Pediatric to Adult Transition in Inflammatory Bowel Disease: Consensus Guidelines for Australia and New Zealand.

BACKGROUND: The incidence of pediatric inflammatory bowel disease (IBD) is rising, and there is an increasing need to support adolescents when they transition to adult care. Evidence supports the use of a structured transition process but there is great variation across Australasia. The study aim was to develop evidence and expert opinion-based consensus statements to guide transitional care services in IBD. METHODS: A modified UCLA-RAND methodology was employed to develop consensus statements. An IBD expert steering committee was formed and a systematic literature review was conducted to guide the drafting of consensus statements. A multidisciplinary group was formed comprising 16 participants (clinicians, nurses, surgeons, psychologists), who anonymously voted on the appropriateness and necessity of the consensus statements using Likert scales (1 = lowest, 9 = highest) with a median ≥7 required for inclusion. Patient support groups, including direct input from young people with IBD, informed the final recommendations. RESULTS: Fourteen consensus statements were devised with key recommendations including use of a structured transition program and transition coordinator, mental health and transition readiness assessment, key adolescent discussion topics, allied health involvement, age for transition, and recommendations for clinical communication and handover, with individualized patient considerations. Each statement reached median ≥8 for appropriateness, and ≥7 for necessity, in the first voting round, and the results were discussed in an online meeting to refine statements. CONCLUSIONS: A multidisciplinary group devised consensus statements to optimize pediatric to adult transitional care for adolescents with IBD. These guidelines should support improved and standardized delivery of IBD transitional care within Australasia.

Transitional care practices for adolescents with inflammatory bowel disease vary across Australasia, and a need for standardized care has been identified. A multidisciplinary team developed Consensus Guidelines to facilitate standardized transition from the pediatric to adult healthcare setting across Australasia.

Impact of bariatric surgery on cytochrome P 450 enzyme activity.

Bariatric surgeries are becoming more prevalent as obesity rates continue to rise. Being that it is an effective weight-loss procedure, it can induce significant anatomical, physiological, and metabolic alterations, which affect the pharmacokinetics of various medications. Cytochrome (CYP) P450 is a group of enzymes that are primarily responsible for metabolizing most medications. Bariatric surgery may affect CYP activity and consequently alter metabolism of various medications, and the resulting weight loss may influence the metabolism of various drugs. This study investigates the impact of bariatric surgery on which CYP enzymes are affected and their effects medications. Authors of this study did an extensive literature review and research in databases including PubMed and EMBASE. The evidence was gathered for medication efficacy influenced by enzyme fluctuations to advocate for further studies for patients that undergo bariatric surgery. The search was limited to English-language results and is deemed up to date as of September 2023. There are numerous studies that indicated alterations of the CYP enzyme activity, which affects the pharmacokinetics of medications used to treat acute and chronic conditions after bariatric surgery. There are various mechanisms involved in CYP enzyme activity leading to fluctuations and the clearance of medications and subsequently compromising the efficacy and safety of these agents. It is imperative to conduct more prospective randomized control studies with longer duration to guide clinicians on how to manage medications with various CYP activity for patients' post-bariatric surgery.

Human Fc gamma receptor IIIA blockade inhibits platelet destruction in a humanized murine model of ITP.

ABSTRACT: Fc gamma receptor (FcγR) IIIA is an important receptor for immunoglobulin G (IgG) and is involved in immune defense mechanisms as well as tissue destruction in some autoimmune diseases including immune thrombocytopenia (ITP). FcγRIIIA on macrophages can trigger phagocytosis of IgG-sensitized platelets, and prior pilot studies observed blockade of FcγRIIIA increased platelet counts in patients with ITP. Unfortunately, although blockade of FcγRIIIA in patients with ITP increased platelet counts, its engagement by the blocking antibody drove serious adverse inflammatory reactions. These adverse events were postulated to originate from the antibody's Fc and/or bivalent nature. The blockade of human FcγRIIIA in vivo with a monovalent construct lacking an active Fc region has not yet been achieved. To effectively block FcγRIIIA in vivo, we developed a high affinity monovalent single-chain variable fragment (scFv) that can bind and block human FcγRIIIA. This scFv (17C02) was expressed in 3 formats: a monovalent fusion protein with albumin, a 1-armed human IgG1 antibody, and a standard bivalent mouse (IgG2a) antibody. Both monovalent formats were effective in preventing phagocytosis of ITP serum-sensitized human platelets. In vivo studies using FcγR-humanized mice demonstrated that both monovalent therapeutics were also able to increase platelet counts. The monovalent albumin fusion protein did not have adverse event activity as assessed by changes in body temperature, whereas the 1-armed antibody induced some changes in body temperature even though the Fc region function was impaired by the Leu234Ala and Leu235Ala mutations. These data demonstrate that monovalent blockade of human FcγRIIIA in vivo can potentially be a therapeutic strategy for patients with ITP.

