Active infection at the time of CD34+ selected stem cell boost is associated with treatment failure and poor survival.

BACKGROUND: The use of CD34+ selected stem cell boost (SCB) post allogeneic hematopoietic cell transplant (alloHCT) has been increasing. Predictors of treatment failure following SCB, both in the context of poor graft function (PGF) or other settings, are not well-characterized. We report among the largest single center retrospective experiences of the use of SCB and evaluate potential predictors of response and outcomes. METHODS: 58 patients who underwent HCT between 2015 and 2022 and who received SCB were identified. The indication for SCB was predominantly PGF, defined as the presence of 2 or more cytopenias for at least two consecutive weeks beyond day +14 after alloHCT in the presence of ≤ 30% bone marrow cellularity and ≥ 90% donor myeloid chimerism in the absence of morphological disease. RESULTS: The median dose of infused CD34+ selected SCB products was 3.88 x 106 CD34+ cells/kg (range: 0.99-9.92). The median 2-year OS and NRM following SCB was 47% and 38%, respectively. The cumulative incidences of 6-month grade III-IV acute and 2-year moderate-severe chronic GVHD following SCB were 3.4% and 12%, respectively. Overall response (CR + PR) was attained in 36/58 (62%) patients, and in 69% with PGF. On multivariable analysis, an active infection at the time of SCB was the greatest predictor of poor response and survival (p=0.013) following SCB. CONCLUSION: SCB can restore hematopoiesis in the majority of patients, particularly for those with poor graft function in whom there is no active infection at infusion.

Comparison of Older Related versus Younger Unrelated Donors for Older Recipients of Allogeneic Hematopoietic Cell Transplantation with Acute Myeloid Leukemia or Myelodysplastic Syndrome: A Large Single-Center Analysis.

For patients undergoing allogeneic hematopoietic cell transplantation (alloHCT), HLA-matched related donors (MRDs) have traditionally been the preferred donor source. However, as the age of recipients increases, their sibling donors are aging as well. In this study, we investigated whether younger matched unrelated donors (MUDs) might be a better donor source than similarly aged sibling donors for patients age >60 years with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). A total of 499 patients age 60 to 70 years with AML or MDS who underwent alloHCT from an older MRD (donor age ≥50 years) or a younger MUD (donor age ≤35 years) between 2010 and 2022 were evaluated. Of these, 360 patients (72%) received an MUD graft and 139 (28%) received an MRD graft. The median recipient age was 64 years in the MRD group and 66 years in the MUD group. With a median follow-up among survivors of 53 months (range, 9 to 147 months ), the 4-year progression-free survival was 40% in the MRD group and 41% in the MUD group (P = .79) and the 4-year overall survival was 50% and 44%, respectively (P = .15), with no between-group differences in nonrelapse mortality, relapse, and acute or chronic graft-versus-host disease. In the MUD group, we also compared the effect of donor age 18 to 24 years and donor age 25 to 35 years and found no differences in outcomes between the groups. We conclude that outcomes are comparable between the use of older MRDs and use of younger MUDs for elderly patients with AML or MDS, that there is no donor age effect among younger MUDs, and that the use of either donor type is reasonable.

Effect of Menstrual Cycle and Menopause on Human Gastric Electrophysiology.

Chronic gastroduodenal symptoms disproportionately affect females of childbearing age; however, the effect of menstrual cycling on gastric electrophysiology is poorly defined. To establish the effect of the menstrual cycle on gastric electrophysiology, healthy subjects underwent non-invasive Body Surface Gastric Mapping (BSGM; 8x8 array), with validated symptom logging App (Gastric AlimetryⓇ, New Zealand). Participants were premenopausal females in follicular (n=26) and luteal phases (n=18). Postmenopausal females (n=30) and males (n=51) were controls. Principal gastric frequency (PGF), BMI-adjusted amplitude, Gastric Alimetry Rhythm Index (GA-RI), fasted-fed amplitude ratio (ff-AR), meal response curves, and symptom burden were analysed. Menstrual cycle-related electrophysiological changes were then transferred to an established anatomically-accurate computational gastric fluid dynamics model (meal viscosity 0.1 Pas), to predict the impact on gastric mixing and emptying. PGF was significantly higher in the luteal vs. follicular phase (mean 3.21 cpm, SD (0.17) vs. 2.94 cpm, SD (0.17), p<0.001) and vs. males (3.01 cpm, SD (0.2), p<0.001). In the computational model, this translated to 8.1% higher gastric mixing strength and 5.3% faster gastric emptying for luteal versus follicular phases. Postmenopausal females also exhibited higher PGF than females in the follicular phase (3.10 cpm, SD (0.24) vs. 2.94 cpm, SD (0.17), p=0.01), and higher BMI-adjusted amplitude (40.7 µV (33.02-52.58) vs. 29.6 µV (26.15-39.65), p<0.001), GA-RI (0.60 (0.48-0.73) vs. 0.43 (0.30-0.60), p=0.005), and ff-AR (2.51 (1.79-3.47) vs. 1.48 (1.21-2.17), p=0.001) than males. There were no differences in symptoms. These results define variations in gastric electrophysiology with regard to human menstrual cycling and menopause.

