False Alarm: XMRV, Cancer, and Chronic Fatigue Syndrome.

Xenotropic murine leukemia virus (MLV)-related virus (XMRV) was first described in 2006 in some human prostate cancers. But it drew little attention until 2009, when it was also found, as infectious virus and as MLV-related DNA, in samples from people suffering from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This discovery was rapidly followed by efforts of the international research community to understand the significance of the association and its potential to spread widely as an important human pathogen. Within a few years, efforts by researchers worldwide failed to repeat these findings, and mounting evidence for laboratory contamination with mouse-derived virus and viral DNA sequences became accepted as the explanation for the initial findings. As researchers engaged in these studies, we present here a historical review of the rise and fall of XMRV as a human pathogen, and we discuss the lessons learned from these events.

Asparagine Dependency is a Targetable Metabolic Vulnerability in TP53-Altered Castration-Resistant Prostate Cancer.

The TP53 tumor suppressor is frequently altered in lethal, castration-resistant prostate cancer (CRPC). However, to date there are no effective treatments that specifically target TP53 alterations. Using transcriptomic and metabolomic analyses, we showed here that TP53-altered prostate cancer (PCa) exhibits an increased dependency on asparagine and overexpresses asparagine synthetase (ASNS), the enzyme catalyzing the synthesis of asparagine. Mechanistically, loss or mutation of TP53 transcriptionally activated ASNS expression, directly as well as via mTORC1-mediated ATF4 induction, driving de novo asparagine biosynthesis to support CRPC growth. TP53-altered CRPC cells were sensitive to asparagine restriction by knockdown of ASNS or L-asparaginase treatment to deplete the intracellular and extracellular sources of asparagine, respectively, and cell viability was rescued by asparagine addition. Notably, pharmacological inhibition of intracellular asparagine biosynthesis using a glutaminase inhibitor and depletion of extracellular asparagine with L-asparaginase significantly reduced asparagine production and effectively impaired CRPC growth. This study highlights the significance of ASNS-mediated metabolic adaptation as a synthetic vulnerability in CRPC with TP53 alterations, providing a rationale for targeting asparagine production to treat these lethal prostate cancers.

Outcomes and Pattern of Care for Spinal Myxopapillary Ependymoma in the Modern Era-A Population-Based Observational Study.

(1) Background: Myxopapillary ependymoma (MPE) is a rare tumor of the spine, typically slow-growing and low-grade. Optimal management strategies remain unclear due to limited evidence given the low incidence of the disease. (2) Methods: We analyzed data from 1197 patients with spinal MPE from the Surveillance, Epidemiology, and End Results (SEER) database (2000-2020). Patient demographics, treatment modalities, and survival outcomes were examined using statistical analyses. (3) Results: Most patients were White (89.9%) with a median age at diagnosis of 42 years. Surgical resection was performed in 95% of cases. The estimated 10-year overall survival was 91.4%. Younger age (hazard ratio (HR) = 1.09, p < 0.001) and receipt of surgery (HR = 0.43, p = 0.007) were associated with improved survival. Surprisingly, male sex was associated with worse survival (HR = 1.86, p = 0.008) and a younger age at diagnosis compared to females. (4) Conclusions: This study, the largest of its kind, underscores the importance of surgical resection in managing spinal MPE. The unexpected association between male sex and worse survival warrants further investigation into potential sex-specific pathophysiological factors influencing prognosis. Despite limitations, our findings contribute valuable insights for guiding clinical management strategies for spinal MPE.

Colon Cancer, Version 3.2024, NCCN Clinical Practice Guidelines in Oncology.

Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and the second leading cause of cancer death in the United States. Management of disseminated metastatic CRC involves various active drugs, either in combination or as single agents. The choice of therapy is based on consideration of the goals of therapy, the type and timing of prior therapy, the mutational profile of the tumor, and the differing toxicity profiles of the constituent drugs. This manuscript summarizes the data supporting the systemic therapy options recommended for metastatic CRC in the NCCN Guidelines for Colon Cancer.

Level and timing of product substitution in a trial of e-cigarettes for smokers not interested in quitting.

