Incidence and survival of pediatric and adult hepatocellular carcinoma, United States, 2001-2020.

BACKGROUND: Hepatocellular carcinoma accounts for approximately 80 % of liver neoplasms. Globally, hepatocellular carcinoma ranks as the third most lethal cancer, with the number of deaths expected to further increase by 2040. In adults, disparities in incidence and survival are well described while pediatric epidemiology is not well characterized. We describe incidence and survival for pediatric (ages 0-19 years) hepatocellular carcinoma cases and compare these measures to adults (ages ≥ 20 years) diagnosed with hepatocellular carcinoma. METHODS: We assessed incidence data from the US Cancer Statistics database during 2003-2020 and 5-year survival from the National Program of Cancer Registries during 2001-2019. Incidence trends were determined by annual percent change (APC) and average APC (AAPC) using joinpoint regression. Five-year survival was evaluated by relative survival, and all-cause survival was estimated using multivariate Cox modeling. Corresponding 95 % confidence intervals (CI) were calculated for all analyses. RESULTS: Incidence rate per 100,000 persons was 0.056 (95 %CI:0.052-0.060) for pediatric cases and 7.793 (7.767-7.819) for adults. Incidence was stable in the pediatric population (0.3 AAPC, - 1.1 to 1.7). In contrast, after periods of increase, incidence declined in adults after 2015 (-1.5 APC). Relative survival increased over time for both pediatric and adult ages and was higher for children and adolescents (46.4 %, 95 %CI:42.4-50.3) than adults (20.7 %, 95 %CI:20.5-20.9). Regression modeling showed that non-Hispanic Black race and ethnicity was associated with higher risk of death in children and adolescents (1.48, 95 %CI:1.07-2.05) and adults (1.11, 95 %CI:1.09-1.12) compared to non-Hispanic white race and ethnicity. CONCLUSIONS: Between 2003 and 2020 in the United States, pediatric incidence was stable while incidence in adults began to decline after 2015. Survival was higher across all stages for children and adolescents compared to adults. Non-Hispanic Black race and ethnicity showed a higher risk of death for both age groups. Further studies could explore the factors that influence these outcome disparities.

Efficacy and outcomes of per oral plication of the (neo)esophagus (POPE) for impaired emptying in achalasia and post-esophagectomy patients.

BACKGROUND: Per-oral plication of the (neo)esophagus (POPE) is an endoscopic procedure used to improve emptying of the defunctionalized esophagus or gastric conduit, with the hope of improving symptoms and quality of life. As this procedure has only been performed in the United States for the past 4 years, safety and efficacy have not been well established. METHODS: This is a retrospective case series for patients who underwent POPE from a single institution between 2019 and 2023. Data collected included demographics, preoperative diagnoses and treatments, imaging, endoscopic data, operative intervention, 90-day complications, and response to treatment. Quality of life and patient satisfaction data were collected by phone survey. RESULTS: Seventeen cases were identified, encompassing 13 primary procedures and 4 repeat POPEs (re-POPE). Eight patients had end-stage achalasia and 5 had impaired gastric emptying after esophagectomy with gastric conduits. Median age was 65 years and median ASA was 3, with 38.5% female patients. POPE was performed with 2-6 plication sutures in an average of 75 min. The majority of patients discharged home the same day. For the 17 procedures, there were 4 complications. Two patients required antibiotics for pneumonia, while 4 required procedural intervention. There were no deaths. Preoperative symptoms improved or resolved at initial follow up in 82.3% of patients. Four patients experienced symptom recurrence and required re-POPE, 1 with achalasia and 3 with gastric conduits. Although all achalasia patients had an "end-stage esophagus," none have required esophagectomy since the introduction of POPE. CONCLUSIONS: POPE is an endoscopic procedure that is efficacious in relieving emptying difficulties for the end-stage esophagus and gastric conduit. It may obviate the need for esophagectomy or conduit replacement. Also, it can be repeated in select patients. While the risk profile of complications is favorable compared to alternative operations, patients with gastric conduits are at higher risk.

