= 0.36) and better executive function (ß^= 0.06) over time, and this association became more evident in those with the lowest inflammatory marker (IL-6, ß^= 0.10). CONCLUSIONS: Dental caries and incomplete dentition were associated with poor memory, attention, and verbal fluency performance. Conversely, tooth wear was associated with better memory performance and executive function. CLINICAL SIGNIFICANCE: For early prevention of dementia, an evaluation of multiple dental and periodontal status in older adults helps predict the risk of dementia in the preclinical phase. Maintaining intact tooth structure without caries progression and eventually tooth loss may help prevent the worsening of memory, attention, and verbal fluency over time.

Busulfan, melphalan and carfilzomib high-dose chemotherapy and autologous haematopoietic stem cell transplantation in multiple myeloma.

The standard of care for fit, newly diagnosed multiple myeloma patients includes induction therapy followed by consolidative high-dose chemotherapy with melphalan and autologous stem cell transplant (AHSCT). Intensified preparative regimens, such as busulfan and melphalan (BuMel), have shown promise to lengthen progression-free survival (PFS). We previously reported that the addition of bortezomib to BuMel improved PFS compared to melphalan alone in CIBMTR-matched controls. We now integrate the second-generation protease inhibitor, carfilzomib, before and after BuMel (BuMelCar) in a phase I/II trial with carfilzomib. Patients with NDMM, relapsed/refractory MM (RRMM) and those failing prior AHSCT were eligible. Primary end-points were safety and tolerability. Secondary end-points included minimal residual disease negativity rates, PFS and OS. The study enrolled 19 patients. 73% were high risk either due to R-ISS III status, adverse genetics or relapsed after prior AHSCT. The maximum tolerated dose (MTD) of carfilzomib was determined to be 36 mg/m2. Noted grade 3 toxicities were febrile neutropenia (79%), mucositis (21%) and diarrhoea (16%). The 2-year PFS for the whole cohort and MTD was 89% and 100% respectively. 80% of all patients and 82% of patients in the MTD cohort achieved MRD negativity. Further studies regarding this regimen are planned.

Endogenous tenocyte activation underlies the regenerative capacity of the adult zebrafish tendon.

Tendons are essential, frequently injured connective tissues that transmit forces from muscle to bone. Their unique highly ordered, matrix-rich structure is critical for proper function. While adult mammalian tendons heal after acute injuries, endogenous tendon cells, or tenocytes, fail to respond appropriately, resulting in the formation of disorganized fibrovascular scar tissue with impaired function and increased propensity for re-injury. Here, we show that, unlike mammals, adult zebrafish tenocytes activate upon injury and fully regenerate the tendon. Using a full tear injury model in the adult zebrafish craniofacial tendon, we defined the hallmark stages and cellular basis of tendon regeneration through multiphoton imaging, lineage tracing, and transmission electron microscopy approaches. Remarkably, we observe that zebrafish tendons regenerate and restore normal collagen matrix ultrastructure by 6 months post-injury (mpi). Tendon regeneration progresses in three main phases: inflammation within 24 h post-injury (hpi), cellular proliferation and formation of a cellular bridge between the severed tendon ends at 3-5 days post-injury (dpi), and re-differentiation and matrix remodeling beginning from 5 dpi to 6 mpi. Importantly, we demonstrate that pre-existing tenocytes are the main cellular source of regeneration, proliferating and migrating upon injury to ultimately bridge the tendon ends. Finally, we show that TGF-ß signaling is required for tenocyte recruitment and bridge formation. Collectively, our work debuts and aptly positions the adult zebrafish tendon as an invaluable comparative system to elucidate regenerative mechanisms that may inspire new therapeutic strategies.

Moderate-high intensity exercise associates with reduced incident alcohol-associated liver disease in high-risk patients.