Transitional care of adolescents with inflammatory bowel disease to adult services varies widely across Australia and New Zealand.

Background and Aim: Children and adolescents account for approximately 14% of inflammatory bowel disease (IBD) diagnoses. At an appropriate age and level of development adolescents with IBD have their care transferred from the pediatric to adult clinical team during a process termed "transition". The study aim was to survey pediatric gastroenterologists throughout Australasia to identify commonality in the transition process to contribute to standardized guideline development. Methods: A descriptive survey captured key variables: transition clinic format, process and infrastructure, transition assessments, and guidelines. The survey was distributed electronically to 59 Pediatric Gastroenterologists throughout Australasia in January 2023. Results: Seventeen (29%) clinicians completed the survey: Australia 13 (76%). New Zealand 4 (24%). Thirteen (76%) respondents had access to a dedicated IBD transition clinic. Adolescents attended transition clinics 1-7 times, and the main processes transferred were: prescription provision, biologic appointments, and adult team contacts. Transition was first discussed age 13-15 years (53%), or 16-18 years (47%), with the main discussion topics including: continuing adherence (88%), smoking (59%), alcohol use (59%), recreational drug use (59%). Transition readiness assessments were done infrequently (24%). The minority (24%) used formal guidelines to inform the transition process, but 15 (88%) considered the development of a standardized Australasian guideline as beneficial/extremely beneficial. Conclusions: This survey highlighted that transition care for adolescents with IBD is variable across Australasia. Australasian guideline development may optimize the transition process for adolescents with IBD and improve their longitudinal outcomes.

Combining a deep learning model with clinical data better predicts hepatocellular carcinoma behavior following surgery.

Hepatocellular carcinoma (HCC) is among the most common cancers worldwide, and tumor recurrence following liver resection or transplantation is one of the highest contributors to mortality in HCC patients after surgery. Using artificial intelligence (AI), we developed an interdisciplinary model to predict HCC recurrence and patient survival following surgery. We collected whole-slide H&E images, clinical variables, and follow-up data from 300 patients with HCC who underwent transplant and 169 patients who underwent resection at the Cleveland Clinic. A deep learning model was trained to predict recurrence-free survival (RFS) and disease-specific survival (DSS) from the H&E-stained slides. Repeated cross-validation splits were used to compute robust C-index estimates, and the results were compared to those obtained by fitting a Cox proportional hazard model using only clinical variables. While the deep learning model alone was predictive of recurrence and survival among patients in both cohorts, integrating the clinical and histologic models significantly increased the C-index in each cohort. In every subgroup analyzed, we found that a combined clinical and deep learning model better predicted post-surgical outcome in HCC patients compared to either approach independently.

Return to sports following discectomy: does a consensus exist?