Donor Limb Functional Restoration via a Novel Clinical Care Pathway following Fibula Free Flap Harvest for Head and Neck Reconstruction.

Patients undergoing head and neck skeletal reconstruction (HNR) often require free tissue transfer from the extremities to ensure proper restoration of form and function. This requires a team-based, highly reliable medical system centered around the patient needs. Surgical intervention across multiple sites and harvesting of donor tissue results in short- and long-term physical impairments. There is a paucity of research objectively measuring impairments resulting from the graft donor site. There is a lack of research that objectively measures impairments and protocols for the management of these patients postoperatively. Patients undergo little, if any, formal approach to dealing with the vast impairments, which are sequelae to this surgery. This leads to large discrepancies in proposed functional progressions, return to duty timelines, and utilization of rehabilitative resources. At a major military medical center, an innovative clinical care pathway for patients undergoing HNR using free tissue transfer was implemented using a multidisciplinary model that focuses on early engagement with rehabilitation. This model, paired with a single surgery, will attempt to return service members to duty months earlier than the traditional approach. This report describes the conceptual framework and implementation of a new criteria-based, multidisciplinary clinical care pathway for HNR patients. The collaboration amongst the multidisciplinary care team has optimized the holistic health of the patient and communication with their support network, yielding faster return to normalization of daily life activities. The long-term goal is to further develop and formalize this pathway to best serve this patient population.

Evolution of species recognition when ecology and sexual selection favor signal stasis.

The process of reproductive character displacement involves divergence and/or the narrowing of variance in traits involved in species recognition, driven by interactions between taxa. However, stabilizing sexual selection may favor stasis and species similarity in these same traits if signals are optimized for transmission through the prevailing environment. Further, sexual selection may promote increased variability within species to facilitate individual recognition. Here we ask how the conflicting selection pressures of species recognition and sexual selection are resolved in a genus of Himalayan birds that sing exceptionally similar songs. We experimentally show that small differences in two traits (note shape and peak frequency) are both necessary and sufficient for species recognition. Song frequency shows remarkable clinal variation along the Himalayan elevational gradient, being most divergent where species co-occur, the classic signature of reproductive character displacement. Note shape shows no such clinal variation but varies more between individuals of an allopatric species than it does among individuals within species which co-occur. We argue that the different note shapes experience similar transmission constraints, and differences produced through species interactions spread back through the entire species range. Our results imply that reproductive character displacement is likely to be common.

Scrotal Cancer Incidence Rates and Trends-United States, 1999-2020.

OBJECTIVE: To examine population-level scrotal cancer incidence rates and trends among adult men in the United States. METHODS: Data from the United States Cancer Statistics, covering approximately 96% of the United States population, were analyzed to calculate age-standardized incidence rates of scrotal cancer among men aged 18 years and older from 1999 to 2020. Trends in incidence rates were evaluated by age, race and ethnicity, Census region, and histology using joinpoint regression. RESULTS: Overall, 4669 men were diagnosed with scrotal cancer (0.20 per 100,000). Incidence rates were highest among men aged 70 years and older (0.82 per 100,000). Rates were higher among non-Hispanic Asian or Pacific Islander men (0.31 per 100,000) compared to other race and ethnicity groups. The most common histologic subtypes were squamous cell carcinoma (35.9%), extramammary Paget disease (20.8%), and sarcoma (20.5%). Incidence rates decreased by 2.9% per year from 1999 to 2019 for non-Hispanic Asian or Pacific Islander men, decreased by 8.1% per year from 1999 to 2006 for basal cell carcinomas, and increased by 1.8% per year from 1999 to 2019 for extramammary Paget disease; otherwise, rates remained stable for all other variables examined. CONCLUSION: While scrotal cancer incidence rates were higher than previously reported, rates were still low and stable over time.

Anterior Cruciate Ligament Reconstruction Surgery Outcomes: A Comparison Between Patients Who Underwent the Procedure During the COVID-19 Pandemic and a Cohort Treated Prior to the Pandemic.