INTRODUCTION: The e-cigarette market is large and diverse. Traditional smoking cessation trials involving a control group and a 6-month observation period are an inefficient methodology for testing the multiple treatment options e-cigarettes provide for harm reduction in cigarette smokers. We determined when product substitution occurred in the e-cigarette provision arm of an e-cigarette substitution trial for cigarette smokers who were not interested in quitting. METHODS: We conducted a secondary analysis of 120 cigarette smokers with severe mental illness (recruitment 2017-2020) who were given disposable e-cigarettes for 8 weeks and assessed at weeks 0 (t0), 2, 4, 6, and 8. We explored product substitution through visit-to-visit correlations in change in product use, then developed a dual process growth model for cigarette and e-cigarette use to test the association between increases in e-cigarette use and concurrent decreases in cigarettes smoked. RESULTS: Mean age of the participants was 45.9 years, and 42.7% smoked ≥20 cigarettes per day. Almost all product substitution occurred between t0 and t2. For the average smoker (18 cigarettes per day), t2 cigarette frequency decreased by 0.39 (95% CI: -0.56 - -0.22) cigarettes for each additional e-cigarette session. There was effect modification (p=0.033), such that baseline light smokers (<10 cigarettes/day) had no significant decrease in t2 cigarette frequency, regardless of their initial increase in e-cigarette use, while heavy smokers (38 cigarettes/day) switched products nearly on a one-to-one basis. CONCLUSIONS: In this study, most product substitution occurred early, and heavier smokers had larger t2 decreases in cigarettes/day with increased e-cigarette use. If confirmed with replication studies, the findings could suggest establishment of a novel outcome for e-cigarette studies - early product substitution - and support the value of short-term comparative effectiveness trials that compare multiple potentially lower harm tobacco products. CLINICAL TRIAL REGISTRATION: The study was registered on the official website of ClinicalTrials.gov. IDENTIFIER: ID NCT03050853.

Discovery of genomic and transcriptomic pleiotropy between kidney function and soluble receptor for advanced glycation end products using correlated meta-analyses: The Long Life Family Study.

Patients with chronic kidney disease (CKD) have increased oxidative stress and chronic inflammation, which may escalate the production of advanced glycation end-products (AGEs). High soluble receptor for AGE (sRAGE) and low estimated glomerular filtration rate (eGFR) levels are associated with CKD and aging. We evaluated whether eGFR calculated from creatinine and cystatin C share pleiotropic genetic factors with sRAGE. We employed whole-genome sequencing and correlated meta-analyses on combined genome-wide association study (GWAS) p-values in 4182 individuals (age range: 24-110) from the Long Life Family Study (LLFS). We also conducted transcriptome-wide association studies (TWAS) on whole blood in a subset of 1209 individuals. We identified 59 pleiotropic GWAS loci (p < 5 × 10-8) and 17 TWAS genes (Bonferroni-p < 2.73 × 10-6) for eGFR traits and sRAGE. TWAS genes, LSP1 and MIR23AHG, were associated with eGFR and sRAGE located within GWAS loci, lncRNA-KCNQ1OT1 and CACNA1A/CCDC130, respectively. GWAS variants were eQTLs in the kidney glomeruli and tubules, and GWAS genes predicted kidney carcinoma. TWAS genes harbored eQTLs in the kidney, predicted kidney carcinoma, and connected enhancer-promoter variants with kidney function-related phenotypes at p < 5 × 10-8. Additionally, higher allele frequencies of protective variants for eGFR traits were detected in LLFS than in ALFA-Europeans and TOPMed, suggesting better kidney function in healthy-aging LLFS than in general populations. Integrating genomic annotation and transcriptional gene activity revealed the enrichment of genetic elements in kidney function and aging-related processes. The identified pleiotropic loci and gene expressions for eGFR and sRAGE suggest their underlying shared genetic effects and highlight their roles in kidney- and aging-related signaling pathways.

Hypofractionated radiotherapy for glioblastoma: A large institutional retrospective assessment of 2 approaches.

