Deliberate foreign body ingestion in patients with underlying mental illness: A retrospective multicentre study.

OBJECTIVE: Deliberate foreign body ingestion (DFBI) is characterised by recurrent presentations among patients with mental health conditions, intellectual disabilities and in prisoners. We aimed to profile the characteristics and evaluate the care of such patients in this study. METHODS: Adult patients with an endoscopic record of attempted foreign body retrieval between January 2013 and September 2020 were identified at three Australian hospitals. Those with a documented mental health diagnosis were included and their standard medical records reviewed. Presentation history, demographics, comorbidities and endoscopic findings were recorded and described. RESULTS: A total of 166 admissions were accounted for by 35 patients, 2/3 of which had borderline personality disorder (BPD). Repetitive presentations occurred in more than half of the cohort. There was an increased trend of hospital admissions throughout the years. At least half of the cohort had a documented mental health review during their admission. An average of 3.3 (2.9) foreign bodies were ingested per single episode. Endoscopic intervention was performed in 76.5% of incidents. The combined Length of stay for all patients was 680 days. CONCLUSION: Deliberate foreign body ingestion in mental health patients is a common, recurring and challenging problem that is increasing in frequency and requires collaborative research to further guide holistic management.

Syk inhibitors interfere with erythrocyte membrane modification during P falciparum growth and suppress parasite egress.

Band 3 (also known as the anion exchanger, SLCA1, AE1) constitutes the major attachment site of the spectrin-based cytoskeleton to the erythrocyte's lipid bilayer and thereby contributes critically to the stability of the red cell membrane. During the intraerythrocytic stage of Plasmodium falciparum's lifecycle, band 3 becomes tyrosine phosphorylated in response to oxidative stress, leading to a decrease in its affinity for the spectrin/actin cytoskeleton and causing global membrane destabilization. Because this membrane weakening is hypothesized to facilitate parasite egress and the consequent dissemination of released merozoites throughout the bloodstream, we decided to explore which tyrosine kinase inhibitors might block the kinase-induced membrane destabilization. We demonstrate here that multiple Syk kinase inhibitors both prevent parasite-induced band 3 tyrosine phosphorylation and inhibit parasite-promoted membrane destabilization. We also show that the same Syk kinase inhibitors suppress merozoite egress near the end of the parasite's intraerythrocytic lifecycle. Because the entrapped merozoites die when prevented from escaping their host erythrocytes and because some Syk inhibitors have displayed long-term safety in human clinical trials, we suggest Syk kinase inhibitors constitute a promising class of antimalarial drugs that can suppress parasitemia by inhibiting a host target that cannot be mutated by the parasite to evolve drug resistance.

Real-world outcomes of unrestricted direct-acting antiviral treatment for hepatitis C in Australia: The South Australian statewide experience.

In March 2016, the Australian government offered unrestricted access to direct-acting antiviral (DAA) therapy for chronic hepatitis C virus (HCV) to the entire population. This included prescription by any medical practitioner in consultation with specialists until sufficient experience was attained. We sought to determine the outcomes and experience over the first twelve months for the entire state of South Australia. We performed a prospective, observational study following outcomes of all treatments associated with the state's four main tertiary centres. A total of 1909 subjects initiating DAA therapy were included, representing an estimated 90% of all treatments in the state. Overall, SVR12 was 80.4% in all subjects intended for treatment and 95.7% in those completing treatment and follow-up. 14.2% were lost to follow-up (LTFU) and did not complete SVR12 testing. LTFU was independently associated with community treatment via remote consultation (OR 1.50, 95% CI 1.04-2.18, P = .03), prison-based treatment (OR 2.02, 95% CI 1.08-3.79, P = .03) and younger age (OR 0.98, 95% CI 0.97-0.99, P = .05). Of the 1534 subjects completing treatment and follow-up, decreased likelihood of SVR12 was associated with genotype 2 (OR 0.23, 95% CI 0.07-0.74, P = .01) and genotype 3 (OR 0.23, 95% CI 0.12-0.43, P ≤ .01). A significant decrease in treatment initiation was observed over the twelve-month period in conjunction with a shift from hospital to community-based treatment. Our findings support the high responses observed in clinical trials; however, a significant gap exists in SVR12 in our real-world cohort due to LTFU. A declining treatment initiation rate and shift to community-based treatment highlight the need to explore additional strategies to identify, treat and follow-up remaining patients in order to achieve elimination targets.

