Fecal Microbiota Transplantation for Sleep Disturbance in Post-acute COVID-19 Syndrome.

BACKGROUND & AIMS: Post-acute COVID-19 syndrome (PACS) is associated with sleep disturbance, but treatment options are limited. The etiology of PACS may be secondary to alterations in the gut microbiome. Here, we report the efficacy of fecal microbiota transplantation (FMT) in alleviating post-COVID insomnia symptoms in a nonrandomized, open-label prospective interventional study. METHODS: Between September 22, 2022, and May 22, 2023, we recruited 60 PACS patients with insomnia defined as Insomnia Severity Index (ISI) ≥8 and assigned them to the FMT group (FMT at weeks 0, 2, 4, and 8; n = 30) or the control group (n = 30). The primary outcome was clinical remission defined by an ISI of <8 at 12 weeks. Secondary outcomes included changes in the Pittsburgh Sleep Quality Index, Generalized Anxiety Disorder-7 scale, Epworth Sleepiness Scale, Multidimensional Fatigue Inventory, blood cortisol and melatonin, and gut microbiome analysis on metagenomic sequencing. RESULTS: At week 12, more patients in the FMT than the control group had insomnia remission (37.9% vs 10.0%; P = .018). The FMT group showed a decrease in ISI score (P < .0001), Pittsburgh Sleep Quality Index (P < .0001), Generalized Anxiety Disorder-7 scale (P = .0019), Epworth Sleepiness Scale (P = .0057), and blood cortisol concentration (P = .035) from baseline to week 12, but there was no significant change in the control group. There was enrichment of bacteria such as Gemmiger formicilis and depletion of microbial pathways producing menaquinol derivatives after FMT. The gut microbiome profile resembled that of the donor in FMT responders but not in nonresponders at week 12. There was no serious adverse event. CONCLUSIONS: This pilot study showed that FMT could be effective and safe in alleviating post-COVID insomnia, and further clinical trials are warranted. CLINICALTRIALS: gov, Number: NCT05556733.

Effect of Real-Time Computer-Aided Polyp Detection System (ENDO-AID) on Adenoma Detection in Endoscopists-in-Training: A Randomized Trial.

BACKGROUND: The effect of computer-aided polyp detection (CADe) on adenoma detection rate (ADR) among endoscopists-in-training remains unknown. METHODS: We performed a single-blind, parallel-group, randomized controlled trial in Hong Kong between April 2021 and July 2022 (NCT04838951). Eligible subjects undergoing screening/surveillance/diagnostic colonoscopies were randomized 1:1 to receive colonoscopies with CADe (ENDO-AID[OIP-1]) or not (control) during withdrawal. Procedures were performed by endoscopists-in-training with <500 procedures and <3 years' experience. Randomization was stratified by patient age, sex, and endoscopist experience (beginner vs intermediate level, <200 vs 200-500 procedures). Image enhancement and distal attachment devices were disallowed. Subjects with incomplete colonoscopies or inadequate bowel preparation were excluded. Treatment allocation was blinded to outcome assessors. The primary outcome was ADR. Secondary outcomes were ADR for different adenoma sizes and locations, mean number of adenomas, and non-neoplastic resection rate. RESULTS: A total of 386 and 380 subjects were randomized to CADe and control groups, respectively. The overall ADR was significantly higher in the CADe group than in the control group (57.5% vs 44.5%; adjusted relative risk, 1.41; 95% CI, 1.17-1.72; P < .001). The ADRs for <5 mm (40.4% vs 25.0%) and 5- to 10-mm adenomas (36.8% vs 29.2%) were higher in the CADe group. The ADRs were higher in the CADe group in both the right colon (42.0% vs 30.8%) and left colon (34.5% vs 27.6%), but there was no significant difference in advanced ADR. The ADRs were higher in the CADe group among beginner (60.0% vs 41.9%) and intermediate-level (56.5% vs 45.5%) endoscopists. Mean number of adenomas (1.48 vs 0.86) and non-neoplastic resection rate (52.1% vs 35.0%) were higher in the CADe group. CONCLUSIONS: Among endoscopists-in-training, the use of CADe during colonoscopies was associated with increased overall ADR. (ClinicalTrials.gov, Number: NCT04838951).