INTRODUCTION: In the USA, lumbar discectomy is one of the most commonly performed spinal procedures. As certain sports are considered to be major risk factors for disc herniation, the question remains as to when highly active patients should return to their previous level of activity. This study aimed to analyze spine surgeons' opinions on when patients may return to activities following discectomy as well as their underlying rationale for their decision. METHODS: A questionnaire was designed by five different fellowship-trained spine surgeons for the 168 members of the Spine Society of Australia. Questions on the surgeons experience, decision making, preferred surgical technique, the postoperative rehabilitation and the response to patient expectations were included. RESULTS: In total, 83.9% of surgeons discuss the postoperative level of activity with their patients. Sport is considered as an important contributor for good functional outcome by 71.0% of surgeons. Surgeons recommend avoiding, often permanently, weightlifting (35.7%) of the time, rugby (21.4%), horseback riding (17.9%) as well as martial arts (14.3%) postoperatively even with previous training. The return to high levels of activity is considered as a major risk factor for disc herniation recurrence by 25.8% of surgeons. Return to high level of activity is typically recommended after 3 months by 48.4% of surgeons. CONCLUSION: So far no consensus on the rehabilitation protocol and return to level of activity exists. Recommendations depend on personal experience as well as the individuals' training, and typically, a period of avoidance of sport for up to 3 months is recommended. LEVEL OF EVIDENCE: Level III, therapeutic and prognostic study.

A suite of selective pressures supports the maintenance of alleles of a Drosophila immune peptide.

The innate immune system provides hosts with a crucial first line of defense against pathogens. While immune genes are often among the fastest evolving genes in the genome, in Drosophila, antimicrobial peptides (AMPs) are notable exceptions. Instead, AMPs may be under balancing selection, such that over evolutionary timescales multiple alleles are maintained in populations. In this study, we focus on the Drosophila antimicrobial peptide Diptericin A, which has a segregating amino acid polymorphism associated with differential survival after infection with the Gram-negative bacteria Providencia rettgeri. Diptericin A also helps control opportunistic gut infections by common Drosophila gut microbes, especially those of Lactobacillus plantarum. In addition to genotypic effects on gut immunity, we also see strong sex-specific effects that are most prominent in flies without functional diptericin A. To further characterize differences in microbiomes between different diptericin genotypes, we used 16S metagenomics to look at the microbiome composition. We used both lab reared and wild caught flies for our sequencing and looked at overall composition as well as the differential abundance of individual bacterial families. Overall, we find flies that are homozygous serine for diptericin A are better equipped to survive a systemic infection from P. rettgeri, but in general homozygous arginine flies have a longer lifespan after being fed common gut commensals. Our results suggest a possible mechanism for the maintenance of genetic variation of diptericin A through the complex interactions of sex, systemic immunity, and the maintenance of the gut microbiome.

Positive Bubble Study But No Evidence of Interatrial Defect in a Patient with Recurrent Cryptogenic Stroke.

Pulmonary arteriovenous malformations (PAVMs) can be asymptomatic or result in a range of complications such as brain abscesses or cryptogenic emboli, which can contribute to morbidity and mortality if not diagnosed and treated in a timely manner. To date, there have been several reports of delayed diagnosis of PAVMs, which have been largely attributed to the misconception that PAVMs are too rare to be of clinical significance. Furthermore, because intracardiac shunting secondary to a patent foramen ovale (PFO) or atrial septal defect (ASD) also results in a positive saline contrast study with echocardiography, PAVM can be easily misdiagnosed as an intracardiac right-toleft shunt. However, there are unique echocardiographic features that differentiate between intracardiac shunting due to a PFO or ASD and extracardiac shunting such as in PAVM. This case details the course of a patient with recurrent cryptogenic strokes that was initially misattributed to a PFO and was only correctly diagnosed with multiple PAVMs after two failed attempts at PFO closure. This case serves as a reminder of an alternative etiology of right-to-left shunt and its presentation on imaging, which echocardiographers must be familiar with.

Effects of bariatric surgery on drug pharmacokinetics-Preclinical studies.

With the rising worldwide obesity rates, bariatric surgeries are increasing. Although the surgery offers an effective treatment option for weight loss, the procedure causes dramatic physiological and metabolic changes. Animal models in rodents provide a valuable tool for studying the systemic effects of the surgery. Since the surgery may significantly influence the pharmacokinetic properties of medications, animal studies should provide essential insight into mechanisms underlying changes in how the body handles the drug. This review summarizes research work in rodents regarding the impact of standard bariatric procedures on pharmacokinetics. A qualitative literature search was conducted via PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL), and EMBASE. Studies that examined bariatric surgery's effects on drug pharmacokinetics in rodent models were included. Clinical studies and studies not involving drug interventions were excluded. A total of 15 studies were identified and assessed in this review. These studies demonstrate the possible impact of bariatric surgery on drug absorption, distribution, metabolism, excretion, and potential mechanisms. Pharmacokinetic changes exhibited in the limited pre-clinical studies highlight a need for further investigation to fully understand the impact and mechanism of bariatric surgery on drug responses.