Short- and long-term reproducibility of body surface gastric mapping using the Gastric Alimetry® system.

BACKGROUND: Many diagnostic tests for gastroduodenal symptoms, such as gastric emptying scintigraphy (GES), gastric emptying breath tests (GEBT), and electrogastrography (EGG) show variable intra-individual reproducibility over time. This study investigated the short- and long-term reproducibility of body surface gastric mapping (BSGM), a non-invasive test for assessing gastric function, in controls and patients with chronic gastroduodenal disorders. METHODS: Participants completed three standardized BSGM tests using Gastric Alimetry® (Alimetry, New Zealand). The test encompassed a fasting baseline (30 min), a 482 kCal standard meal, and a 4 h postprandial recording. The first two tests were >6 months apart and the last occurred ~1 week after the second test, to evaluate long and short-term reproducibility. RESULTS: Fourteen patients with upper gastrointestinal symptoms and 14 healthy controls were recruited. There were no significant differences in any BSGM metrics between the tests at short and long term (all p > 0.180). Lin's concordance correlation coefficients (CCC) for the primary metrics were high, ranging from 0.58 to 0.96, with intra-individual coefficients of variance (CVintra) ranging from 0.2% to 1.9%. Reproducibility was higher, and intra-individual variation lower, than in previous studies of GES (CCC = 0.54-0.83, CVintra = 3%-77%), GEBT (CVintra = 8%-11%), and EGG (CVintra = 3%-78%). CONCLUSIONS: BSGM spectral metrics demonstrate high reproducibility and low intra-individual variation at both short and long term, with superior results to comparable tests. The high reproducibility of Gastric Alimetry supports its role as a diagnostic aid for gastric dysfunction and a reliable tool for evaluating treatment outcomes and disease progression over time.

Innovations in conditioning and post-transplant maintenance in AML: genomically informed revelations on the graft-versus-leukemia effect.

Acute Myeloid Leukemia (AML) is the prototype of cancer genomics as it was the first published cancer genome. Large-scale next generation/massively parallel sequencing efforts have identified recurrent alterations that inform prognosis and have guided the development of targeted therapies. Despite changes in the frontline and relapsed standard of care stemming from the success of small molecules targeting FLT3, IDH1/2, and apoptotic pathways, allogeneic stem cell transplantation (alloHSCT) and the resulting graft-versus-leukemia (GVL) effect remains the only curative path for most patients. Advances in conditioning regimens, graft-vs-host disease prophylaxis, anti-infective agents, and supportive care have made this modality feasible, reducing transplant related mortality even among patients with advanced age or medical comorbidities. As such, relapse has emerged now as the most common cause of transplant failure. Relapse may occur after alloHSCT because residual disease clones persist after transplant, and develop immune escape from GVL, or such clones may proliferate rapidly early after alloHSCT, and outpace donor immune reconstitution, leading to relapse before any GVL effect could set in. To address this issue, genomically informed therapies are increasingly being incorporated into pre-transplant conditioning, or as post-transplant maintenance or pre-emptive therapy in the setting of mixed/falling donor chimerism or persistent detectable measurable residual disease (MRD). There is an urgent need to better understand how these emerging therapies modulate the two sides of the GVHD vs. GVL coin: 1) how molecularly or immunologically targeted therapies affect engraftment, GVHD potential, and function of the donor graft and 2) how these therapies affect the immunogenicity and sensitivity of leukemic clones to the GVL effect. By maximizing the synergistic action of molecularly targeted agents, immunomodulating agents, conventional chemotherapy, and the GVL effect, there is hope for improving outcomes for patients with this often-devastating disease.