Background and objective During the coronavirus disease 2019 (COVID-19) pandemic, many elective orthopedic surgeries, including anterior cruciate ligament reconstruction (ACLR), were temporarily postponed. The purpose of this study was to compare the outcomes of ACLR in patients who underwent surgery during the COVID-19 pandemic with those in a cohort treated before the pandemic. Materials and methods This retrospective review compared patients who underwent primary ACLR during two periods: March to June 2020 (the pandemic group) and January to December 2018 (the pre-pandemic group). Matched cohorts (1:1) were created using propensity matching. Time from injury-to-first visit, injury-to-surgery, and first visit-to-surgery were calculated. Subjective and objective outcomes, minimal clinically important difference (MCID) achievement, and complication rates were recorded for up to two years postoperatively. Statistical analysis included 𝛘2 or Fisher's exact tests for categorical data, and t- or Wilcoxon signed-rank tests for continuous data with significance set at P < 0.05. Results The pandemic and pre-pandemic groups consisted of 33 and 217 patients, respectively. Matched cohorts consisted of 33 patients each. The time from injury-to-surgery and the first visit-to-surgery was prolonged in the pandemic group. When unmatched, visual analog scale (VAS) scores at three months postoperatively and Patient-Reported Outcomes Measurement Information System (PROMIS)-pain interference (PI) at six months postoperatively and at the final follow-up were higher in the pandemic group. When matched, PROMIS-PI at six months postoperatively was higher in the pandemic group, and VAS scores at one year postoperatively were higher in the pre-pandemic group. MCID achievement and complication rates did not significantly differ between the groups. Conclusions ACLR procedures were significantly delayed in the early months of the COVID-19 pandemic. While patients treated before and during the pandemic experienced varying pain levels during recovery, their functional outcomes, MCID achievement, and complication rates did not differ significantly.

Comparing the Clinical and Radiographic Outcomes of Humeral Shaft Fractures by Treatment Type.

PURPOSE: Humeral shaft fractures are common orthopedic injuries, representing 1-5% of all fractures. There is conflicting literature regarding the superiority of operative versus nonoperative treatment of these fractures. The purpose of this study was to examine functional outcomes and time to radiographic union in humeral shaft fractures with the hypothesis that both would be improved in patients treated operatively relative to those treated nonoperatively. METHODS: This retrospective cohort study examined patients with humeral shaft fractures treated at a single large healthcare system between 2010 and 2020. A chart and radiograph review were performed to collect information on demographics, fracture, treatment, and outcome information. These measures were compared between patients treated operatively and nonoperatively. RESULTS: Five hundred seventeen adult patients meeting inclusion criteria were identified; 233 were treated nonoperatively, and 284 were treated operatively. The mean patient age was 50.2 years in those who underwent surgery relative to 59.9 years in those treated without surgery (P<0.001). Operatively-treated patients had significantly faster time to radiographic union at a median of 113 days compared to a median of 161 days in nonoperatively-treated patients (P=0.001). The operative group was made weight-bearing as tolerated significantly faster than the nonoperative group (84 days versus 98 days, respectively, P=0.002). No statistically significant difference was seen between the two treatment groups in rates of complications or range of motion at the time of radiographic union. However, patients who underwent surgery were found to be up to two times more likely to achieve full shoulder forward elevation by the time of their final follow-up than those treated without surgery (P=0.011). CONCLUSION: Patients with humeral shaft fractures treated operatively have faster time to union, earlier weight bearing, and no change in the rate of complications compared to patients treated nonoperatively.

Increased number of excitatory synapsis and decreased number of inhibitory synapsis in the prefrontal cortex in autism.