Use of over-the-scope clip (OTSC) versus standard therapy for the prevention of rebleeding in large peptic ulcers (size ≥1.5 cm): an open-labelled, multicentre international randomised controlled trial.

INTRODUCTION: Over-the-scope clip (OTSC) has been used recently for primary haemostasis of peptic ulcers. This study aimed to compare the efficacy of OTSC to standard endoscopic therapy in primary treatment of patients with peptic ulcer bleeding that are of size ≥1.5 cm. The target population accounts for only 2.5% of all upper GI bleeders. METHODS: This was a multicentre international randomised controlled trial from July 2017 to October 2020. All patients with Forest IIa or above peptic ulcers of ≥1.5 cm were included. Primary outcome was 30-day clinical rebleeding. Secondary endpoints include 3-day all-cause mortality, transfusion requirement, hospital stay, technical and clinical success, and further interventions. 100 patients are needed to yield a power of 80% to detect a difference of -0.15 at the 0.05 significance level (alpha) using a two-sided Z-test (pooled). RESULTS: 100 patients were recruited. Success in achieving primary haemostasis was achieved in 46/50 (92%) and 48/50 (96%) in the OTSC and conventional arm, respectively. Among patients who had success in primary haemostasis, 2/46 (4.35%) patients in the OTSC arm and 9/48 (18.75%) patients in the conventional arm developed 30-day rebleeding (p=0.03). However, in an intention-to-treat analysis, there was no difference in rebleeding within 30 days (5/50 (10%) OTSC vs 9/50 (18%) standard, p=0.23) or all-cause mortality (2/50 (4%) OTSC vs 4/50 (8%) standard, p=0.68; OR=2.09, 95% CI 0.37 to 11.95). There was also no difference in transfusion requirement, hospital stay, intensive care unit admission and further interventions. CONCLUSION: The routine use of OTSC as primary haemostasis in large bleeding peptic ulcers was not associated with a significant decrease in 30-day rebleeding. TRIAL REGISTRATION NUMBER: NCT03160911.

Incidence and predictors of hypophosphataemia after ferric carboxymaltose use-A 3-year experience from a single institution in Singapore.

Ferric carboxymaltose (FCM) administration helps reduce transfusion requirements in the perioperative situation, which improves patient outcomes and reduces healthcare costs. However, there is increasing evidence of hypophosphataemia after FCM use. We aim to determine the incidence of hypophosphataemia after FCM administration and elucidate potential biochemical factors associated with the development of subsequent hypophosphataemia. A retrospective review of anonymised data of all FCM administrations in a single institution was conducted from August 2018 to August 2021. Each unique FCM dose administered was examined to assess its effect on Hb and serum phosphate levels within the subsequent 28 days from each FCM administration. Phosphate levels were repeatedly measured within the 28-day interval and the lowest phosphate level within that period was determined. Patients' serum phosphate levels within 28 days of FCM administration were compared against normal serum phosphate levels within 2 weeks before FCM administration. The odds ratios of various pre-FCM serum markers were calculated to elucidate potential biochemical predictors of post-FCM hypophosphataemia. In 3 years, a total of 1296 doses of FCM were administered to 1069 patients. The mean improvement in Hb was 2.45 g/dL (SD = 1.94) within 28 days of FCM administration, with the mean time taken to peak Hb levels being 6.3 days (SD = 8.63), which is earlier than expected, but was observed in this study and hence reported. The incidence of hypophosphataemia <0.8 mmol/L was 22.7% (n = 186), and <0.4 mmol/L was 1.6% (n = 9). This figure is lower than the numbers reported in previously published meta-analyses given that routine checks of serum phosphate levels were not conducted initially and hence could possibly be higher. The odds of developing hypophosphataemia (<0.8 mmol/L) were 27.7 (CI: 17.3-44.2, p < 0.0001) if baseline serum phosphate was less than 1 mmol/L. The odds of developing hypophosphataemia (<0.8 mmol/L) were 1.3 (CI: 1.08-1.59, p < 0.01) if the change in Hb levels observed after FCM administration were more than 4 g/dL. Hypophosphataemia after FCM administration is significant and FCM should be used by clinicians with caution.

Hypophosphatemia related to intravenous iron therapy with ferric carboxymaltose: A case series.