Point-of-Need Additive Manufacturing in Austere Arctic Environments: An Evaluation of Medical Logistics Requirements and Capabilities Demonstration.

Medical response to military conflicts, natural disasters, and humanitarian crises are challenged by operational logistics with unreliable supply chains, delayed medical evacuation, and compatibility of the disparate medical equipment and consumables. In these environments, stocks of supplies will become more quickly depleted and the need for equipment parts increases secondary to their higher likelihood for failure from overuse. Additive Manufacturing (AM), or 3D printing, at or closer to the point-of-need provides potential solutions to mitigate these logistics challenges. AM's ability to tailor the resultant product through computer design enables real-time modification of a product to meet a specific situation. In this study, we deployed two different 3D printers to an arctic locale to demonstrate the utility of 3D printing and bioprinting in austere environments. Deployment of AM solutions in austere environments will likely impact medical care following natural disasters and conflicts with contested logistics. The work presented here furthers the readiness status of AM for use in austere environments to manufacture medical equipment parts and demonstrates its potential use for tissue engineering and advanced medical treatments in remote environments.

Characterization of gastric dysfunction after fundoplication using body surface gastric mapping.

BACKGROUND: Adverse gastric symptoms persist in up to 20% of fundoplication operations completed for gastroesophageal reflux disease, causing significant morbidity and driving the need for revisional procedures. Noninvasive techniques to assess the mechanisms of persistent postoperative symptoms are lacking. This study aimed to investigate gastric myoelectrical abnormalities and symptoms in patients after fundoplication using a novel noninvasive body surface gastric mapping (BSGM) device. METHODS: Patients with a previous fundoplication operation and ongoing significant gastroduodenal symptoms and matched controls were included. BSGM using Gastric Alimetry (Alimetry Ltd) was employed, consisting of a high-resolution 64-channel array, validated symptom-logging application, and wearable reader. RESULTS: A total of 16 patients with significant chronic symptoms after fundoplication were recruited, with 16 matched controls. Overall, 6 of 16 patients (37.5%) showed significant spectral abnormalities defined by unstable gastric myoelectrical activity (n = 2), abnormally high gastric frequencies (n = 3), or high gastric amplitudes (n = 1). Patients with spectral abnormalities had higher Patient Assessment of Upper Gastrointestinal Disorders-Symptom Severity Index scores than those of patients without spectral abnormalities (3.2 [range, 2.8-3.6] vs 2.3 [range, 2.2-2.8], respectively; P = .024). Moreover, 7 of 16 patients (43.8%) had BSGM test results suggestive of gut-brain axis contributions and without myoelectrical dysfunction. Increasing Principal Gastric Frequency Deviation and decreasing Rhythm Index scores were associated with symptom severity (r > .40; P < .05). CONCLUSION: A significant number of patients with persistent postfundoplication symptoms displayed abnormal gastric function on BSGM testing, which correlated with symptom severity. Our findings advance the pathophysiologic understanding of postfundoplication disorders, which may inform diagnosis and patient selection for medical therapy and revisional procedures.

Social media for learning: A qualitative exploration of the factors that impact clinical learners' attitudes and intentions.

BACKGROUND: Social media has created a revolution in learning and teaching. This study set out to provide a theory-informed exploration of the factors influencing medical students' perspectives of learning with social media using the theory of planned behaviour (TPB) as a framework. METHODS: The study collected data using semi-structured interviews from seven third year medical students at an undergraduate Australian medical school, who were in their first clinical year. The data were analysed inductively and deductively using TPB. RESULTS: Three themes emerged relating to the factors that influence medical students' attitudes and intentions regarding using social media for learning: (1) Social media aligns with the needs and preferences of the contemporary learner; (2) rise of medical professionals on social media during the COVID-19 pandemic; and (3) being an informed user of social media for learning. Participants had largely positive views and attitudes towards social media as a learning tool especially for preclinical content due to its capacity for multimodal information delivery and evolving social norms. However, this positivity was tempered by the challenges they faced in determining quality of resources, linking their learning to clinical medicine and accessing specialist content. CONCLUSION: Social media can play a significant role in medical students' learning. However, its potential as an educational tool can be enhanced by widening access to resources, and implementing strategies that help students increase their evaluative judgement skills to make informed decisions regarding the quality of social media resources and to translate their social media-mediated learning into clinical practice.