BACKGROUND: Therapies to prevent alcohol-associated liver disease (ALD) in high-risk patients are needed. AIMS: In this retrospective association study, we examined whether patients with alcohol use disorder (AUD) who reported greater exercise were less likely to develop liver disease. METHODS: In this retrospective cohort study, we used the Mass General Brigham Biobank to investigate the impact of both moderate-high and light-intensity exercise on the development of ALD in patients with AUD, using clinician-provided diagnostic International Classification of Diseases 10 codes. Exercise was evaluated using a questionnaire completed after an AUD diagnosis, and before evidence of liver disease. Cox regressions were used to generate hazard ratios (HRs) for the development of ALD. RESULTS: 1987 patients met inclusion criteria. These patients were followed for an average of 10.7 years. In multivariable analyses, we found that patients that reported at least 2.5 h of moderate-high intensity exercise/week (confidence interval recommendation for exercise) were less likely to develop ALD compared to patients that did not exercise (HR: 0.26, 95%CI: 0.085-0.64, P = 0.007). Indeed, each hour of moderate-high intensity exercise was associated with progressively decreasing odds of developing ALD (HR: 0.76, 95%CI: 0.58-0.91, P = 0.02). Conversely, patients who did not engage in any moderate-high intensity exercise were more likely to develop ALD (HR: 2.76, 95%CI: 1.44-5.40, P = 0.003). CONCLUSIONS: In our cohort, patients with AUD who reported moderate-high intensity exercise showed a lower association with incidence of ALD development than patients who did not exercise.

Endogenous Tenocyte Activation Underlies the Regenerative Capacity of Adult Zebrafish Tendon.

Tendons are essential, frequently injured connective tissues that transmit forces from muscle to bone. Their unique highly ordered, matrix-rich structure is critical for proper function. While adult mammalian tendons heal after acute injuries, endogenous tendon cells, or tenocytes, fail to respond appropriately, resulting in the formation of disorganized fibrovascular scar tissue with impaired function and increased propensity for re-injury. Here, we show that unlike mammals, adult zebrafish tenocytes activate upon injury and fully regenerate the tendon. Using a full tear injury model in the adult zebrafish craniofacial tendon, we defined the hallmark stages and cellular basis of tendon regeneration through multiphoton imaging, lineage tracing, and transmission electron microscopy approaches. Remarkably, we observe that the zebrafish tendon can regenerate and restore normal collagen matrix ultrastructure by 6 months post-injury (mpi). We show that tendon regeneration progresses in three main phases: inflammation within 24 hours post-injury (hpi), cellular proliferation and formation of a cellular bridge between the severed tendon ends at 3-5 days post-injury (dpi), and re-differentiation and matrix remodeling beginning from 5 dpi to 6 mpi. Importantly, we demonstrate that pre-existing tenocytes are the main cellular source of regeneration. Collectively, our work debuts the zebrafish tendon as one of the only reported adult tendon regenerative models and positions it as an invaluable comparative system to identify regenerative mechanisms that may inspire new tendon injury treatments in the clinic.

Embracing the diversity of model systems to deconstruct the basis of regeneration and tissue repair.

The eighth EMBO conference in the series 'The Molecular and Cellular Basis of Regeneration and Tissue Repair' took place in Barcelona (Spain) in September 2022. A total of 173 researchers from across the globe shared their latest advances in deciphering the molecular and cellular basis of wound healing, tissue repair and regeneration, as well as their implications for future clinical applications. The conference showcased an ever-expanding diversity of model organisms used to identify mechanisms that promote regeneration. Over 25 species were discussed, ranging from invertebrates to humans. Here, we provide an overview of the exciting topics presented at the conference, highlighting novel discoveries in regeneration and perspectives for regenerative medicine.

Creation of an Inpatient Alcohol Liver Service Improves Early Liver Disease Detection in Patients With Alcohol Use Disorder.