Colonic Epstein-Barr Virus-Associated Mucocutaneous Ulcer Associated With Ulcerative Colitis.

Epstein-Barr virus-associated mucocutaneous ulcer is a rare lymphoproliferative disorder that occurs in immunosuppressed states that can develop in the gastrointestinal tract and mimic inflammatory bowel disease or other malignancies. We present the case of a 61-year-old man who presented with concurrent acute severe ulcerative colitis and colonic Epstein-Barr virus-associated mucocutaneous ulcer requiring rituximab therapy and a subtotal colectomy.

An obscure cause of gastrointestinal bleeding: Recurrent duodenal variceal hemorrhage treated with intramuscular octreotide in the absence of portal hypertension.

Duodenal varices (DVs) are ectopic gastrointestinal varices (ECVs) associated with portal hypertension (PH). We present the case of an 82-year-old woman who presented with symptomatic anemia secondary to DV hemorrhage diagnosed on oesophagogastroduodenoscopy. This lesion was treated with endoscopic adrenaline injection and clip application. The patient re-presented on multiple occasions with bleeding recurrence localized to the duodenum, which was managed with intramuscular octreotide and oral beta-blockade resulting in sustained remission of bleeding. This case highlights a rare cause of upper gastrointestinal hemorrhage and highlights the value of somatostatin analogues for conservative treatment of DVs.

Objective Sleep Quality and the Underlying Functional Neural Correlates Among Older Adults with Possible Mild Cognitive Impairment.

BACKGROUND: Poor sleep quality is common among older individuals with mild cognitive impairment (MCI) and may be a consequence of functional alterations in the brain; yet few studies have investigated the underlying neural correlates of actigraphy-measured sleep quality in this cohort. OBJECTIVE: The objective of this study was to examine the relationship between brain networks and sleep quality measured by actigraphy. METHODS: In this cross-sectional analysis, sleep efficiency and sleep fragmentation were estimated using Motionwatch8 (MW8) over a period of 14 days in 36 community-dwelling older adults with possible MCI aged 65-85 years. All 36 participants underwent resting-state functional magnetic resonance imaging (fMRI) scanning. Independent associations between network connectivity and MW8 measures of sleep quality were determined using general linear modeling via FSL. Networks examined included the somatosensory network (SMN), frontoparietal network (FPN), and default mode network (DMN). RESULTS: Across the 36 participants (mean age 71.8 years; SD = 5.2 years), mean Montreal Cognitive Assessment score was 22.5 (SD = 2.7) and Mini-Mental State Examination score was 28.3 (SD = 1.5). Mean sleep efficiency and fragmentation index was 80.1% (SD = 10.0) and 31.8 (SD = 10.4) respectively. Higher sleep fragmentation was significantly correlated with increased connectivity between the SMN and insula, the SMN and posterior cingulate, as well as FPN and primary motor area (FDR-corrected, p < 0.004). CONCLUSION: Functional connectivity between brain regions involved in attentional and somatosensory processes may be associated with disrupted sleep in older adults with MCI.

Impact of cytochrome P450 2D6 polymorphisms on decision-making and clinical outcomes in adjuvant hormonal therapy for breast cancer.