Referral patterns of GIST patients: data from a nationwide study.

BACKGROUND: This study compares the characteristics, referral and treatment patterns and overall survival (OS) of gastrointestinal stromal tumor (GIST) patients treated in reference and non-reference centers in the Netherlands. PATIENTS AND METHODS: This retrospective cohort study on patients diagnosed between 2016 and 2019, utilises data from the Netherlands Cancer Registry and the Dutch Nationwide Pathology Database. Patients were categorized into two groups: patients diagnosed in or referred to reference centers and patients diagnosed in non-reference centers without referral. RESULTS: This study included 1,550 GIST patients with a median age of 67.0 in reference and 68.0 years in non-reference centers. Eighty-seven per cent of patients were diagnosed in non-reference centers, of which 36.5% (493/1,352) were referred to a reference center. Referral rates were higher for high-risk (62.2% [74/119]) and metastatic patients (67.2% [90/134]). Mutation analysis was performed in 96.9% and 87.6% of these cases in reference and in non-reference centers (p < 0.01), respectively. Systemic therapy was given in reference centers versus non-reference in 89.5% versus 82.0% (p < 0.01) of high-risk and in 94.1% versus 65.9% (p < 0.01) of metastatic patients, respectively. The proportion of positive resection margins and tumor rupture did not differ between reference and non-reference centers. Median OS was not reached. CONCLUSION: A substantial amount of metastatic GIST patients in non-reference centers did not receive systemic treatment. This might be due to valid reasons. However, optimisation of the referral strategy of GIST patients in the Netherlands could benefit patients. Further research is needed to explore reasons for not starting systemic treatment in metastatic GIST patients.

p21 as a Predictor and Prognostic Indicator of Clinical Outcome in Rectal Cancer Patients.

The cell cycle plays a key and complex role in the development of human cancers. p21 is a potent cyclin-dependent kinase inhibitor (CDKI) involved in the promotion of cell cycle arrest and the regulation of cellular senescence. Altered p21 expression in rectal cancer cells may affect tumor cells' behavior and resistance to neoadjuvant and adjuvant therapy. Our study aimed to ascertain the relationship between the differential expression of p21 in rectal cancer and patient survival outcomes. Using tissue microarrays, 266 rectal cancer specimens were immunohistochemically stained for p21. The expression patterns were scored separately in cancer cells retrieved from the center and the periphery of the tumor; compared with clinicopathological data, tumor regression grade (TRG), disease-free, and overall survival. Negative p21 expression in tumor periphery cells was significantly associated with longer overall survival upon the univariate (p = 0.001) and multivariable analysis (p = 0.003, HR = 2.068). Negative p21 expression in tumor periphery cells was also associated with longer disease-free survival in the multivariable analysis (p = 0.040, HR = 1.769). Longer overall survival times also correlated with lower tumor grades (p= 0.011), the absence of vascular and perineural invasion (p = 0.001; p < 0.005), the absence of metastases (p < 0.005), and adjuvant treatment (p = 0.009). p21 expression is a potential predictive and prognostic biomarker for clinical outcomes in rectal cancer patients. Negative p21 expression in tumor periphery cells demonstrated significant association with longer overall survival and disease-free survival. Larger prospective studies are warranted to investigate the ability of p21 to identify rectal cancer patients who will benefit from neoadjuvant and adjuvant therapy.

Prophylactic maintenance with venetoclax/azacitidine after reduced-intensity conditioning allogeneic transplant for high-risk MDS and AML.