OBJECTIVES: This case series would like to highlight hypophosphatemia related to ferric carboxymaltose and its adverse clinical consequences. BACKGROUND: Intravenous iron supplementation is a good alternative to oral iron replacement in iron deficiency anaemia due to its ability to correct iron deficit with minimal infusions without incurring the gastrointestinal side effects of oral iron replacement. Ferric carboxymaltose is one common formula for intravenous iron supplementation. However, an increasingly recognised adverse side-effect of intravenous ferric carboxymaltose is hypophosphatemia. There has been increasing reports and studies highlighting hypophosphatemia related to intra-venous iron therapy. Though initially thought to be transient and asymptomatic, recent studies have shown that persistent hypophosphatemia in iron therapy can result in debilitating disease including myopathy, fractures and osteomalacia. METHODS: A retrospective analysis of all patients who had ferric carboxymaltose was performed. RESULTS: We highlight 3 cases where hyposphatemia affected the clinical outcomes. CONCLUSION: With the increased use of IV iron it is important to be aware of the high potential for hypophosphatemia secondary to ferric carboxymaltose.

Evaluation of oropharyngeal deglutitive pressure dynamics in patients with Parkinson's disease.

In Parkinson's disease (PD), oropharyngeal dysphagia is common and clinically relevant. The neurophysiology of dysphagia in PD is complex and incompletely understood. The aim of the study was to determine the changes in oropharyngeal deglutitive pressure dynamics in PD and to correlate these with clinical characteristics including dysphagia and PD severity. In prospective consecutive series of 64 patients with PD [mean age: 66.9 ± 8.3 (SD)], we evaluated dysphagia severity clinically as well as with Sydney Swallow Questionnaire (SSQ) and Swallow Quality-of-Life Questionnaire (SWAL-QOL). PD severity was assessed with Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS). We used high-resolution pharyngeal impedance manometry (HRPIM) to objectively evaluate swallow function and compared data from 23 age-matched healthy controls [mean age 62.3 ± 9.1 (SD)]. Metrics assessed were upper esophageal sphincter (UES), integrated relaxation pressure (IRP), relaxation time (RT), maximum opening (MaxAdm), and pharyngeal intrabolus pressure (IBP) and pharyngeal contractility (PhCI). Mean MDS-UPDRS score was positively associated with dysphagia severity on SSQ and SWAL-QOL. HRPIM in PD compared with controls showed impaired UES relaxation parameters, with shorter RT, and elevated IRP and IBP. MaxAdm was not affected. The overall pharyngeal contractility was significantly higher in PD. Only the IBP and IRP were associated with PD severity and only IBP was significantly associated with dysphagia severity. UES dysfunction leading to increased flow resistance is common in patients with PD and correlates with dysphagia severity. Increased flow resistance may suggest impaired UES relaxation and/or impaired neuromodulation to bolus volume.NEW & NOTEWORTHY In Parkinson's disease, objective assessment of swallow function with high-resolution impedance manometry identifies upper esophageal sphincter dysfunction leading to increased flow resistance.

Direct health-care cost utilization in Hong Kong inflammatory bowel disease patients in the initial 2 years following diagnosis.

BACKGROUND AND AIM: There are scanty data on the health-care utilization from Asia where the incidence of inflammatory bowel disease (IBD) is rising rapidly. We aim to determine the direct health-care costs in the first 2 years of diagnosis in an IBD cohort from Hong Kong and the factors associated with high cost outliers. METHODS: This is a retrospective cohort study that included patients newly diagnosed with IBD in a territory-wide IBD registry. Patients' clinical information, hospitalization records, investigations, and IBD treatments were retrieved for up to 2 years following diagnosis of IBD. RESULTS: Four hundred and thirty-five newly diagnosed IBD patients were included: 198 with Crohn's disease and 237 with ulcerative colitis. Total direct medical expenditure for this cohort 2 years after the IBD diagnosis was $7 072 710: hospitalizations (33%), 5-aminosalicylic acid (23%), imaging and endoscopy (17%), outpatient visits (10%), surgery (8%), and biologics (6%). Mean direct medical costs per patient-year were significantly higher for Crohn's disease ($9918) than ulcerative colitis ($6634; P, 0.001). The total direct health-care cost decreased significantly after transition to the second year (P < 0.01). High cost (> 90th percentile) outliers were associated with surgery (OR 7.1, 95% CI 2.9-17.2) and low hemoglobin on presentation (OR 0.83, 95% CI 0.70-0.96). CONCLUSIONS: Hospitalization and 5-aminosalicylic acid usage accounted for 56% of total direct medical costs in the first 2 years of our newly diagnosed IBD patients. Direct health-care costs were higher in the first year compared with the second year of diagnosis. Surgery and low hemoglobin on presentation were associated with high cost outliers.