Longitudinal growth and health outcomes in nutritionally at-risk children who received long-term nutritional intervention.

BACKGROUND: The benefits of short-term oral nutritional supplementation (ONS) in undernourished children are well-established. The benefits of long-term ONS in promoting longitudinal growth and health in children who are at risk of undernutrition have not been reported previously. METHODS: In this 48-week prospective, single-arm, multicentre trial, 200 Filipino children aged 3-4 years with weight-for-height percentiles from 5th to 25th (WHO Child Growth Standards) were enrolled. Parents received dietary counselling at baseline, and at weeks 4 and 8. Two servings of ONS (450 mL) were consumed daily, providing 450 kcal, 13.5 g protein and micronutrients. Weight, height, dietary intake using 24-h dietary recalls, and physical activity and appetite using the visual analogue scales were assessed at baseline and weeks 4, 8, 16, 24, 32, 40 and 48. The number of sick days for acute illnesses was collected over the study period. RESULTS: At baseline, mean age was 41.2 months with 50% being male. Weight-for-height percentiles showed the greatest increase in the first 4 weeks (12.1 and 12.8 percentiles, respectively, P < 0.0001) and remained significantly higher than baseline (P < 0.0001) but were relatively stable from week 4 onwards. Height-for-age percentiles increased steadily over time and became significantly higher than baseline from week 24 onwards (P < 0.0001). Appetite and physical activity scores at all post-baseline visits improved from baseline (P < 0.0001), and a reduction in the number of sick days from week 16 onwards was also observed (P < 0.0001). Higher parental education level, being male and higher baseline weight-for-height percentiles were significantly associated with higher ponderal and linear growth over time in repeated measures analysis of covariance. CONCLUSIONS: Intervention consisting of initial dietary counselling and continued ONS helped sustain normal growth after a catch-up growth in nutritionally at-risk children.

Effects of oral nutritional supplementation in the management of malnutrition in hospital and post-hospital discharged patients in India: a randomised, open-label, controlled trial.

BACKGROUND: Hospital malnutrition is a significant problem that still remains under-recognised and under-treated in India. The present study assessed the effects of oral nutritional supplementation (ONS) in conjunction with dietary counselling versus dietary counselling (control) alone in malnourished patients when given in hospital and post-hospital discharge. METHODS: The present study was conducted in nine private and four public hospitals. Patients from various medical wards were screened for malnutrition using modified Subjective Global Assessment (mSGA) and randomised to control (n = 106) or ONS (n = 106) for 12 weeks. Two servings (460 mL) of ONS were prescribed daily, providing 432 kcal, 16 g of protein and 28 micronutrients. The primary outcome was weight gain over 12 weeks. Other outcomes included change in body mass index (BMI), serum pre-albumin, albumin and C-reactive protein levels, energy and nutrient intakes, and handgrip strength at weeks 4, 8 and 12, as well as mSGA score at week 12. RESULTS: The mean age of patients was 39 years. Fifty-five percent were males and 90.3% were moderately malnourished (mSGA score B) at baseline. At week 12, ONS significantly improved certain parameters compared to control: weight (2.0 versus 0.9 kg; P < 0.001), BMI (0.76 versus 0.37 kg m(-2) ; P < 0.001) and energy intake per day (560 versus 230 kcal; P < 0.05). There were no differences in biochemical parameters and mSGA score between groups. Additionally, patients on ONS who were more functionally impaired at baseline had significantly greater weight gain and improved handgrip strength scores than controls. CONCLUSIONS: ONS use throughout hospital stay and post-hospital discharge significantly improved energy intake and weight in malnourished Indian patients. Those patients with poorer functional status at baseline demonstrated the most benefit.

Nuclear localization or inclusion body formation of ataxin-2 are not necessary for SCA2 pathogenesis in mouse or human.