ABSTRACT: We conducted a phase 1 trial assessing safety and efficacy of prophylactic maintenance therapy with venetoclax and azacitidine (Ven/Aza) for patients with high-risk myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML) undergoing reduced intensity allogeneic stem cell transplantation (allo-SCT) after Ven and fludarabine/busulfan conditioning (Ven/FluBu2 allo-SCT) with tacrolimus and methotrexate as graft-versus-host disease (GVHD) prophylaxis. Among 27 patients who underwent Ven/FluBu2 allo-SCT (55.6% with prior Ven exposure, and 96% with positive molecular measurable residual disease), 22 received maintenance therapy with Aza 36 mg/m2 intravenously on days 1 to 5, and Ven 400 mg by mouth on days 1 to 14 per assigned dose schedule/level (42-day cycles × 8, or 28-day cycles × 12). During maintenance, the most common grade 3-4 adverse events were leukopenia, neutropenia, and thrombocytopenia, which were transient and manageable. Infections were uncommon (n = 4, all grade 1-2). The 1-year and 2-year moderate/severe chronic GVHD rates were 4% (95% confidence interval [CI], 0.3%-18%) and 22% (95% CI, 9%-40%), respectively. After a median follow-up of 25 months among survivors, the median overall survival (OS) was not reached. Among the 22 patients who received Ven/Aza maintenance, the 2-year OS, progression-free survival, nonrelapse mortality, and cumulative incidence of relapse rates were 67% (95% CI, 43%-83%), 59% (95% CI, 36%-76%), 0%, and 41% (95% CI, 20%-61%), respectively. Immune monitoring demonstrated no significant impact on T-cell expansion but identified reduced B-cell expansion compared with controls. This study demonstrates prophylactic Ven/Aza maintenance can be safely administered for patients with high-risk MDS/AML, but a randomized study is required to properly assess any potential benefit. This trial was registered at www.clinicaltrials.gov as #NCT03613532.

Idiopathic Slow Transit Constipation: Pathophysiology, Diagnosis, and Management.

Slow transit constipation (STC) has an estimated prevalence of 2-4% of the general population, and although it is the least prevalent of the chronic constipation phenotypes, it more commonly causes refractory symptoms and is associated with significant psychosocial stress, poor quality of life, and high healthcare costs. This review provides an overview of the pathophysiology, diagnosis, and management options in STC. STC occurs due to colonic dysmotility and is thought to be a neuromuscular disorder of the colon. Several pathophysiologic features have been observed in STC, including reduced contractions on manometry, delayed emptying on transit studies, reduced numbers of interstitial cells of Cajal on histology, and reduced amounts of excitatory neurotransmitters within myenteric plexuses. The underlying aetiology is uncertain, but autoimmune and hormonal mechanisms have been hypothesised. Diagnosing STC may be challenging, and there is substantial overlap with the other clinical constipation phenotypes. Prior to making a diagnosis of STC, other primary constipation phenotypes and secondary causes of constipation need to be ruled out. An assessment of colonic transit time is required for the diagnosis and can be performed by a number of different methods. There are several different management options for constipation, including lifestyle, dietary, pharmacologic, interventional, and surgical. The effectiveness of the available therapies in STC differs from that of the other constipation phenotypes, and prokinetics often make up the mainstay for those who fail standard laxatives. There are few available management options for patients with medically refractory STC, but patients may respond well to surgical intervention. STC is a common condition associated with a significant burden of disease. It can present a clinical challenge, but a structured approach to the diagnosis and management can be of great value to the clinician. There are many therapeutic options available, with some having more benefits than others.

Gastric Alimetry Expands Patient Phenotyping in Gastroduodenal Disorders Compared with Gastric Emptying Scintigraphy.

INTRODUCTION: Gastric emptying testing (GET) assesses gastric motility, however, is nonspecific and insensitive for neuromuscular disorders. Gastric Alimetry (GA) is a new medical device combining noninvasive gastric electrophysiological mapping and validated symptom profiling. This study assessed patient-specific phenotyping using GA compared with GET. METHODS: Patients with chronic gastroduodenal symptoms underwent simultaneous GET and GA, comprising a 30-minute baseline, 99m TC-labelled egg meal, and 4-hour postprandial recording. Results were referenced to normative ranges. Symptoms were profiled in the validated GA App and phenotyped using rule-based criteria based on their relationships to the meal and gastric activity: (i) sensorimotor, (ii) continuous, and (iii) other. RESULTS: Seventy-five patients were assessed, 77% female. Motility abnormality detection rates were as follows: GET 22.7% (14 delayed, 3 rapid), GA spectral analysis 33.3% (14 low rhythm stability/low amplitude, 5 high amplitude, and 6 abnormal frequency), and combined yield 42.7%. In patients with normal spectral analysis, GA symptom phenotypes included sensorimotor 17% (where symptoms strongly paired with gastric amplitude, median r = 0.61), continuous 30%, and other 53%. GA phenotypes showed superior correlations with Gastroparesis Cardinal Symptom Index, Patient Assessment of Upper Gastrointestinal Symptom Severity Index, and anxiety scales, whereas Rome IV Criteria did not correlate with psychometric scores ( P > 0.05). Delayed emptying was not predictive of specific GA phenotypes. DISCUSSION: GA improves patient phenotyping in chronic gastroduodenal disorders in the presence and absence of motility abnormalities with increased correlation with symptoms and psychometrics compared with gastric emptying status and Rome IV criteria. These findings have implications for the diagnostic profiling and personalized management of gastroduodenal disorders.