One of the most common and devastating complications of alcohol use disorder (AUD) is the development of alcohol-associated liver disease (ALD).1 Unfortunately, outcomes of patients with ALD are poor, in large part because patients with ALD are diagnosed at a much later stage of disease compared with patients with other causes of liver disease.2 Accordingly, earlier detection is critical in combating the high mortality associated with ALD. In this work, we sought to assess the feasibility and impact of evaluating high-risk patients with no prior documented liver disease for the presence of advanced ALD while admitted to the hospital.

Osteoclast-mediated resorption primes the skeleton for successful integration during axolotl limb regeneration.

Early events during axolotl limb regeneration include an immune response and the formation of a wound epithelium. These events are linked to a clearance of damaged tissue prior to blastema formation and regeneration of the missing structures. Here, we report the resorption of calcified skeletal tissue as an active, cell-driven, and highly regulated event. This process, carried out by osteoclasts, is essential for a successful integration of the newly formed skeleton. Indeed, the extent of resorption is directly correlated with the integration efficiency, and treatment with zoledronic acid resulted in osteoclast function inhibition and failed tissue integration. Moreover, we identified the wound epithelium as a regulator of skeletal resorption, likely releasing signals involved in recruitment/differentiation of osteoclasts. Finally, we reported a correlation between resorption and blastema formation, particularly, a coordination of resorption with cartilage condensation. In sum, our results identify resorption as a major event upon amputation, playing a critical role in the overall process of skeletal regeneration.

The impact of Drew Noden's work on our understanding of craniofacial musculoskeletal integration.

The classical anatomist Drew Noden spearheaded craniofacial research, laying the foundation for our modern molecular understanding of development, evolution, and disorders of the craniofacial skeleton. His work revealed the origin of cephalic musculature and the role of cranial neural crest (CNC) in early formation and patterning of the head musculoskeletal structures. Much of modern cranial tendon research advances a foundation of knowledge that Noden built using classical quail-chick transplantation experiments. This elegant avian chimeric system involves grafting of donor quail cells into host chick embryos to identify the cell types they can form and their interactions with the surrounding tissues. In this review, we will give a brief background of vertebrate head formation and the impact of CNC on the patterning, development, and evolution of the head musculoskeletal attachments. Using the zebrafish as a model system, we will discuss examples of modifications of craniofacial structures in evolution with a special focus on the role of tendon and ligaments. Lastly, we will discuss pathologies in craniofacial tendons and the importance of understanding the molecular and cellular dynamics during craniofacial tendon development in human disease.

Structural racism is a mediator of disparities in acute myeloid leukemia outcomes.

Non-Hispanic Black (NHB) and Hispanic patients with acute myeloid leukemia (AML) have higher mortality rates than non-Hispanic White (NHW) patients despite more favorable genetics and younger age. A discrete survival analysis was performed on 822 adult patients with AML from 6 urban cancer centers and revealed inferior survival among NHB (hazard ratio [HR] = 1.59; 95% confidence interval [CI]: 1.15, 2.22) and Hispanic (HR = 1.25; 95% CI: 0.88, 1.79) patients compared with NHW patients. A multilevel analysis of disparities was then conducted to investigate the contribution of neighborhood measures of structural racism on racial/ethnic differences in survival. Census tract disadvantage and affluence scores were individually calculated. Mediation analysis of hazard of leukemia death between groups was examined across 6 composite variables: structural racism (census tract disadvantage, affluence, and segregation), tumor biology (European Leukemia Network risk and secondary leukemia), health care access (insurance and clinical trial enrollment), comorbidities, treatment patterns (induction intensity and transplant utilization), and intensive care unit (ICU) admission during induction chemotherapy. Strikingly, census tract measures accounted for nearly all of the NHB-NHW and Hispanic-NHW disparity in leukemia death. Treatment patterns, including induction intensity and allogeneic transplant, and treatment complications, as assessed by ICU admission during induction chemotherapy, were additional mediators of survival disparities in AML. This is the first study to formally test mediators for observed disparities in AML survival and highlights the need to investigate the mechanisms by which structural racism interacts with known prognostic and treatment factors to influence leukemia outcomes.