Previous studies in autism spectrum disorder demonstrated an increased number of excitatory pyramidal cells and a decreased number of inhibitory parvalbumin+ chandelier interneurons in the prefrontal cortex of postmortem brains. How these changes in cellular composition affect the overall abundance of excitatory and inhibitory synapses in the cortex is not known. Herein, we quantified the number of excitatory and inhibitory synapses in the prefrontal cortex of 10 postmortem autism spectrum disorder brains and 10 control cases. To identify excitatory synapses, we used VGlut1 as a marker of the presynaptic component and postsynaptic density protein-95 as marker of the postsynaptic component. To identify inhibitory synapses, we used the vesicular gamma-aminobutyric acid transporter as a marker of the presynaptic component and gephyrin as a marker of the postsynaptic component. We used Puncta Analyzer to quantify the number of co-localized pre- and postsynaptic synaptic components in each area of interest. We found an increase in the number of excitatory synapses in upper cortical layers and a decrease in inhibitory synapses in all cortical layers in autism spectrum disorder brains compared with control cases. The alteration in the number of excitatory and inhibitory synapses could lead to neuronal dysfunction and disturbed network connectivity in the prefrontal cortex in autism spectrum disorder.

Negative Pressure Wound Therapy to Reduce Surgical Site Infections after CRS/HIPEC.

BACKGROUND: Surgical site infections (SSIs) are a common cause of morbidity after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal malignancy. Negative pressure wound therapy (NPWT) has been proposed as a method to reduce the rates of SSIs; however, there is paucity in the literature on the efficacy in this population. The goal of this study was to determine whether routine use of NPWT in patients undergoing CRS/HIPEC could reduce the risk of developing SSI. METHODS: We performed a retrospective before-after study to assess the rates of SSI with NPWT compared with a standard postoperative surgical dressing (SSD) in all patients undergoing CRS/HIPEC from November 2013 to December 2021 at a single tertiary care center. The primary outcome was rate of SSI. A multivariate logistic regression analysis was performed to evaluate for risk factors for SSI. RESULTS: A total of 178 patients were treated with CRS/HIPEC over the study period. Seventy patients had placement of SSD, and 108 patients had placement of NPWT. Rates of SSI were 11.4% (8/70) and 5.6% (6/108) in the two groups, respectively (p = 0.16). On multivariate analysis, patients treated with NPWT had a significantly lower risk of developing an SSI (OR 0.24 [0.06, 0.92], p = 0.037). Patients living >50 km from the hospital had significantly higher risk of developing SSI (OR 2.03 [1.09, 3.78], p = 0.026). CONCLUSIONS: These results suggest that routine use of NPWT can reduce the risk of developing an SSI in patients undergoing CRS/HIPEC for peritoneal malignancy.

The Impact of Adjusting for Hysterectomy Prevalence on Cervical Cancer Incidence Rates and Trends Among Women Aged 30 Years and Older - United States, 2001-2019.

Hysterectomy protects against cervical cancer when the cervix is removed. However, measures of cervical cancer incidence often fail to exclude women with a hysterectomy from the population at risk denominator, underestimating and distorting disease burden. In this study, we estimated hysterectomy prevalence from the Behavioral Risk Factor Surveillance System surveys to remove the women who were not at risk of cervical cancer from the denominator and combined these estimates with the United States Cancer Statistics data. From these data, we calculated age-specific and age-standardized incidence rates for women aged >30 years from 2001-2019, adjusted for hysterectomy prevalence. We calculated the difference between unadjusted and adjusted incidence rates and examined trends by histology, age, race and ethnicity, and geographic region using Joinpoint regression. The hysterectomy-adjusted cervical cancer incidence rate from 2001-2019 was 16.7 per 100,000 women-34.6% higher than the unadjusted rate. After adjustment, incidence rates were higher by approximately 55% among Black women, 56% among those living in the East South Central division, and 90% among women aged 70-79 and >80 years. These findings underscore the importance of adjusting for hysterectomy prevalence to avoid underestimating cervical cancer incidence rates and masking disparities by age, race, and geographic region.

Incidence and survival of pediatric and adult hepatocellular carcinoma, United States, 2001-2020.