Opportunistic Infections in Patients Receiving Post-Transplantation Cyclophosphamide: Impact of Haploidentical versus Unrelated Donor Allograft.

Post-transplantation cyclophosphamide (PTCy) is an effective strategy for graft-versus-host disease (GVHD) prophylaxis and is the standard of care for haploidentical hematopoietic cell transplantation (HCT). It is increasingly used for matched and mismatched unrelated donor (MUD/MMUD) HCT, but infections remain a concern. The objective of this study was to evaluate the characteristics and risk factors for infections in haploidentical and unrelated donor HCT recipients treated with PTCy-based GVHD prophylaxis. This single-center retrospective study examined 354 consecutive adults undergoing HCT with PTCy-based GVHD prophylaxis (161 MUD/MMUD; 193 haploidentical) between 2015 and 2022. Opportunistic infections (OIs), including cytomegalovirus (CMV), adenovirus (AdV), Epstein-Barr virus (EBV), and invasive fungal disease (IFD), were assessed from day 0 through day +365. The 1-year cumulative incidence functions of OIs and nonrelapse mortality (NRM) were calculated using dates of relapse and repeat HCT as competing risks. Secondary analysis evaluated risk factors for OIs and NRM using univariate and multivariable Cox regression models. Haploidentical HCT recipients had an increased risk of OIs compared to unrelated donor allograft recipients (39% for haploidentical versus 25% for MUD/MMUD; hazard ratio [HR], 1.70; 95% confidence interval [CI], 1.16 to 2.49; P = .006). On multivariable analysis, haploidentical donor (HR, 1.50; 95% CI, 1.01 to 2.23; P = .046), prior HCT (HR, 1.99; 95% CI, 1.29 to 3.09; P = .002), and diagnosis of aGVHD (HR, 1.47; 95% CI, 1.02 to 2.14; P = .041) were associated with increased risk of OIs. NRM within the first year was not significantly different between the 2 cohorts (HR, 1.11; 95% CI, .64 to 1.93; P = .70). Overall, haploidentical donor was a significant risk factor for OIs in patients receiving PTCy, although 1-year NRM was not different between haploidentical HCT and MUD/MMUD HCT recipients. CMV and AdV infections were significantly increased among haploidentical HCT recipients, whereas the incidences of EBV infection and IFD were similar in the 2 cohorts. Our findings may have implications for infection monitoring and prophylaxis in the setting of PTCy, particularly in haploidentical HCT recipients.

Trends in epidemiology and primary treatment of anal squamous cell carcinoma in the Netherlands (1990-2021).

A rapid increase in the incidence of anal squamous cell carcinoma (SCC) was reported in several countries over the past decades. This study assessed trends in epidemiology and primary treatment over a 32-year period (1990-2021) using the Netherlands Cancer Registry. The study population included 4273 patients, 44.2% male and 55.8% female (median age 63 years). The age-standardised incidence rate (European Standardised Rate, ESR) increased from 0.5 to 1.6 per 100,000, which entailed an average annual percentage change (AAPC) of 5.0% (95% confidence interval [CI]: 4.5%-5.8%). While incidence among females increased continuously over the total period (AAPC 4.9%; 95%CI: 4.4%-5.6%), to 1.8 per 100,000 ESR in 2021, incidence among males increased until 2016 (annual percentage change [APC] of 6.3%; 95%CI: 5.6%-10.7%), after which it seemed to stabilise (APC -2.1%; 95%CI: -16.8%-4.5%). Significant trends were also observed in distribution of age, tumour stage and primary treatment modalities. Five-year relative survival (RS) was estimated using the Pohar-Perme estimator, and this improved from 56.1% in 1990-1997 (95%CI: 49.3%-62.4%) to 67.9% in 2014-2021 (95%CI: 64.7%-70.9%), but remained poor for stage IV disease. Evaluation through a multivariable Poisson regression model demonstrated diagnosis in the most recent period to be independently associated with better RS, in addition to female sex, younger age, early disease stage and any treatment. In conclusion, the rising incidence of anal SCC seems to decline in males, but not in females, and advances in diagnostics and therapeutic management have likely contributed to improved prognosis.