Effects of intraosseous epinephrine in a cardiac arrest swine model.

BACKGROUND: Interruptions in cardiopulmonary resuscitation (CPR) to obtain vascular access reduces blood flow to vital organs. Tibial intraosseous (TIO) access may be a faster alternative to intravenous (IV) access for delivery of vasoactive medications. The purpose of this study was to examine the differences in pharmacokinetics and pharmacodynamics of TIO- and IV-delivered epinephrine. MATERIALS AND METHODS: A prospective, between subjects, experimental design comparing Cmax, Tmax, return of spontaneous circulation (ROSC), and time to ROSC. Adult male swine were divided into three equal groups (n = 7) all received CPR and defibrillation: the second group received IV epinephrine and the third group received tibial intraosseous epinephrine. Swine were placed in cardiac arrest for 2 min before CPR was initiated. After 2 min of CPR, epinephrine was delivered by IV or TIO, and serial blood samples were collected over 4 min. RESULTS: There were no significant differences between IV versus TIO epinephrine in achieving ROSC, time to ROSC, and Cmax. A one-way analysis of variance demonstrated a significant difference between the IV and TIO groups in Tmax (P = 0.025). A Fisher exact test demonstrated a significant difference between IV epinephrine versus CPR/Defib only (P = 0.035) and TIO epinephrine versus CPR/Defib only (P = 0.010) in achieving ROSC. A multivariate analysis of variance showed significant differences in IV versus intraosseous epinephrine concentration at specific time intervals: 60 (P = 0.023), 90 (P = 0.001), and 120 (P < 0.000) sec. CONCLUSIONS: In the context of ROSC, epinephrine delivered via TIO route is a clinically relevant alternative to IV administration. When IV access cannot be immediately obtained in cardiac arrest patients, TIO access should be considered.

The prevalence of gastroesophageal reflux disease and laryngopharyngeal reflux in patients with dysphagia after radiotherapy for nasopharyngeal carcinoma.

BACKGROUND: The prevalence of gastroesophageal reflux disease (GERD) and laryngopharyngeal reflux (LPR) in post-irradiated patients with nasopharyngeal carcinoma (NPC) is unknown. MATERIALS AND METHODS: In a cross-sectional study, 31 NPC and 12 control patients completed questionnaires for GERD/LPR before esophageal manometry and 24-h pH monitoring. The DeMeester score and reflux finding score (RFS) were used to define GERD and LPR, respectively. Risk factors were identified. RESULTS: 51.6% of NPC and 8.3% of control patients, and 77.4% of NPC and 33% of control patients, were GERD-positive and LPR-positive, respectively. The GERD/LPR questionnaire failed to identify either condition in patients with NPC. No parameter differences in esophageal manometry or pneumonia incidence were noted between GERD/LPR-positive and GERD/LPR-negative patients. Post radiotherapy duration, high BMI, lack of chemotherapy, and dysphagia were positive risk factors for GERD/LPR. CONCLUSIONS: A high prevalence of GERD/LPR in patients with post-irradiated NPC exists, but reflux symptoms are inadequate for diagnosis.

Renal Cell Tumor and Cystic Lung Disease: A Genetic Link for Generalists to Be Aware of.

Birt-Hogg-Dubé syndrome (BHDS) is a rare autosomal dominant condition characterized by multiple pulmonary cysts, fibrofolliculomas, and renal cell carcinoma. The typical presentations leading to diagnosis include fibrofolliculomas and spontaneous pneumothoraxes. We present a case of a 52-year-old Chinese male who was diagnosed with BHDS after the incidental pickup of an echogenic heterogenous lesion on an abdominal ultrasound done to investigate an abnormal liver function test. The presence of renal cell carcinoma with cystic pulmonary disease should prompt the clinician to consider the diagnosis of BHDS. Knowledge of extrapulmonary findings of common cystic lung diseases may contribute to improved diagnosis of this condition.