Importance: Hepatocellular carcinoma accounts for approximately 80% of liver neoplasms. Globally, hepatocellular carcinoma ranks as the third most lethal cancer, with the number of deaths expected to further increase by 2040. In adults, disparities in incidence and survival are well described while pediatric epidemiology is not well characterized. Objective: To describe incidence and survival for pediatric (ages 0-19 years) hepatocellular carcinoma cases and compare these measures to adults (ages ≥20 years) diagnosed with hepatocellular carcinoma. We evaluated demographic factors and clinical characteristics that influence incidence and outcomes. Design: Population-based cohort study. Setting: Incidence data from the US Cancer Statistics database from 2003 to 2020 and 5-year relative survival from the National Program of Cancer Registries from 2001 to 2019, covering 97% and 83% of the US population, respectively. Participants: 355,349 US Cancer Statistics and 257,406 the National Program of Cancer Registries patients were identified using ICD-O-3 C22.0 and 8170-5 codes. Main Outcomes and Measures: Incidence annual percent change (APC) and average APC (AAPC) using joinpoint regression. Five-year relative survival. All-cause survival estimated using multivariate Cox modeling. Corresponding 95% confidence intervals (CI) were calculated. Results: Incidence rate per 100,000 persons was 0.056 (95%CI:0.052-0.060) for pediatric cases and 7.793 (7.767-7.819) for adults. Incidence was stable in the pediatric population (0.3 AAPC, -1.1-1.7). In contrast, after periods of increase, incidence declined in adults after 2015 (-1.5 APC). Relative survival increased over time for both pediatric and adult ages and was higher for children and adolescents (46.4%, 95%CI:42.4-50.3) than adults (20.7%, 95%CI:20.5-20.9) overall and when stratified by stage. Regression modeling showed that non-Hispanic Black race and ethnicity was associated with higher risk of death in children and adolescents (1.48, 95%CI:1.07-2.05) and adults (1.11, 95%CI:1.09-1.12) compared to non-Hispanic white race and ethnicity. Conclusions and Relevance: Between 2003 and 2020 in the United States, pediatric incidence was stable while incidence in adults began to decline after 2015. Survival was higher across all stages for children and adolescents compared to adults. Non-Hispanic Black race and ethnicity showed a higher risk of death for both age groups. Further studies could explore the factors that influence these outcome disparities.

Analysis of Player Performance and Financial Costs Associated With Implementation of an Updated National Hockey League Concussion Protocol: A Retrospective Comparative Study.

Background: An updated National Hockey League (NHL) concussion protocol (NHLCP) was established in the 2016-2017 season to mitigate the negative outcomes of sport-related concussions. However, few studies on the effects of implementing the NHLCP have been performed. Purpose: To define concussion incidence and investigate differences in NHL player performance after a concussion during periods before and after NHLCP implementation and assess the financial impact on NHL teams associated with NHLCP implementation. Study Design: Cohort study; Level of evidence, 3. Methods: This was a retrospective review of NHL players who sustained a concussion before (2000-2001 to 2015-2016 seasons) and after (2016-2017 to 2020-2021 seasons) implementing the NHLCP (pre-NHLCP and post-NHLCP groups). For each group, multiple performance metrics-including 30 days, 1 season, and 3 seasons before and after concussion-were compared for both groups. Return to play, total concussion cost, and association of return to play with cost were investigated using regression analysis. Results: A total of 452 players (423 skaters, 29 goalies) sustained concussions during the study period, including 331 players (315 skaters, 16 goalies) in the pre-NHLCP group and 121 players (108 skaters, 13 goalies) in the post-NHLCP group. For both groups, no significant differences in standard performance were observed during the 30-day and 1-season periods before and after concussion. The mean return to play was significantly higher in the pre-NHLCP group than in the post-NHLCP group (20.1 vs 15.7 days; P = .022). The mean adjusted player salary was not different between groups; nonetheless, the mean adjusted replacement player salary was significantly higher in the post-NHLCP group ($744,505 vs $896,942; P = .032). The mean cost of time missed did not differ between groups. The mean return to play time significantly decreased over the entire study period (R2 = 0.33; P = .005), and the mean return to play time was positively associated with cost R2 = 0.215; P = .030). Conclusion: Concussion incidence did not change after implementation of the updated NHLCP; nonetheless, players had significantly less missed time from injury after protocol implementation. Changes in player performance 30 days and 1 year before and after concussion injury were not different before and after NHLCP implementation. No differences were found in the financial cost of concussions between the pre- and post-NHLCP groups, and missed time was significantly correlated with mean cost from missed time.