Background: Glioblastoma (GBM) poses therapeutic challenges due to its aggressive nature, particularly for patients with poor functional status and/or advanced disease. Hypofractionated radiotherapy (RT) regimens have demonstrated comparable disease outcomes for this population while allowing treatment to be completed more quickly. Here, we report our institutional outcomes of patients treated with 2 hypofractionated RT regimens: 40 Gy/15fx (3w-RT) and 50 Gy/20fx (4w-RT). Methods: A single-institution retrospective analysis was conducted of 127 GBM patients who underwent 3w-RT or 4w-RT. Patient characteristics, treatment regimens, and outcomes were analyzed. Univariate and multivariable Cox regression models were used to estimate progression-free survival (PFS) and overall survival (OS). The impact of chemotherapy and RT schedule was explored through subgroup analyses. Results: Median OS for the entire cohort was 7.7 months. There were no significant differences in PFS or OS between 3w-RT and 4w-RT groups overall. Receipt and timing of temozolomide (TMZ) emerged as the variable most strongly associated with survival, with patients receiving adjuvant-only or concurrent and adjuvant TMZ having significantly improved PFS and OS (P < .001). In a subgroup analysis of patients that did not receive TMZ, patients in the 4w-RT group demonstrated a trend toward improved OS as compared to the 3w-RT group (P = .12). Conclusions: This study demonstrates comparable survival outcomes between 3w-RT and 4w-RT regimens in GBM patients. Receipt and timing of TMZ were strongly associated with survival outcomes. The potential benefit of dose-escalated hypofractionation for patients not receiving chemotherapy warrants further investigation and emphasizes the importance of personalized treatment approaches.

Effects of intestine-specific deletion of FGF15 on the development of fatty liver disease with vertical sleeve gastrectomy.

BACKGROUND: Vertical sleeve gastrectomy (SGx) is a type of bariatric surgery to treat morbid obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). The molecular mechanisms of SGx to improve MASLD are unclear, but increased bile acids (BAs) and FGF19 (mouse FGF15) were observed. FGF15/19 is expressed in the ileum in response to BAs and is critical in not only suppressing BA synthesis in the liver but also promoting energy expenditure. We hypothesized the reduction of obesity and resolution of MASLD by SGx may be mediated by FGF15/19. METHODS: First, we conducted hepatic gene expression analysis in obese patients undergoing SGx, with the results showing increased expression of FGF19 in obese patients' livers. Next, we used wild-type and intestine-specific Fgf15 knockout mice (Fgf15ile-/-) to determine the effects of FGF15 deficiency on improving the metabolic effects. RESULTS: SGx improved metabolic endpoints in both genotypes, evidenced by decreased obesity, improved glucose tolerance, and reduced MASLD progression. However, Fgf15ile-/- mice showed better improvement compared to wild-type mice after SGx, suggesting that other mediators than FGF15 are also responsible for the beneficial effects of FGF15 deficiency. Further gene expression analysis in brown adipose tissue suggests increased thermogenesis. CONCLUSIONS: FGF15 deficiency, the larger BA pool and higher levels of secondary BAs may increase energy expenditure in extrahepatic tissues, which may be responsible for improved metabolic functions following SGx.

Key Anatomical Concepts, Landmarks, and Proposed Terminology for Nerve-Sparing Gynecologic Surgery: A Narrative Review.

OBJECTIVE: To synthesize the terminology utilized in nerve-sparing surgical literature and propose standardized and nonconflicting terms to allow for consistent vocabulary. DESIGN: We performed a literature search on PubMed using the search terms "pelvis" and "nerve-sparing." Nongynecologic surgery and animal studies were excluded. A narrative review was performed, focusing on nerves, fasciae, ligaments, and retroperitoneal spaces. Terms from included papers were discussed by all authors, who are surgeons versed in nerve-sparing procedures and one anatomist, and recommendations were made regarding the most appropriate terms based on the frequency of occurrence in the literature and the possibility of overlapping names with other structures. RESULTS: 224 articles were identified, with 81 included in the full-text review. Overall, 48% of articles focused on cervical cancer and 26% on deeply infiltrating endometriosis. Findings were synthesized both narratively and visually. Inconsistencies in pelvic anatomical nomenclature were prevalent across publications. The structure with the most varied terminology was the rectal branch of the inferior hypogastric plexus with 14 names. A standardized terminology for pelvic autonomic nerve structures, fasciae, ligaments, and retroperitoneal spaces was proposed to avoid conflicting terms. CONCLUSION: Surgeons and anatomists should use consistent terminology to facilitate increased uptake of nerve-sparing techniques in gynecologic surgery through a better understanding of surgical technique description. We have proposed a standardized terminology believed to facilitate this goal.