Heightened TLR7 signaling primes BCR-activated B cells in chronic graft-versus-host disease for effector functions.

ABSTRACT: Chronic graft-versus-host disease (cGVHD) is a debilitating, autoimmune-like syndrome that can occur after allogeneic hematopoietic stem cell transplantation. Constitutively activated B cells contribute to ongoing alloreactivity and autoreactivity in patients with cGVHD. Excessive tissue damage that occurs after transplantation exposes B cells to nucleic acids in the extracellular environment. Recognition of endogenous nucleic acids within B cells can promote pathogenic B-cell activation. Therefore, we hypothesized that cGVHD B cells aberrantly signal through RNA and DNA sensors such as Toll-like receptor 7 (TLR7) and TLR9. We found that B cells from patients and mice with cGVHD had higher expression of TLR7 than non-cGVHD B cells. Using ex vivo assays, we found that B cells from patients with cGVHD also demonstrated increased interleukin-6 production after TLR7 stimulation with R848. Low-dose B-cell receptor (BCR) stimulation augmented B-cell responses to TLR7 activation. TLR7 hyperresponsiveness in cGVHD B cells correlated with increased expression and activation of the downstream transcription factor interferon regulatory factor 5. Because RNA-containing immune complexes can activate B cells through TLR7, we used a protein microarray to identify RNA-containing antigen targets of potential pathological relevance in cGVHD. We found that many of the unique targets of active cGVHD immunoglobulin G (IgG) were nucleic acid-binding proteins. This unbiased assay identified the autoantigen and known cGVHD target Ro-52, and we found that RNA was required for IgG binding to Ro-52. Herein, we find that BCR-activated B cells have aberrant TLR7 signaling responses that promote potential effector responses in cGVHD.

Optimal Agents for Visualizing Collagen Tissue Microarchitecture Using Contrast-Enhanced MicroCT.

Micro-computed tomography (microCT) is a common tool for the visualization of the internal composition of organic tissues. Collagen comprises approximately 25-35% of the whole-body protein content in mammals, and the structure and arrangement of collagen fibers contribute significantly to the integrity of tissues. Collagen type I is also frequently used as a key structural component in tissue-engineered and bioprinted tissues. However, the imaging of collagenous tissues is limited by their inherently low X-ray attenuation, which makes them indistinguishable from most other soft tissues. An imaging contrast agent that selectively alters X-ray attenuation is thus essential to properly visualize collagenous tissue using a standard X-ray tube microCT scanner. This review compares various contrast-enhanced techniques reported in the literature for MicroCT visualization of collagen-based tissues. An ideal microCT contrast agent would meet the following criteria: (1) it diffuses through the tissue quickly; (2) it does not deform or impair the object being imaged; and (3) it provides sufficient image contrast for reliable visualization of the orientation of individual fibers within the collagen network. The relative benefits and disadvantages of each method are discussed. Lugol's solution (I3K), phosphotungstic acid (H3PW12O40), mercury(II) chloride (HgCl2), and Wells-Dawson polyoxometalates came closest to fitting the criteria. While none of the contrast agents discussed in the literature met all criteria, each one has advantages to consider in the context of specific lab capabilities and imaging priorities.

Role of Baseline Gut Microbiota on Response to Fiber Intervention in Individuals with Irritable Bowel Syndrome.