BACKGROUND: There are concerns that tamoxifen is less effective in Asian women because of the high prevalence of impaired function cytochrome P450 2D6 (CYP2D6) polymor-phisms. AIM: To evaluate how knowledge of CYP2D6 genotype impacted the choice of hormonal agent and how CYP2D6 genotype and agent were associated with clinical outcomes. METHODS: Eighty-two women were recruited. Seventy-eight completed CYP2D6 genotyping and were categorized into poor, intermediate (IM) and extensive or ultra metabolizer phenotypes. Women with poor metabolizer and IM phenotypes were recommended aromatase inhibitors as the preferred agent. RESULTS: More than 70% of the women had an IM phenotype, 32% an extensive or ultra metabolizer phenotype, and 0% had a poor metabolizer phenotype. Regardless of genotype, more women opted for aromatase inhibitors. Overall, 80% of women completed 5 years of hormonal therapy. Five women developed recurrence, 3 contralateral breast cancer, 5 died, and 1 was diagnosed with a second primary cancer. Five-year recurrence-free and overall survival were slightly better in women with the extensive or ultra metabolizer phenotype compared to those with the IM phenotype, though not statistically significant [P = 0.743, hazard ratio (HR): 1.441, 95% confidence interval (CI): 0.191 to 10.17 and P = 0.798, HR: 1.327, 95%CI: 0.172 to 9.915, respectively]. Women receiving aromatase inhibitors also appeared to have a better, but also nonsignificant, 5-year recurrence-free and overall survival (P = 0.253, HR: 0.368, 95%CI: 0.031 to 0.258 and P = 0.292, HR: 0.252, 95%CI: 0.005 to 4.951, respectively). CONCLUSION: The IM phenotype was highly prevalent but was not associated with clinical outcome.

The association of sleep and cortical thickness in mild cognitive impairment.

We investigated whether device-measured sleep parameters are associated with cortical thickness in older adults with probable mild cognitive impairment (MCI). We performed a cross-sectional, exploratory analysis of sleep and structural MRI data. Sleep data were collected with MotionWatch8© actigraphy over 7 days. We computed average and variability for sleep duration, sleep efficiency, and fragmentation index. T1-weighted MRI scans were used to measure cortical thickness in FreeSurfer. We employed surface-based analysis to determine the association between sleep measures and cortical thickness, adjusting for age, sex, Montreal Cognitive Assessment (MoCA) score, and sleep medication use. Our sample included 113 participants (age = 73.1 [5.7], female = 72 [63.7 %]). Higher fragmentation index variability predicted lower cortical thickness in the left superior frontal gyrus (cluster size = 970.9 mm2, cluster-wise p = 0.017, cortical thickness range = 2.1 mm2 to 3.0 mm2), adjusting for age, sex, MoCA, and sleep medication. Our results suggest that higher variability in sleep fragmentation, an indicator of irregular sleep pattern, is linked to lower cortical thickness. Future longitudinal studies are needed to determine the directionality of these associations.

Spinal extradural arachnoid cyst: A rare cause of thoracic myelopathy.

A spinal extradural arachnoid cyst (SEAC) is a rare condition which can lead to back pain, radiculopathy, and compressive myelopathy. It accounts for approximately 1% of spinal tumours. The exact aetiology of SEACs is not well understood; however, this study is supportive of a traumatic aetiology of this disease in addition to supporting a uni-directional valve as a mechanism of CSF accumulation. The purpose of this study is to review the presentation, work-up, treatment and postoperative course of a patient with SEAC. We present the case of a 40-year-old male with a history of trauma who developed a SEAC and was treated surgically at our unit. Although a rare disease, we highlight the importance of early diagnosis and surgical treatment as it is a surgically curable disease with a good postoperative prognosis.

Can Contrast-Enhanced Spectral Mammography (CESM) Reduce Benign Breast Biopsy?