Instability of CAG DNA trinucleotide repeats is the mutational mechanism for several neurodegenerative diseases resulting in the expansion of a polyglutamine (polyQ) tract. Proteins with long polyQ tracts have an increased tendency to aggregate, often as truncated fragments forming ubiquitinated intranuclear inclusion bodies. We examined whether similar features define spinocerebellar ataxia type 2 (SCA2) pathogenesis using cultured cells, human brains and transgenic mouse lines. In SCA2 brains, we found cytoplasmic, but not nuclear, microaggregates. Mice expressing ataxin-2 with Q58 showed progressive functional deficits accompanied by loss of the Purkinje cell dendritic arbor and finally loss of Purkinje cells. Despite similar functional deficits and anatomical changes observed in ataxin-1[Q80] transgenic lines, ataxin-2[Q58] remained cytoplasmic without detectable ubiquitination.

Neurofibromatosis 2 tumour suppressor schwannomin interacts with betaII-spectrin.

NF2 is the most commonly mutated gene in benign tumours of the human nervous system. The NF2 protein, called schwannomin or merlin, is absent in virtually all schwannomas, and many meningiomas and ependymomas. Using the yeast two-hybrid system, we identified betaII-spectrin (also known as fodrin) as a schwannomin-binding protein. Interaction occurred between the carboxy-terminal domain of schwannomin isoform 2 and the ankyrin-binding region of betaII-spectrin. Isoform 1 of schwannomin, in contrast, interacted weakly with betaII-spectrin, presumably because of its strong self-interaction. Thus, alternative splicing of NF2 may regulate betaII-spectrin binding. Schwannomin co-immunoprecipitated with betaII-spectrin at physiological concentrations. The two proteins interacted in vitro and co-localized in several target tissues and in STS26T cells. Three naturally occurring NF2 missense mutations showed reduced, but not absent, betaII-spectrin binding, suggesting an explanation for the milder phenotypes seen in patients with missense mutations. STS26T cells treated with NF2 antisense oligonucleotides showed alterations of the actin cytoskeleton. Schwannomin itself lacks the actin binding sites found in ezrin, radixin and moesin, suggesting that signalling to the actin cytoskeleton occurs via actin-binding sites on betaII-spectrin. Thus, schwannomin is a tumour suppressor directly involved in actin-cytoskeleton organization, which suggests that alterations in the cytoskeleton are an early event in the pathogenesis of some tumour types.

Learning deficits, but normal development and tumor predisposition, in mice lacking exon 23a of Nf1.

Neurofibromatosis type 1 (NF1) is a commonly inherited autosomal dominant disorder. Previous studies indicated that mice homozygous for a null mutation in Nf1 exhibit mid-gestation lethality, whereas heterozygous mice have an increased predisposition to tumors and learning impairments. Here we show that mice lacking the alternatively spliced exon 23a, which modifies the GTPase-activating protein (GAP) domain of Nf1, are viable and physically normal, and do not have an increased tumor predisposition, but show specific learning impairments. Our findings have implications for the development of a treatment for the learning disabilities associated with NF1 and indicate that the GAP domain of NF1 modulates learning and memory.

Robotic iliopubic tract (r-IPT) repair: technique and preliminary outcomes of a minimally invasive tissue repair for inguinal hernia.

PURPOSE: The iliopubic tract repair was first introduced by Nyhus in 1959, as an open non-mesh posterior preperitoneal repair for inguinal hernia. We have adapted this repair using a robotic approach to offer a minimally invasive (MIS) non-mesh inguinal hernia repair, termed the robotic iliopubic tract (r-IPT) repair. The aim of this pilot study is to evaluate the safety and effectiveness of this new technique. METHODS: Starting in 2015, patients were enrolled in a Phase I trial of r-IPT repair. Inclusion criteria included low-risk patients with small inguinal hernias. Using a robotic TAPP approach, the direct and/or indirect defects were repaired by approximating the transversalis arch to the iliopubic tract. This trial was then expanded in Phase II to include a wider range of patients. Outcomes were collected prospectively. RESULTS: Twenty-four inguinal hernias were repaired in 13 patients via r-IPT as outpatients. Patients were followed for a mean of 24.9 months (range 2.7-55.3, median 24). There were no surgical site occurrences and no recurrences. One (7.7%) patient had acute post-operative genital branch neuralgia, which self-resolved. One (7.7%) patient has chronic pain. CONCLUSION: The Nyhus-inspired robotic iliopubic tract (r-IPT) repair is an MIS approach to provide a non-mesh repair in inguinal hernia. The repair is safe with acceptable preliminary outcomes in low-risk patients. We propose the r-IPT repair to be a MIS option for non-mesh inguinal hernia repair in low-risk patients.