Characterization of pain-related behaviors in a rat model of acute-to-chronic low back pain: single vs. multi-level disc injury.

Introduction: Low back pain is the most common type of chronic pain. We examined pain-related behaviors across 18 weeks in rats that received injury to one or two lumbar intervertebral discs (IVD) to determine if multi-level disc injuries enhance/prolong pain. Methods: Twenty-three Sprague-Dawley adult female rats were used: 8 received disc puncture (DP) of one lumbar IVD (L5/6, DP-1); 8 received DP of two lumbar IVDs (L4/5 & L5/6, DP-2); 8 underwent sham surgery. Results: DP-2 rats showed local (low back) sensitivity to pressure at 6- and 12-weeks post-injury, and remote sensitivity to pressure (upper thighs) at 12- and 18-weeks and touch (hind paws) at 6, 12 and 18-weeks. DP-1 rats showed local and remote pressure sensitivity at 12-weeks only (and no tactile sensitivity), relative to Sham DP rats. Both DP groups showed reduced distance traveled during gait testing over multiple weeks, compared to pre-injury; only DP-2 rats showed reduced distance relative to Sham DP rats at 12-weeks. DP-2 rats displayed reduced positive interactions with a novel adult female rat at 3-weeks and hesitation and freezing during gait assays from 6-weeks onwards. At study end (18-weeks), radiological and histological analyses revealed reduced disc height and degeneration of punctured IVDs. Serum BDNF and TNFα levels were higher at 18-weeks in DP-2 rats, relative to Sham DP rats, and levels correlated positively with remote sensitivity in hind paws (tactile) and thighs (pressure). Discussion: Thus, multi-level disc injuries resulted in earlier, prolonged and greater discomfort locally and remotely, than single-level disc injury. BDNF and TNFα may have contributing roles.

Synthesis and Characterization of a Terminal Iron(II)-PH2 Complex and a Series of Iron(II)-PH3 Complexes.

Reported is the reaction of a series of iron(II) bisphosphine complexes with PH3 in the presence of NaBArF4 [where BArF4 = tetrakis(3,5-bis(trifluoromethyl)phenyl)borate]. The iron(II) bisphosphine reagents bear two chlorides or a hydride and a chloride motif. We have isolated six different cationic terminal-bound PH3 complexes and undertaken rigorous characterization by NMR spectroscopy, single crystal X-ray diffraction, and mass spectrometry, where the PH3 often remains intact during the ionization process. Unusual bis- and tris-PH3 complexes are among the compounds isolated. Changing the monophosphine from PH3 to PMe3 results in the formation of an unusual Fe7 cluster, but with no PMe3 being ligated. Finally, by using an iron(0) source, we have provided a rare example of a terminally bound iron-PH2 complex.

Monoclonal antibodies derived from B cells in subjects with cystic fibrosis reduce Pseudomonas aeruginosa burden in mice.

Pseudomonas aeruginosa (PA) is an opportunistic, frequently multidrug-resistant pathogen that can cause severe infections in hospitalized patients. Antibodies against the PA virulence factor, PcrV, protect from death and disease in a variety of animal models. However, clinical trials of PcrV-binding antibody-based products have thus far failed to demonstrate benefit. Prior candidates were derivations of antibodies identified using protein-immunized animal systems and required extensive engineering to optimize binding and/or reduce immunogenicity. Of note, PA infections are common in people with cystic fibrosis (pwCF), who are generally believed to mount normal adaptive immune responses. Here we utilized a tetramer reagent to detect and isolate PcrV-specific B cells in pwCF and, via single-cell sorting and paired-chain sequencing, identified the B cell receptor (BCR) variable region sequences that confer PcrV-specificity. We derived multiple high affinity anti-PcrV monoclonal antibodies (mAbs) from PcrV-specific B cells across 3 donors, including mAbs that exhibit potent anti-PA activity in a murine pneumonia model. This robust strategy for mAb discovery expands what is known about PA-specific B cells in pwCF and yields novel mAbs with potential for future clinical use.

Relation of preconception eating behaviours to dietary pattern trajectories and gestational weight gain from preconception to late pregnancy.