TM9SF4 Is a Crucial Regulator of Inflammation and ER Stress in Inflammatory Bowel Disease.

BACKGROUND & AIMS: Inflammatory bowel disease (IBD) is a major intestinal disease. Excessive inflammation and increased endoplasmic reticulum (ER) stress are the key events in the development of IBD. Search of a genome-wide association study database identified a remarkable correlation between a TM9SF4 single-nucleotide polymorphism and IBD. Here, we aimed to resolve its underlying mechanism. METHODS: The role of TM9SF4 was determined with experimental mouse models of IBD. ER stress cascades, barrier functions, and macrophage polarization in colonic tissues and cells were assessed in vivo and in vitro. The expression of TM9SF4 was compared between inflamed regions of ulcerative colitis patients and normal colon samples. RESULTS: In mouse models of IBD, genetic knockout of the TM9SF4 gene aggravated the disease symptoms. In colonic epithelial cells, short hairpin RNA-mediated knockdown of TM9SF4 expression promoted inflammation and increased ER stress. In macrophages, TM9SF4 knockdown promoted M1 macrophage polarization but suppressed M2 macrophage polarization. Genetic knockout/knockdown of TM9SF4 also disrupted epithelial barrier function. Mechanistically, TM9SF4 deficiency may act through Ca2+ store depletion and cytosolic acidification to induce an ER stress increase. Furthermore, the expression level of TM9SF4 was found to be much lower in the inflamed colon regions of human ulcerative colitis patients than in normal colon samples. CONCLUSIONS: Our study identified a novel IBD-associated protein, TM9SF4, the reduced expression of which can aggravate intestinal inflammation. Deficiency of TM9SF4 increases ER stress, promotes inflammation, and impairs the intestinal epithelial barrier to aggravate IBD.

An Atypical Presentation of Rheumatoid Arthritis as an Asymmetrical Arthropathy.

We report a rare entity of distinctly asymmetrical rheumatoid arthritis (RA) in a 71-year-old Chinese lady with a history of cervical radiculopathy secondary to trauma sustained during childhood. The joints on the side of the paresis were spared from severe clinical and radiological manifestations of RA. We review the plausible mechanisms that could explain the link between neurological impairment and rheumatoid joint involvement.

Cricopharyngeal peroral endoscopic myotomy improves oropharyngeal dysphagia in patients with Parkinson's disease.

Background and study aims Oropharyngeal dysphagia (OPD) is prevalent in patients with Parkinson's disease (PD). Upper esophageal sphincter (UES) dysfunction is an important pathophysiological factor for OPD in PD. The cricopharyngeus (CP) is the main component of UES. We assessed the preliminary efficacy of cricopharyngeal peroral endoscopic myotomy (C-POEM) as a treatment for dysphagia due to UES dysfunction in PD. Patients and methods Consecutive dysphagic PD patients with UES dysfunction underwent C-POEM. Swallow metrics derived using high-resolution pharyngeal impedance manometry (HRPIM) including raised UES integrated relaxation pressure (IRP), raised hypopharyngeal intrabolus pressure (IBP), reduced UES opening caliber and relaxation time defined UES dysfunction. Sydney Swallow Questionnaire (SSQ) and Swallowing Quality of Life Questionnaire (SWAL-QOL) at before and 1 month after C-POEM measured symptomatic improvement in swallow function. HRPIM was repeated at 1-month follow-up. Results C-POEM was performed without complications in all (n = 8) patients. At 1 month, there was an improvement in both the mean SSQ (from 621.5 to 341.8, mean difference -277.3, 95 %CI [-497.8, -56.7], P  = 0.02) and SWAL-QOL (from 54.9 to 68.3, mean difference 9.1, 95 %CI [0.7, 17.5], P  = 0.037) scores. Repeat HRPIM confirmed a decrease in both the mean UES IRP (13.7 mm Hg to 3.6 mm Hg, mean difference -10.1 mm Hg, 95 %CI [-16.3, -3.9], P  = 0.007) and the mean hypopharyngeal IBP (23.5 mm Hg to 10.4 mm Hg, mean difference -11.3 mm Hg, 95 %CI [-17.2, -5.4], P  = 0.003). Conclusions In dysphagic PD patients with UES dysfunction, C-POEM is feasible and enhances UES relaxation and reduces sphincteric resistance to flow during the swallow, thereby improving dysphagia symptoms.