Correlation of serum protein biomarkers with disease activity in psoriatic arthritis.

Objective: To assess the correlation of serum protein biomarkers with disease activity across different domains of psoriatic arthritis (PsA).Material and methods: A cross-sectional cohort of 45 adult patients with PsA fulfilling the classification for psoriatic arthritis (CASPAR) criteria was recruited from University of California San Diego (UCSD) Arthritis Clinics. Clinical data and serum samples were collected and serum was analyzed for protein biomarkers hypothesized to be relevant to disease activity in PsA. Correlations were evaluated for clinical disease activity measures across disease domains.Results: Biomarkers with the highest correlation to the composite indices and disease domains were SAA, IL-6, YKL-40, and ICAM-1. In addition, several biomarkers were moderately correlated with individual composite indices and/or disease domains. Low or no correlation was observed with some biomarkers, e.g. MMP-3, MMP-1, EGF, VEGF, and IL-6R. In contrast, the correlation of all biomarkers with certain disease domains was low; specifically, pain, percent body surface area of psoriasis, and patient global assessment. The multi-biomarker disease activity score (MBDA) developed for rheumatoid arthritis (RA) showed high correlations with most composite indices and some disease domains in PsA.Conclusions: These data suggest biomarker analysis can reflect disease activity across disease domains in PsA. Certain domains would likely benefit from the evaluation of additional biomarkers.

Durable targeting of B-lymphocytes in living mice.

Transfer to and enduring expression of genes in B cells has proved a vexing challenge. We report here a novel method for the specific and durable targeting of B lymphocytes in living mice. The method involves generation of lentiviruses pseudotyped with an anti-CD19 antibody. CD19 targeting viruses injected in the spleen of living mice efficiently transduced B cells and plasma cells detected by flow cytometry analysis of GFP expression. Expression of the reporter gene could be detected in the intact animal by external imaging for more than a year and was enhanced by booster immunization. Our method thus enables the specific delivery, expression and localization by external imaging of exogenous genes to the B cells and plasma cells of living individuals.

Whole-exome sequencing of cell-free DNA and circulating tumor cells in multiple myeloma.

Liquid biopsies including circulating tumor cells (CTCs) and cell-free DNA (cfDNA) have enabled minimally invasive characterization of many cancers, but are rarely analyzed together. Understanding the detectability and genomic concordance of CTCs and cfDNA may inform their use in guiding cancer precision medicine. Here, we report the detectability of cfDNA and CTCs in blood samples from 107 and 56 patients with multiple myeloma (MM), respectively. Using ultra-low pass whole-genome sequencing, we find both tumor fractions correlate with disease progression. Applying whole-exome sequencing (WES) to cfDNA, CTCs, and matched tumor biopsies, we find concordance in clonal somatic mutations (~99%) and copy number alterations (~81%) between liquid and tumor biopsies. Importantly, analyzing CTCs and cfDNA together enables cross-validation of mutations, uncovers mutations exclusive to either CTCs or cfDNA, and allows blood-based tumor profiling in a greater fraction of patients. Our study demonstrates the utility of analyzing both CTCs and cfDNA in MM.

Genetic factors in lipoprotein metabolism. Analysis of a genetic cross between inbred mouse strains NZB/BINJ and SM/J using a complete linkage map approach.