Objectives: To evaluate the potential of contrast-enhanced spectral mammography (CESM) in reducing benign breast biopsy rate, thereby improving resource utilization. To explore its potential as a value-adding modality in the management of BI-RADS 4/5 lesions. Materials and Methods: This was a prospective study conducted between July 2016 and September 2018. Patients with BI-RADS 4/5 lesions detected on conventional imaging (mammogram, digital breast tomosynthesis, and ultrasound) were enrolled for adjunct CESM. Histopathologic correlation was done for all lesions. Additional suspicious lesions detected on CESM were all identified on second-look ultrasound and subsequently biopsied. Images were evaluated independently by two radiologists trained in breast imaging using BI-RADS classification. Presence of enhancement on CESM, BI-RADS score, and histopathology of each lesion were analyzed and tested with the chi-square/fisher-exact test for statistical significance. Results: The study included 105 lesions in 63 participants-1 man and 62 women, an average age of 53.7 ± 10.8 years. On CESM, 22 (20.9%) of the lesions did not show enhancement. All 22 lesions had been classified as BI-RADS 4A and were subsequently proven to be benign. Of the remaining 83 enhancing lesions, 54 (65.1%) were malignant and 29 (34.9%) were benign (p < 0.05). CESM detected 6 additional lesions which were not identified on initial conventional imaging. Four of these were proven malignant and were in a different quadrant than the primary lesion investigated. Conclusion: There is evidence that the absence of enhancement in CESM strongly favors benignity. It may provide the reporting radiologist with greater confidence in imaging assessment, especially in BI-RADS 4A cases, where a proportion of them are in actuality BI-RADS 3. Greater accuracy of BI-RADS grading can reduce nearly half of benign biopsies and allow better resource allocation. CESM also increases the detection rate of potentially malignant lesions, thereby changing the treatment strategies.

Association between Breast Cancer Polygenic Risk Score and Chemotherapy-Induced Febrile Neutropenia: Null Results.

BACKGROUND: The hypothesis that breast cancer (BC) susceptibility variants are linked to chemotherapy-induced toxicity has been previously explored. Here, we investigated the association between a validated 313-marker-based BC polygenic risk score (PRS) and chemotherapy-induced neutropenia without fever and febrile neutropenia (FNc) in Asian BC patients. METHODS: This observational case-control study of Asian BC patients treated with chemotherapy included 161 FNc patients, 219 neutropenia patients, and 936 patients who did not develop neutropenia. A continuous PRS was calculated by summing weighted risk alleles associated with overall, estrogen receptor- (ER-) positive, and ER-negative BC risk. PRS distributions neutropenia or FNc cases were compared to controls who did not develop neutropenia using two-sample t-tests. Odds ratios (OR) and corresponding 95% confidence intervals were estimated for the associations between PRS (quartiles and per standard deviation (SD) increase) and neutropenia-related outcomes compared to controls. RESULTS: PRS distributions were not significantly different in any of the comparisons. Higher PRSoverall quartiles were negatively correlated with neutropenia or FNc. However, the associations were not statistically significant (PRS per SD increase OR neutropenia: 0.91 [0.79-1.06]; FNc: 0.87 [0.73-1.03]). No dose-dependent trend was observed for the ER-positive weighted PRS (PRSER-pos) and ER-negative weighted PRS (PRSER-neg). CONCLUSION: BC PRS was not strongly associated with chemotherapy-induced neutropenia or FNc.

Juvenile muscular atrophy of the distal upper extremity (Hirayama syndrome): a systematic review.

INTRODUCTION: Hirayama syndrome is likely caused by a forward displacement of the posterior dura during cervical flexion leading to changes in the muscles of the fingers and wrist. The aim of this systematic review was to document the number of reported cases, the necessity of dynamic MRI of the cervical spine and the subsequent treatment. METHODS AND MATERIALS: A systematic review was conducted and the Pubmed/Medbase, Cochrane, Google, Embase and Ovid database were searched for (Hirayama) AND ((disease) OR (syndrome)). A total of 42 studies were included for analysis reporting 2311 patients. RESULTS: The mean age was 20.2 ± 2.26 years and predominantly males (92.8%) were identified. On MRI the "snake eyes" appearance of the spinal cord was present in 27.8% and the typical time between onset of symptoms and diagnosis was 41.5 ± 16.4 months. A variety of different treatments have been reported, although there is no substantial evidence that any of them are superior to observation. CONCLUSION: The delay in diagnosis from initial presentation of symptoms shows that this condition may be underdiagnosed in a variety of cases. Further, this study shows the necessity of either a dynamic MRI in flexion or a static MRI scan in neutral position and in flexion, to identify functional spinal and/or foraminal stenosis for a prompt diagnosis and subsequent treatment.