Subventricular zone stem cell niche injury is associated with intestinal perforation in preterm infants and predicts future motor impairment.

Brain injury is highly associated with preterm birth. Complications of prematurity, including spontaneous or necrotizing enterocolitis (NEC)-associated intestinal perforations, are linked to lifelong neurologic impairment, yet the mechanisms are poorly understood. Early diagnosis of preterm brain injuries remains a significant challenge. Here, we identified subventricular zone echogenicity (SVE) on cranial ultrasound in preterm infants following intestinal perforations. The development of SVE was significantly associated with motor impairment at 2 years. SVE was replicated in a neonatal mouse model of intestinal perforation. Examination of the murine echogenic subventricular zone (SVZ) revealed NLRP3-inflammasome assembly in multiciliated FoxJ1+ ependymal cells and a loss of the ependymal border in this postnatal stem cell niche. These data suggest a mechanism of preterm brain injury localized to the SVZ that has not been adequately considered. Ultrasound detection of SVE may serve as an early biomarker for neurodevelopmental impairment after inflammatory disease in preterm infants.

The photoionization of methoxymethanol: Fingerprinting a reactive C2 oxygenate in a complex reactive mixture.

Methoxymethanol (CH3OCH2OH) is a reactive C2 ether-alcohol that is formed by coupling events in both heterogeneous and homogeneous systems. It is found in complex reactive environments-for example those associated with catalytic reactors, combustion systems, and liquid-phase mixtures of oxygenates. Using tunable synchrotron-generated vacuum-ultraviolet photons between 10.0 and 11.5 eV, we report on the photoionization spectroscopy of methoxymethanol. We determine that the lowest-energy photoionization process is the dissociative ionization of methoxymethanol via H-atom loss to produce [C2H5O2]+, a fragment cation with a mass-to-charge ratio (m/z) = 61.029. We measure the appearance energy of this fragment ion to be 10.24 ± 0.05 eV. The parent cation is not detected in the energy range examined. To elucidate the origin of the m/z = 61.029 (C2H5O2) fragment, we used automated electronic structure calculations to identify key stationary points on the cation potential energy surface and compute conformer-specific microcanonical rate coefficients for the important unimolecular processes. The calculated H-atom dissociation pathway results in a [C2H5O2]+ fragment appearance at 10.21 eV, in excellent agreement with experimental results.

A gut microbial signature for combination immune checkpoint blockade across cancer types.

Immune checkpoint blockade (ICB) targeting programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte protein 4 (CTLA-4) can induce remarkable, yet unpredictable, responses across a variety of cancers. Studies suggest that there is a relationship between a cancer patient's gut microbiota composition and clinical response to ICB; however, defining microbiome-based biomarkers that generalize across cohorts has been challenging. This may relate to previous efforts quantifying microbiota to species (or higher taxonomic rank) abundances, whereas microbial functions are often strain specific. Here, we performed deep shotgun metagenomic sequencing of baseline fecal samples from a unique, richly annotated phase 2 trial cohort of patients with diverse rare cancers treated with combination ICB (n = 106 discovery cohort). We demonstrate that strain-resolved microbial abundances improve machine learning predictions of ICB response and 12-month progression-free survival relative to models built using species-rank quantifications or comprehensive pretreatment clinical factors. Through a meta-analysis of gut metagenomes from a further six comparable studies (n = 364 validation cohort), we found cross-cancer (and cross-country) validity of strain-response signatures, but only when the training and test cohorts used concordant ICB regimens (anti-PD-1 monotherapy or combination anti-PD-1 plus anti-CTLA-4). This suggests that future development of gut microbiome diagnostics or therapeutics should be tailored according to ICB treatment regimen rather than according to cancer type.