Studies examining preconception eating behaviours with longitudinal dietary patterns from preconception to late pregnancy as well as gestational weight gain (GWG) are limited. We derived dietary pattern trajectories from preconception to late-pregnancy, and related preconception eating behaviours to these trajectories and GWG. Preconception eating behaviours were assessed using the Three-Factor Eating Questionnaire measuring cognitive restraint (CR) - conscious restriction of food intake, emotional eating (EE) - overeating in response to negative emotions, and uncontrolled eating (UE) - overeating with a feeling of lack of control. Dietary intakes were measured at preconception, 20-21 and 34-36 weeks' gestation with food frequency questionnaires. Dietary patterns were determined using factor analysis, and trajectories derived using group-based trajectory modelling. Inadequate and excessive GWG were defined according to Institute of Medicine guidelines based on weights at preconception and the last antenatal visit (median: 38 weeks' gestation). Two dietary patterns were derived: 'Fast Food, Fried Snacks and Desserts (FFD)' and 'Soup, Fish and Vegetables (SFV)'. Adherence trajectories from preconception to late-pregnancy were characterised as consistently high ("stable-high") and low ("stable-low"). Women with higher UE scores had higher odds of being in the "stable-high" trajectory (n = 34) of the FFD pattern [Odds Ratio (OR): 1.25, 95% Confidence Interval (CI): 1.03, 1.51], compared to "stable-low" (n = 260). Percentages of women with inadequate, adequate or excessive GWG were 21.7% (n = 70), 25.8% (n = 83), and 52.5% (n = 169), respectively; women with higher EE scores had a higher likelihood of excessive GWG [Relative Risk Ratio (RRR): 1.35, 95% CI: 1.02, 1.80], but this association was attenuated after adjusting for preconception body mass index. Eating behaviour interventions to improve dietary patterns among pregnant women may need to start as early as preconception, incorporating strategies to manage UE.

Tobacco, Alcohol, and Drug Use Among Young Adults with Serious Mental Illness.

To inform early intervention, this study describes correlates of substance use among young people with serious mental illness (SMI) enrolled in integrated care in community mental health settings. 227 adults ages 18-35 were assessed for clinical characteristics and substance use. Logistic regressions were used to describe relationships between substance use and participant characteristics. Over a third (38.9%) reported daily cannabis, 15.9% past month other illicit drug, 13.5% frequent/heavy alcohol and 47.4% any of these; 50.2% reported daily tobacco smoking and 23.3% current vaping. Daily cannabis and tobacco were the most common combination. Alcohol, drug, and cannabis with tobacco were associated with higher mental health symptoms but not with emergency room or hospital utilization. Cannabis and other substance use was common and associated with higher symptoms but not with greater hospital utilization, suggesting that early intervention could prevent long-term negative consequences.

Nerve transfer for restoration of lower motor neuron-lesioned bladder, urethral and anal sphincter function. Part 4: Effectiveness of the motor reinnervation.

In pilot work, we showed that somatic nerve transfers can restore motor function in long-term decentralized dogs. We continue to explore the effectiveness of motor reinnervation in 30 female dogs. After anesthesia, 12 underwent bilateral transection of coccygeal and sacral (S) spinal roots, dorsal roots of lumbar (L)7, and hypogastric nerves. Twelve months postdecentralization, eight underwent transfer of obturator nerve branches to pelvic nerve vesical branches, and sciatic nerve branches to pudendal nerves, followed by 10 mo recovery (ObNT-ScNT Reinn). The remaining four were euthanized 18 mo postdecentralization (Decentralized). Results were compared with 18 Controls. Squat-and-void postures were tracked during awake cystometry. None showed squat-and-void postures during the decentralization phase. Seven of eight ObNT-ScNT Reinn began showing such postures by 6 mo postreinnervation; one showed a return of defecation postures. Retrograde dyes were injected into the bladder and urethra 3 wk before euthanasia, at which point, roots and transferred nerves were electrically stimulated to evaluate motor function. Upon L2-L6 root stimulation, five of eight ObNT-ScNT Reinn showed elevated detrusor pressure and four showed elevated urethral pressure, compared with L7-S3 root stimulation. After stimulation of sciatic-to-pudendal transferred nerves, three of eight ObNT-ScNT Reinn showed elevated urethral pressure; all showed elevated anal sphincter pressure. Retrogradely labeled neurons were observed in L2-L6 ventral horns (in laminae VI, VIII, and IX) of ObNT-ScNT Reinn versus Controls in which labeled neurons were observed in L7-S3 ventral horns (in lamina VII). This data supports the use of nerve transfer techniques for the restoration of bladder function.NEW & NOTEWORTHY This data supports the use of nerve transfer techniques for the restoration of bladder function.