Regulation of cell proliferation and migration by TAK1 via transcriptional control of von Hippel-Lindau tumor suppressor.

Skin maintenance and healing after wounding requires complex epithelial-mesenchymal interactions purportedly mediated by growth factors and cytokines. We show here that, for wound healing, transforming growth factor-beta-activated kinase 1 (TAK1) in keratinocytes activates von Hippel-Lindau tumor suppressor expression, which in turn represses the expression of platelet-derived growth factor-B (PDGF-B), integrin beta1, and integrin beta5 via inhibition of the Sp1-mediated signaling pathway in the keratinocytes. The reduced production of PDGF-B leads to a paracrine-decreased expression of hepatocyte growth factor in the underlying fibroblasts. This TAK1 regulation of the double paracrine PDGF/hepatocyte growth factor signaling can regulate keratinocyte cell proliferation and is required for proper wound healing. Strikingly, TAK1 deficiency enhances cell migration. TAK1-deficient keratinocytes displayed lamellipodia formation with distinct microspike protrusion, associated with an elevated expression of integrins beta1 and beta5 and sustained activation of cdc42, Rac1, and RhoA. Our findings provide evidence for a novel homeostatic control of keratinocyte proliferation and migration mediated via TAK1 regulation of von Hippel-Lindau tumor suppressor. Dysfunctional regulation of TAK1 may contribute to the pathology of non-healing chronic inflammatory wounds and psoriasis.

Anasarca in Newly Diagnosed Type 1 Diabetes: Review of the Pathophysiology of Insulin Edema.

Insulin edema is a rare complication of insulin therapy that can occur after the initiation of insulin. Various timelines to the initiation of insulin have been reported after insulin therapy. Here, we report the occurrence of generalized edema in a 40-year-old woman early after the initiation of insulin. Significant differentials were excluded and resolution achieved after two weeks with diuretics. We reviewed the current literature and the possible mechanisms behind this phenomenon.

Significant Medical and Surgical Morbidity in Perianal Crohn's Disease: Results from a Territory-Wide Study.

BACKGROUND: The presence of perianal fistulas in Crohn's disease [CD] denotes increased disease aggressiveness. We studied the epidemiology and clinical outcomes of perianal CD [PCD] using the Hong Kong territory-wide IBD Registry [HKIBDR]. METHODS: Consecutive patients with PCD were identified from the HKIBDR, and disease characteristics, treatments, and outcomes were analysed. The risks for medical and surgical therapies were assessed using Kaplan-Meier analysis. RESULTS: Among 981 patients with CD with 10530 patient-years of follow-up, 283 [28.8%] had perianal involvement, of which 120 [42.4%] were as first presentation. The mean age at diagnosis of PCD was 29.1 years, and 78.8% were male. The median follow-up duration was 106 months (interquartile range [IQR]: 65-161 months]. Perianal fistula [84.8%] and perianal abscess [52.7%] were the two commonest forms. Male, younger age at diagnosis of CD, and penetrating phenotypes were associated with development of PCD in multivariate analysis. Of 242 patients with fistulizing PCD, 70 [29.2%] required ≥5 courses of antibiotics, and 98 [40.5%] had ≥2 surgical procedures. Nine patients required defunctioning surgery and 4 required proctectomy. Eighty-four patients [34.7%] received biologics. Cumulative probabilities for use of biologics were 4.7%, 5.8%, and 8.6% at 12 months, 36 months, and 96 months, respectively, while the probabilities for surgery were 67.2%, 71.6%, and 77.7%, respectively. Five mortalities were recorded, including 2 cases of anal cancer, 2 CD-related complications, and one case of pneumonia. CONCLUSION: Over 40% of CD patients presented with perianal disease at diagnosis. Patients with PCD had poor outcome, with young age of onset, multiple antibiotic use, and repeated surgery.