Oncogenic ETS fusions promote DNA damage and proinflammatory responses via pericentromeric RNAs in extracellular vesicles.

Aberrant expression of the E26 transformation-specific (ETS) transcription factors characterizes numerous human malignancies. Many of these proteins, including EWS:FLI1 and EWS:ERG fusions in Ewing sarcoma (EwS) and TMPRSS2:ERG in prostate cancer (PCa), drive oncogenic programs via binding to GGAA repeats. We report here that both EWS:FLI1 and ERG bind and transcriptionally activate GGAA-rich pericentromeric heterochromatin. The respective pathogen-like HSAT2 and HSAT3 RNAs, together with LINE, SINE, ERV, and other repeat transcripts, are expressed in EwS and PCa tumors, secreted in extracellular vesicles (EVs), and are highly elevated in plasma of patients with EwS with metastatic disease. High human satellite 2 and 3 (HSAT2,3) levels in EWS:FLI1- or ERG-expressing cells and tumors were associated with induction of G2/M checkpoint, mitotic spindle, and DNA damage programs. These programs were also activated in EwS EV-treated fibroblasts, coincident with accumulation of HSAT2,3 RNAs, proinflammatory responses, mitotic defects, and senescence. Mechanistically, HSAT2,3-enriched cancer EVs induced cGAS-TBK1 innate immune signaling and formation of cytosolic granules positive for double-strand RNAs, RNA-DNA, and cGAS. Hence, aberrantly expressed ETS proteins derepress pericentromeric heterochromatin, yielding pathogenic RNAs that transmit genotoxic stress and inflammation to local and distant sites. Monitoring HSAT2,3 plasma levels and preventing their dissemination may thus improve therapeutic strategies and blood-based diagnostics.

An updated management approach of Pompe disease patients with high-sustained anti-rhGAA IgG antibody titers: experience with bortezomib-based immunomodulation.

Introduction: High sustained anti-rhGAA antibody titers (HSAT; ≥12,800) are directly linked to reduced efficacy of enzyme replacement therapy (ERT) and subsequent clinical deterioration in infantile-onset Pompe disease (IOPD). We have previously demonstrated the safety and effectiveness of a bortezomib-based immune-tolerance induction (ITI) regimen (bortezomib, rituximab, methotrexate, and IVIG) in eliminating HSAT. Methods: Here, we describe two IOPD cases (patients 6 and 8) who developed HSAT at 8 and 10 weeks on ERT despite transient low-dose methotrexate ITI administration in the ERT-naïve setting and were treated with a bortezomib-based ITI regimen, and we compare their courses to a series of six historical patients (patients 1-5, and 7) with a similar presentation who exemplify our evolving approach to treatment. Results: In total, patients 6 and 8 received 16 and 8 doses of bortezomib (4 doses=1 cycle) respectively reducing titers from 25,600 to seronegative, but differences in the course of their therapy were instructive regarding the optimal approach to initial treatment of HSAT; specifically, patient 6 was treated initially with only a single course of bortezomib rescue therapy, while patient 8 received two back-to-back courses. Patient 8 received IVIG therapy throughout the immunosuppression whereas patient 6 received IVIG therapy and was switched to subcutaneous IgG replacement. Patient 6 had a transient reduction in anti-rhGAA antibodies, after receiving a single initial cycle of bortezomib, but had a recurrence of high anti-rhGAA antibody titer after 160 weeks that required 3 additional cycles of bortezomib to ultimately achieve tolerance. In contrast, patient 8 achieved tolerance after being given two consecutive cycles of bortezomib during their initial treatment and had B cell recovery by week 54. Since the reduction in anti-rhGAA antibodies, both patients are doing well clinically, and have decreasing ALT, AST, and CK. No major infections leading to interruption of treatment were observed in either patient. The bortezomib-based ITI was safe and well-tolerated, and patients continue to receive ERT at 40 mg/kg/week. Discussion: These case studies and our previous experience suggest that to achieve an effective reduction of anti-rhGAA antibodies in the setting of HSAT, bortezomib should be initiated at the earliest sign of high anti-rhGAA antibodies with a minimum of two consecutive cycles as shown in the case of patient 8. It is important to note that, despite initiation of ERT at age 2.3 weeks, patient 8 quickly developed HSAT. We recommend close monitoring of anti-rhGAA antibodies and early intervention with ITI as soon as significantly elevated anti-rhGAA antibody titers are noted.