Safety and feasibility of establishing an adjuvant hepatic artery infusion program.

BACKGROUND: Hepatic artery infusion (HAI) is less frequently used in the adjuvant setting for resectable colorectal liver metastasis (CRLM) due to concerns regarding toxicity. Our objective was to evaluate the safety and feasibility of establishing an adjuvant HAI program. METHODS: Patients who underwent HAI pump placement between January 2019 and February 2023 for CRLM were identified. Complications and HAI delivery were compared between patients who received HAI in the unresectable and adjuvant settings. RESULTS: Of 51 patients, 23 received HAI for unresectable CRLM and 28 in the adjuvant setting. Patients with unresectable CRLM more commonly had bilobar disease (n = 23/23 vs n = 18/28, p < 0.01) and more preoperative liver metastases (median 10 [IQR 6-15] vs 4 [IQR 3-7], p < 0.01). Biliary sclerosis was the most common complication (n = 2/23 vs n = 4/28); however, there were no differences in postoperative or HAI-specific complications. In the most recent two years, 0 patients in the unresectable group vs 2 patients in the adjuvant group developed biliary sclerosis. All patients were initiated on HAI with no difference in treatment times or dose reductions. CONCLUSION: Adjuvant HAI is safe and feasible for patients with resectable CRLM. HAI programs can carefully consider including patients with resectable CRLM if managed by an experienced multidisciplinary team with quality assurance controls in place.

Trajectories of lifestyle patterns from 2 to 8 years of age and cardiometabolic risk in children: the GUSTO study.

BACKGROUND: Tracking combinations of lifestyle behaviours during childhood ("lifestyle pattern trajectories") can identify subgroups of children that might benefit from lifestyle interventions aiming to improve health outcomes later in life. However, studies on the critical transition period from early to middle childhood are limited. We aimed to describe lifestyle patterns trajectories in children from 2 to 8 years of age and evaluated their associations with cardiometabolic risk markers at age 8 years in a multi-ethnic Asian cohort. METHODS: Twelve lifestyle behaviours related to child's diet, physical activity, screen use, and sleep were ascertained using questionnaires at ages 2, 5, and 8 years. Age-specific lifestyle patterns were derived using principal component analysis and trajectories were determined using group-based multi-trajectory modelling. Child cardiometabolic risk markers were assessed at age 8 years, and associations with trajectories examined using multiple regression, adjusted for confounders. RESULTS: Among 546 children, two lifestyle patterns "healthy" and "unhealthy" were observed at ages 2, 5, and 8 years separately. Three trajectory groups from 2 to 8 years were identified: consistently healthy (11%), consistently unhealthy (18%), and mixed pattern (71%). Children in the consistently unhealthy group (vs. mixed pattern) had increased odds of pre-hypertension (OR = 2.96 [95% CI 1.18-7.41]) and higher levels of diastolic blood pressure (ß = 1.91 [0.27-3.55] mmHg), homeostasis model assessment of insulin resistance (ß = 0.43 [0.13-0.74]), triglycerides (ß = 0.11 [0.00-0.22] mmol/L), and metabolic syndrome score (ß = 0.85 [0.20-1.49]), but not with BMI z-score or any anthropometric measurements. The consistently healthy group showed no differences in cardiometabolic outcomes compared to the mixed pattern group. CONCLUSION: Three distinct lifestyle pattern trajectories were identified from early to middle childhood. Children in the consistently unhealthy lifestyle group did not have a raised BMI but was associated with several elevated cardiometabolic risk markers. These findings suggest the potential benefits of initiating holistic lifestyle interventions to improve children's health and well-being from an early age. TRIAL REGISTRATION: Trial registration number: NCT01174875. Name of registry: ClinicalTrials.gov. URL of registry: https://classic. CLINICALTRIALS: gov/ct2/show/NCT01174875 . Date of registration: August 4, 2010. Date of enrolment of the first participant to the trial: June 2009.