A genetic cross was constructed from two parental inbred strains of mice, NZB/BINJ and SM/J, which differ markedly in their plasma lipoprotein levels. Plasma lipid and apolipoprotein values were measured in 184 F2 progeny on a normal chow diet and on an atherogenic diet. Genetic markers were typed at 126 loci spanning all chromosomes except the Y. Statistical analysis revealed significant linkage or suggestive linkage of lipoprotein levels with markers on a number of chromosomes. Chromosome 1 markers were linked to levels of total cholesterol (lod 5.9) and high density lipoprotein (HDL) cholesterol (lod 8.1), chromosome 5 markers were linked to levels of total cholesterol (lod 6.7) and HDL cholesterol (lod 5.6), and chromosome 7 markers were linked to levels of total plasma triglycerides (lod 5.1) and free fatty acids (lod 5.6). Plasma apoAII levels were linked to the apoAII gene (lod score 19.6) and were highly correlated with plasma HDL cholesterol levels (r = 0.63, P = 0.0001), indicating that apoAII expression influences HDL cholesterol levels. Molecular studies suggested that structural differences in the apoAII polypeptide of the two strains may contribute to differences in clearance of the protein.

Transgenic mice expressing high levels of human apolipoprotein B develop severe atherosclerotic lesions in response to a high-fat diet.

We previously generated transgenic mice expressing human apolipoprotein (apo-) B and demonstrated that the plasma of chow-fed transgenic animals contained markedly increased amounts of LDL (Linton, M. F., R. V. Farese, Jr., G. Chiesa, D. S. Grass, P. Chin, R. E. Hammer, H. H. Hobbs, and S. G. Young 1992. J. Clin. Invest. 92:3029-3037). In this study, we fed groups of transgenic and nontransgenic mice either a chow diet or a diet high in fat (16%) and cholesterol (1.25%). Lipid and lipoprotein levels were assessed, and after 18 wk of diet, the extent of aortic atherosclerotic lesions in each group of animals was quantified. Compared with the female transgenic mice on the chow diet, female transgenic mice on the high-fat diet had higher plasma levels of cholesterol (312 +/- 17 vs 144 +/- 7 mg/dl; P < 0.0001) and human apo-B (120 +/- 8 vs 84 +/- 3 mg/dl; P < 0.0001). The higher human apo-B levels were due to increased plasma levels of human apo-B48; the human apo-B100 levels did not differ in animals on the two diets. In mice on the high-fat diet, most of the human apo-B48 and apo-B100 was found in LDL-sized particles. Compared with nontransgenic mice on the high-fat diet, the transgenic animals on the high-fat diet had significantly increased levels of total cholesterol (312 +/- 17 vs 230 +/- 19 mg/dl; P < 0.0001) and non-HDL cholesterol (283 +/- 17 vs 193 +/- 19 mg/dl; P < 0.0001). The extent of atherosclerotic lesion development within the ascending aorta was quantified by measuring total lesion area in 60 progressive sections, using computer-assisted image analysis. Neither the chow-fed transgenic mice nor the chow-fed nontransgenic mice had significant atherosclerotic lesions. Nontransgenic animals on the high-fat diet had relatively small atherosclerotic lesions (< 15,000 microns 2/section), almost all of which were confined to the proximal 400 microns of the aorta near the aortic valve. In contrast, transgenic animals on the high-fat diet had extensive atherosclerotic lesions (> 160,000 microns 2/section) that were widely distributed throughout the proximal 1,200 microns of the aorta. Thus, human apo-B expression, in the setting of a diet rich in fats, causes severe atherosclerosis in mice.

Identification of an obesity quantitative trait locus on mouse chromosome 2 and evidence of linkage to body fat and insulin on the human homologous region 20q.

Chromosomal synteny between the mouse model and humans was used to map a gene for the complex trait of obesity. Analysis of NZB/BINJ x SM/J intercross mice located a quantitative trait locus (QTL) for obesity on distal mouse chromosome 2, in a region syntenic with a large region of human chromosome 20, showing linkage to percent body fat (likelihood of the odds [LOD] score 3.6) and fat mass (LOD score 4.3). The QTL was confirmed in a congenic mouse strain. To test whether the QTL contributes to human obesity, we studied linkage between markers located within a 52-cM region extending from 20p12 to 20q13.3 and measures of obesity in 650 French Canadian subjects from 152 pedigrees participating in the Quebec Family Study. Sib-pair analysis based on a maximum of 258 sib pairs revealed suggestive linkages between the percentage of body fat (P < 0.004), body mass index (P < 0.008), and fasting insulin (P < 0.0005) and a locus extending approximately from ADA (the adenosine deaminase gene) to MC3R (the melanocortin 3 receptor gene). These data provide evidence that a locus on human chromosome 20q contributes to body fat and insulin in a human population, and demonstrate the utility of using interspecies syntenic relationships to find relevant disease loci in humans.