Healthcare Provider Perspectives Regarding Use of Medical Interpreters During End-of-Life Conversations With Limited English Proficient Patients.

BACKGROUND: Healthcare providers increasingly care for patients with Limited English Proficiency (LEP). There is limited research evaluating healthcare provider utilization practices, attitudes, perceived benefits and barriers regarding the use of medical interpreters in end of life (EOL) and goals of care (GOC) conversations. OBJECTIVES: To elicit healthcare providers' opinions of the role, factors that impact decisions to use medical interpreters and perceived utility of using medical interpreters when conducting EOL and GOC conversations with LEP patients and their families. DESIGN: Cross-sectional survey of internal medicine trainees and attending physicians from a U.S. medical center. RESULTS: A total of 117 surveys were collected with a response rate of 51%. In-person medical interpreters received higher ratings with regard to their helpfulness compared to telephone medical interpreters during EOL and GOC conversations. Being an attending physician and having received training in the use of a medical interpreter predicted higher composite scores reflecting greater awareness of the roles of medical interpreters and endorsement of best communication practices. In-person interpreters were viewed by a subset of participants as "standard of care" during EOL and GOC conversations. CONCLUSION: Having more years in practice and receiving training in the use of medical interpreters correlated with more favorable attitudes toward the role of medical interpreters and positive communication practices. Incorporating early training in the use of medical interpreters could help enhance communication practices and outcomes during EOL and GOC conversations with LEP patients.

Symmetry breaking of tissue mechanics in wound induced hair follicle regeneration of laboratory and spiny mice.

Tissue regeneration is a process that recapitulates and restores organ structure and function. Although previous studies have demonstrated wound-induced hair neogenesis (WIHN) in laboratory mice (Mus), the regeneration is limited to the center of the wound unlike those observed in African spiny (Acomys) mice. Tissue mechanics have been implicated as an integral part of tissue morphogenesis. Here, we use the WIHN model to investigate the mechanical and molecular responses of laboratory and African spiny mice, and report these models demonstrate opposing trends in spatiotemporal morphogenetic field formation with association to wound stiffness landscapes. Transcriptome analysis and K14-Cre-Twist1 transgenic mice show the Twist1 pathway acts as a mediator for both epidermal-dermal interactions and a competence factor for periodic patterning, differing from those used in development. We propose a Turing model based on tissue stiffness that supports a two-scale tissue mechanics process: (1) establishing a morphogenetic field within the wound bed (mm scale) and (2) symmetry breaking of the epidermis and forming periodically arranged hair primordia within the morphogenetic field (µm scale). Thus, we delineate distinct chemo-mechanical events in building a Turing morphogenesis-competent field during WIHN of laboratory and African spiny mice and identify its evo-devo advantages with perspectives for regenerative medicine.

Four Cycles of Etoposide plus Cisplatin for Patients with Good-Risk Advanced Germ Cell Tumors.