Cancer Risk in 2621 Chinese Patients with Inflammatory Bowel Disease: A Population-based Cohort Study.

BACKGROUND: Studies on cancer risk in inflammatory bowel disease (IBD) have yielded inconsistent results. We conducted a population-based study to determine the risk of cancer in patients with Crohn's disease (CD) and ulcerative colitis (UC). METHODS: Using a territory-wide IBD registry in Hong Kong, we identified 2621 patients with IBD and no history of cancer from 1990 to 2016. We followed them from diagnosis until either September 2016, cancer development, proctocolectomy, or death. Standardized incidence ratios (SIRs) of overall cancer and site-specific cancers were calculated. RESULTS: Of 2621 patients with IBD (1108 CD; 1603 UC; median age, 49 yr; 59.5% men) followed for 26,234 person-years, 88 patients developed cancer after IBD diagnosis. Patients with CD had an increased risk of anorectal cancers (SIR 4.11; 95% confidence interval (CI), 1.84-9.14) and hematological cancers (SIR 3.86, 95% CI, 1.61-9.27) including leukemia (SIR 5.98; 95% CI, 1.93-18.54). Nonmelanoma skin cancer was significantly increased in both CD and UC (CD: SIR 13.88; 95% CI, 1.95-98.51; UC: SIR 9.05; 95% CI, 2.26-36.19). Patients with CD had a higher risk of renal-cell carcinoma (SIR 6.89; 95% CI, 2.22-21.37), and patients with UC had a higher risk of prostate cancer (SIR 2.47; 95% CI, 1.24-4.95). CONCLUSIONS: In a population-based study, Chinese patients with CD are at an increased risk of anorectal cancers and hematological cancers compared with the general population. A higher risk of nonmelanoma skin cancer was also observed in CD and UC. Cancer surveillance should be considered.

The rapid identification of elution conditions for therapeutic antibodies from cation-exchange chromatography resins using high-throughput screening.

Cation-exchange chromatography is widely used in the purification of therapeutic antibodies, wherein parameters such as elution pH and counterion concentration require optimization for individual antibodies across different chromatography resins. With a growing number of antibodies in clinical trials and the pressure to expedite process development, we developed and automated a high-throughput batch-binding screen to more efficiently optimize elution conditions for cation-exchange chromatography resins. The screen maps the binding behavior of antibodies and impurities as a function of pH and counterion concentration in terms of a partition coefficient (Kp). Using this approach, the binding behavior of a library of antibodies was assessed on Poros 50HS and SP Sepharose Fast Flow resins. The diversity in binding behavior between antibodies and across resins translated to the requirement of a variable counterion concentration to elute each antibody. This requirement can be met through the use of a gradient elution. However, a gradient of increasing counterion concentration spans the transition from binding to non-binding for impurities as well as the antibody, resulting in the elution of impurities within the antibody elution peak. Step elution conditions that selectively elute the antibody while retaining impurities on the resin can now be rapidly identified using our high-throughput approach. We demonstrate that by correlating antibody Kp to elution pool volume and yield on packed-bed columns and through the calculation of a separation factor, we can efficiently optimize step elution conditions that maximize impurity clearance and yield for each antibody.

Evaluation of Heavy-Chain C-Terminal Deletion on Product Quality and Pharmacokinetics of Monoclonal Antibodies.

Due to their potential influence on stability, pharmacokinetics, and product consistency, antibody charge variants have attracted considerable attention in the biotechnology industry. Subtle to significant differences in the level of charge variants and new charge variants under various cell culture conditions are often observed during routine manufacturing or process changes and pose a challenge when demonstrating product comparability. To explore potential solutions to control charge heterogeneity, monoclonal antibodies (mAbs) with native, wild-type C-termini, and mutants with C-terminal deletions of either lysine or lysine and glycine were constructed, expressed, purified, and characterized in vitro and in vivo. Analytical and physiological characterization demonstrated that the mAb mutants had greatly reduced levels of basic variants without decreasing antibody biologic activity, structural stability, pharmacokinetics, or subcutaneous bioavailability in rats. This study provides a possible solution to mitigate mAb heterogeneity in C-terminal processing, improve batch-to-batch consistency, and facilitate the comparability study during process changes.