Effects of Percussive Massage Treatments on Symptoms Associated with Eccentric Exercise-Induced Muscle Damage.

Percussive massage (PM) is an emerging recovery treatment despite the lack of research on its effects post-eccentric exercise (post-EE). This study investigated the effects of PM treatments (immediately, 24, 48, and 72 h post-EE) on the maximal isometric torque (MIT), range of motion (ROM), and an 11-point numerical rating scale (NRS) of soreness of the nondominant arm's biceps brachii from 24-72 h post-EE. Seventeen untrained, college-aged subjects performed 60 eccentric elbow flexion actions with their nondominant arms. Nine received 1 minute of PM, versus eight who rested quietly (control [CON]). In order, NRS, ROM, and MIT (relative to body mass) were collected pre-eccentric exercise (pre-EE) and after treatment (AT) at 24, 48, and 72 h post-EE. NRS was also collected before treatment (BT). Electromyographic (EMG) and mechanomyographic (MMG) amplitudes were collected during the MIT and normalized to pre-EE. There were no interactions for MIT, EMG, or MMG, but there were interactions for ROM and NRS. For ROM, the PM group had higher values than the CON 24-72 h by ~6-8°, a faster return to pre-EE (PM: 48 h, CON: 72 h), and exceeded their pre-EE at 72 h by ~4°. The groups' NRS values did not differ BT 24-72 h; however, the PM group lowered their NRS from BT to AT within every visit by ~1 point per visit, which resulted in them having lower values than the CON from 24-72 h by ~2-3 points. Additionally, the PM group returned their NRS to pre-EE faster than the CON (PM: BT 72 h, CON: never). In conclusion, PM treatments may improve ROM without affecting isometric strength or muscle activation 24-72 h post-EE. Although the PM treatments did not enhance the recovery from delayed onset muscle soreness until 72 h, they consistently provided immediate, temporary relief when used 24-72 h post-EE.

Molecular, Metabolic, and Subcellular Mapping of the Tumor Immune Microenvironment via 3D Targeted and Non-Targeted Multiplex Multi-Omics Analyses.

Most platforms used for the molecular reconstruction of the tumor-immune microenvironment (TIME) of a solid tumor fail to explore the spatial context of the three-dimensional (3D) space of the tumor at a single-cell resolution, and thus lack information about cell-cell or cell-extracellular matrix (ECM) interactions. To address this issue, a pipeline which integrated multiplex spatially resolved multi-omics platforms was developed to identify crosstalk signaling networks among various cell types and the ECM in the 3D TIME of two FFPE (formalin-fixed paraffin embedded) gynecologic tumor samples. These platforms include non-targeted mass spectrometry imaging (glycans, metabolites, and peptides) and Stereo-seq (spatial transcriptomics) and targeted seqIF (IHC proteomics). The spatially resolved imaging data in a two- and three-dimensional space demonstrated various cellular neighborhoods in both samples. The collection of spatially resolved analytes in a voxel (3D pixel) across serial sections of the tissue was also demonstrated. Data collected from this analytical pipeline were used to construct spatial 3D maps with single-cell resolution, which revealed cell identity, activation, and energized status. These maps will provide not only insights into the molecular basis of spatial cell heterogeneity in the TIME, but also novel predictive biomarkers and therapeutic targets, which can improve patient survival rates.