BACKGROUND: The National Comprehensive Cancer Network recommends either three cycles of bleomycin, etoposide, and cisplatin or four cycles of etoposide and cisplatin (EPx4) as initial chemotherapy for the treatment of good-risk germ cell tumors (GCTs). To assess the response, toxicity, and survival outcomes of EPx4, we analyzed our experience. MATERIAL AND METHODS: Response and survival outcomes, selected toxicities, and adherence to chemotherapy dose and schedule were assessed in patients with good-risk GCT who received EPx4 at Memorial Sloan Kettering Cancer Center between 1982 and 2016. The results were compared with our past results and published data. RESULTS: Between 1982 and 2016, 944 patients with GCT were treated with EPx4, 289 who were previously reported plus 655 treated between January 2000 and August 2016. A favorable response was achieved in 928 of 944 patients (98.3%). Five-year progression-free, disease-specific, and overall survival rates were 93.9%, 98.6%, and 97.9%, respectively. Median follow-up was 7.3 years (range, 2.8 months to 35.5 years). Viable, nonteratomatous malignant GCT was present in 3.5% of 432 postchemotherapy retroperitoneal lymph node dissection specimens from patients with nonseminomatous GCT. Febrile neutropenia and thromboembolic events occurred in 16.0% and 8.9%, respectively, with one treatment-related death. In the more recent 655-patient cohort, full-dose EPx4 was administered to 631 (96.3%), with deviations from planned treatment driven mainly by vascular (n = 13), hematologic (n = 11), renal (n = 7), or infectious (n = 5) events. CONCLUSION: EPx4 is highly effective and well tolerated in patients with good-risk GCTs and remains a standard of care. IMPLICATIONS FOR PRACTICE: Four cycles of etoposide and cisplatin (EPx4) is a standard-of-care regimen for all patients with good-risk germ cell tumors with a favorable response rate and disease-specific survival of 98%. Full-dose administration of etoposide and cisplatin and complete resection of residual disease lead to optimal outcomes. EPx4 should be the recommended regimen in active smokers, patients with reduced or borderline kidney function, and patients aged 50 years or older, which are patient groups at increased risk for bleomycin pulmonary toxicity. Because of a risk of acquired severe pulmonary illness, EPx4 may also be favored for patients who vape or use e-cigarettes and during ongoing transmission of severe acute respiratory syndrome coronavirus 2.

Bringing tendon biology to heel: Leveraging mechanisms of tendon development, healing, and regeneration to advance therapeutic strategies.

Tendons are specialized matrix-rich connective tissues that transmit forces from muscle to bone and are essential for movement. As tissues that frequently transfer large mechanical loads, tendons are commonly injured in patients of all ages. Following injury, mammalian tendons heal poorly through a slow process that forms disorganized fibrotic scar tissue with inferior biomechanical function. Current treatments are limited and patients can be left with a weaker tendon that is likely to rerupture and an increased chance of developing degenerative conditions. More effective, alternative treatments are needed. However, our current understanding of tendon biology remains limited. Here, we emphasize why expanding our knowledge of tendon development, healing, and regeneration is imperative for advancing tendon regenerative medicine. We provide a comprehensive review of the current mechanisms governing tendon development and healing and further highlight recent work in regenerative tendon models including the neonatal mouse and zebrafish. Importantly, we discuss how present and future discoveries can be applied to both augment current treatments and design novel strategies to treat tendon injuries.

Inhibition of Wound Epidermis Formation via Full Skin Flap Surgery During Axolotl Limb Regeneration.

Classical experiments in salamander regenerative biology over the last century have long established that the wound epidermis is a crucial signaling structure that forms rapidly post-amputation and is required for limb regeneration. However, methods to study its precise function at the molecular level over the last decades have been limited due to a paucity of precise functional techniques and genomic information available in salamander model systems. Excitingly, the recent plethora of sequencing technologies coupled with the release of various salamander genomes and the advent of functional genetic testing methods, including CRISPR, makes it possible to re-visit these foundational experiments at unprecedented molecular resolution. Here, I describe how to perform the classically developed full skin flap (FSF) surgery in adult axolotls in order to inhibit wound epidermis formation immediately following amputation. The wound epidermis normally forms via distal migration of epithelial cells in the skin proximal to the amputation plane to seal off the wound from the outside environment. The surgery entails immediately suturing full thickness skin (which includes both epidermal and dermal layers) over the amputation plane to hinder epithelial cell migration and contact with the underlying damaged mesenchymal tissues. Successful surgeries result in the inhibition of blastema formation and limb regeneration. By combining this surgery method with contemporary downstream molecular and functional analyses, researchers can begin to uncover the molecular underpinnings of wound epidermis function and biology during limb regeneration.