Irritable bowel syndrome (IBS) is one of the most prevalent functional gut disorders in the world. Partially hydrolyzed guar gum, a low-viscosity soluble fiber, has shown promise in the management of IBS-related symptoms. In this study, we aimed to determine if an individual's baseline gut microbiota impacted their response to a partially hydrolyzed guar gum intervention. Patients diagnosed with IBS undertook a 90-day intervention and follow-up. IBS symptom severity, tolerability, quality-of-life, and fecal microbiome composition were recorded during this study. Patients with normal microbiota diversity (Shannon index ≥ 3) showed significant improvements to IBS symptom scores, quality-of-life, and better tolerated the intervention compared to patients with low microbiota diversity (Shannon index < 3). Our findings suggest that an individual's baseline microbiome composition exerts a substantial influence on their response to fiber intervention. Future investigations should explore a symbiotic approach to the treatment of IBS.

Flavones provide resistance to DUX4-induced toxicity via an mTor-independent mechanism.

Facioscapulohumeral muscular dystrophy (FSHD) is among the most common of the muscular dystrophies, affecting nearly 1 in 8000 individuals, and is a cause of profound disability. Genetically, FSHD is linked to the contraction and/or epigenetic de-repression of the D4Z4 repeat array on chromosome 4, thereby allowing expression of the DUX4 gene in skeletal muscle. If the DUX4 transcript incorporates a stabilizing polyadenylation site the myotoxic DUX4 protein will be synthesized, resulting in muscle wasting. The mechanism of toxicity remains unclear, as many DUX4-induced cytopathologies have been described, however cell death does primarily occur through caspase 3/7-dependent apoptosis. To date, most FSHD therapeutic development has focused on molecular methods targeting DUX4 expression or the DUX4 transcript, while therapies targeting processes downstream of DUX4 activity have received less attention. Several studies have demonstrated that inhibition of multiple signal transduction pathways can ameliorate DUX4-induced toxicity, and thus compounds targeting these pathways have the potential to be developed into FSHD therapeutics. To this end, we have screened a group of small molecules curated based on their reported activity in relevant pathways and/or structural relationships with known toxicity-modulating molecules. We have identified a panel of five compounds that function downstream of DUX4 activity to inhibit DUX4-induced toxicity. Unexpectedly, this effect was mediated through an mTor-independent mechanism that preserved expression of ULK1 and correlated with an increase in a marker of active cellular autophagy. This identifies these flavones as compounds of interest for therapeutic development, and potentially identifies the autophagy pathway as a target for therapeutics.

Longitudinal outcome monitoring in patients with chronic gastroduodenal symptoms investigated using the Gastric Alimetry system: study protocol.

INTRODUCTION: The Gastric Alimetry platform offers a multimodal assessment of gastric function through body surface gastric mapping (BSGM) and concurrent symptom-tracking via a validated App. We aim to perform a longitudinal cohort study to examine the impact of Gastric Alimetry, and changes in clinical management on patient symptoms, quality of life and psychological health. METHODS AND ANALYSIS: This is a prospective multicentre longitudinal observational cohort study of participants with chronic gastroduodenal symptoms. Consecutive participants undergoing Gastric Alimetry will be invited to participate. Quality of life will be assessed via EuroQol-5D and the Patient Assessment of Upper Gastrointestinal Disorders-Quality of Life score. Gastrointestinal symptoms will be assessed via the Patient Assessment of Upper Gastrointestinal Symptom Severity index, and the Gastroparesis Cardinal Symptom Index. Psychometrics will be assessed, including anxiety via the General Anxiety Disorder-7, perceived stress using the Perceived Stress Scale 4, and depression via the Patient Health Questionnaire 9. Clinical parameters including diagnoses, investigations and treatments (medication and procedures) will also be captured. Assessments will be made the week after the BSGM test, at 30 days, 90 days, 180 days and 360 days thereafter. The primary outcome is feasibility of longitudinal follow-up of a cohort that have undergone Gastric Alimetry testing; from which patients' continuum of care can be characterised. Secondary outcomes include changes in patient-reported symptoms, quality of life and psychometrics (anxiety, stress and depression). Inferential causal analyses will be performed at the within patient level to explore causal associations between treatment changes and clinical outcomes. The impact of Gastric Alimetry on clinical management will also be captured. ETHICS AND DISSEMINATION: The protocol has been approved in Aotearoa New Zealand by the Auckland Health Research Ethics Committee. Results will be submitted for conference presentation and peer-reviewed publication.