Persistence of low disease activity after tumour necrosis factor inhibitor (TNFi) discontinuation in patients with psoriatic arthritis.

OBJECTIVE: To determine the duration of clinical benefit among patients with psoriatic arthritis (PsA) discontinuing tumour necrosis factor inhibitor (TNFi) therapy while in low disease activity (LDA), and to identify patient characteristics associated with prolonged clinical benefit. METHODS: We performed an observational cohort study assessing patients with PsA from the Consortium of Rheumatology Researchers of North America (CORRONA) registry who had discontinued TNFi after achieving LDA, defined as clinical disease activity index (CDAI) score ≤10 and physician's global assessment (PGA) of skin psoriasis ≤20/100. Kaplan-Meier method was used to estimate the duration of clinical benefit. RESULTS: Of the 5945 patients with PsA in CORRONA, 302 patients had discontinued TNFi (n=325) while in LDA and had follow-up data available. At time of discontinuation, mean PsA duration was 9.8 years, mean CDAI was 3.9, and mean duration of TNFi use was 1.5 years; 52.6% of patients had discontinued their first TNFi. Median time to loss of benefit was 29.2 months. 179 (55.1%) patients had persistent benefit at their previous clinic visit. An increased risk of losing clinical benefit was seen among patients with higher disease activity at discontinuation (CDAI≥3.2 vs <3.2; HR 1.43 (p=0.32)) and among smokers (HR 1.78 (p=0.027)). CONCLUSIONS: Patients with PsA who achieve LDA may maintain clinical benefit after discontinuation of TNFi therapy.

The LIN28B/let-7 axis is a novel therapeutic pathway in multiple myeloma.

MYC is a major oncogenic driver of multiple myeloma (MM) and yet almost no therapeutic agents exist that target MYC in MM. Here we report that the let-7 biogenesis inhibitor LIN28B correlates with MYC expression in MM and is associated with adverse outcome. We also demonstrate that the LIN28B/let-7 axis modulates the expression of MYC, itself a let-7 target. Further, perturbation of the axis regulates the proliferation of MM cells in vivo in a xenograft tumor model. RNA-sequencing and gene set enrichment analyses of CRISPR-engineered cells further suggest that the LIN28/let-7 axis regulates MYC and cell cycle pathways in MM. We provide proof of principle for therapeutic regulation of MYC through let-7 with an LNA-GapmeR (locked nucleic acid-GapmeR) containing a let-7b mimic in vivo, demonstrating that high levels of let-7 expression repress tumor growth by regulating MYC expression. These findings reveal a novel mechanism of therapeutic targeting of MYC through the LIN28B/let-7 axis in MM that may impact other MYC-dependent cancers as well.

Environmentally friendly power generator based on moving liquid dielectric and double layer effect.

An electrostatic power generator converts mechanical energy to electrical energy by utilising the principle of variable capacitance. This change in capacitance is usually achieved by varying the gap or overlap between two parallel metallic plates. This paper proposes a novel electrostatic micro power generator where the change in capacitance is achieved by the movement of an aqueous solution of NaCl. A significant change in capacitance is achieved due to the higher than air dielectric constant of water and the Helmholtz double layer capacitor formed by ion separation at the electrode interfaces. The proposed device has significant advantages over traditional electrostatic devices which include low bias voltage and low mechanical frequency of operation. This is critical if the proposed device is to have utility in harvesting power from the environment. A figure of merit exceeding 10000(10(8)µW)/(mm(2)HzV(2)) which is two orders of magnitude greater than previous devices, is demonstrated for a prototype operating at a bias voltage of 1.2 V and a droplet frequency of 6 Hz. Concepts are presented for large scale power harvesting.