Assessing in vitro stability of remdesivir (GS-5734) and conversion to GS-441524 in feline plasma and whole blood.

Feline infectious peritonitis (FIP) is a potentially fatal coronavirus-driven disease of cats. Treatment with nucleoside analogue GS-441524 and or prodrug remdesivir (RDV) have produced remission in both experimentally induced and naturally occurring FIP, yet information regarding metabolism of RDV into GS-441524 in cats is scarce. This study assessed possible phase I metabolism of RDV in cats, utilising an in vitro feline microsome model with in vitro t1/2 and in vitro Clint calculated using the substrate depletion method. A previously validated high-performance liquid chromatography (HPLC) fluorescence method was utilised for detection and analysis of RDV and GS-441524. Qualitative yield of RDV and intermediate metabolite GS-441524 were determined following microsome incubation, then compared to whole blood and plasma incubations. In vitro microsome incubation resulted in rapid depletion of RDV, though it did not appear to resemble a conventional phase I-dependent reaction in cats, as it is in humans and dogs. Depletion of RDV into GS-441524 was demonstrated in whole blood in vitro, suggesting cats convert RDV to GS-441524, likely via blood esterases, as observed in mice and rats. RDV metabolism is unlikely to be impacted by impaired liver function in cats. Furthermore, as RDV depletes within minutes, whereas GS-441524 is very stable, whole blood or plasma GS-441524 concentrations, rather than plasma RDV concentrations, are more appropriate for therapeutic drug monitoring (TDM) in cats receiving RDV.

Correlation Between Mobile-Application Electronic Bowel Diary and Validated Questionnaires in Women with Fecal Incontinence.

INTRODUCTION AND HYPOTHESIS: Despite growing interest in a mobile-app bowel diary to assess fecal incontinence (FI) symptoms, data are limited regarding the correlation between mobile-app diary and questionnaire-based outcomes. The primary aim is to determine whether percentage reduction in FI episodes (FIEs)/week recorded on a mobile-app diary correlates with changes in scores of validated FI-symptom measures from baseline to 12 weeks in women with FI undergoing percutaneous tibial nerve stimulation (PTNS) versus sham. METHODS: This is a planned secondary analysis of a multicenter randomized trial in which women with FI underwent PTNS or sham. FIEs were collected using a mobile-app diary at baseline and after 12 weekly sessions. FI-symptom-validated measures included St. Mark's, Accidental Bowel Leakage Evaluation, FI Severity Index (FISI), Colorectal Anal Distress Inventory, Colorectal Anal Impact Questionnaire, FI Quality of Life, Patient Global Impression of Improvement (PGI-I), and Patient Global Symptom Control (PGSC) rating. Spearman's correlation coefficient (ρ) was computed between %-reduction in FIEs/week and change in questionnaire scores from baseline to 12 weeks. Significance was set at 0.005 to account for multiple comparisons. RESULTS: Baseline characteristics of 163 women (109 PTNS, 54 sham) include mean age 63.4±11.6, 81% white, body mass index 29.4±6.6 kg/m2, 4% previous FI surgeries, 6.6±5.5 FIEs/week, and St. Mark's score 17.4±2.6. A significant correlation was demonstrated between %-reduction in FIEs/week and all questionnaires (p<0.005). A moderate-strength correlation (|ρ|>0.4) was observed for St. Mark's (ρ=0.48), FISI (ρ=0.46), PGI-I (ρ=0.51), and PGSC (ρ=-0.43). CONCLUSIONS: In women with FI randomized to PTNS versus sham, a moderate correlation was noted between FIEs measured via mobile-app diary and FI-symptom-validated questionnaire scores.

Evolution of therapy for locally advanced rectal cancer.

Rectal cancer is a prevalent disease worldwide. The standard treatment of locally advanced rectal cancer (LARC) is preoperative chemoradiotherapy followed by surgery and adjuvant systemic chemotherapy. Studies have been done to determine the best sequence of treatments to improve survival, cure rate and long term toxicity profile. In this paper, we will review the literature regarding the evolution of LARC treatment.