Clofarabine monotherapy in aggressive, relapsed and refractory Langerhans cell histiocytosis.

Over 50% of patients with systemic LCH are not cured with front-line therapies, and data to guide salvage options are limited. We describe 58 patients with LCH who were treated with clofarabine. Clofarabine monotherapy was active against LCH in this cohort, including heavily pretreated patients with a systemic objective response rate of 92.6%, higher in children (93.8%) than adults (83.3%). BRAFV600E+ variant allele frequency in peripheral blood is correlated with clinical responses. Prospective multicentre trials are warranted to determine optimal dosing, long-term efficacy, late toxicities, relative cost and patient-reported outcomes of clofarabine compared to alternative LCH salvage therapy strategies.

Potential of dietary polyphenols for protection from age-related decline and neurodegeneration: a role for gut microbiota?

Many epidemiological studies have shown the beneficial effects of a largely plant-based diet, and the strong association between the consumption of a Mediterranean-type diet with healthy aging including a lower risk of cognitive decline. The Mediterranean diet is characterized by a high intake of olive oil, fruits and vegetables and is rich in dietary fiber and polyphenols - both of which have been postulated to act as important mediators of these benefits. Polyphenols are large molecules produced by plants to protect them from environmental threats and injury. When ingested by humans, as little as 5% of these molecules are absorbed in the small intestine with the majority metabolized by the gut microbiota into absorbable simple phenolic compounds. Flavan-3-ols, a type of flavonoid, contained in grapes, berries, pome fruits, tea, and cocoa have been associated with many beneficial effects on several risk factors for cardiovascular disease, cognitive function and brain regions involved in memory formation. Both preclinical and clinical studies suggest that these brain and heart benefits can be attributed to endothelial vascular effects and anti-inflammatory properties among others. More recently the gut microbiota has emerged as a potential modulator of the aging brain and intriguingly polyphenols have been shown to alter microbiota composition and be metabolized by different microbial species. However, there is a need for well controlled studies in large populations to identify predictors of response, particularly given the vast inter-individual variation of human gut microbiota.

A method for beam's eye view breath-hold monitoring during breast volumetric modulated arc therapy.

Background and purpose: Deep inspiration breath-hold (DIBH) is a technique that is widely utilised to spare the heart and lungs during breast radiotherapy. In this study, a method was developed to validate directly the intrafraction accuracy of DIBH during breast volumetric modulated arc therapy (VMAT) via internal chest wall (CW) monitoring. Materials and methods: In-house software was developed to automatically extract and compare the treatment position of the CW in cine-mode electronic portal image device (EPID) images with the planned CW position in digitally reconstructed radiographs (DRR) for breast VMAT treatments. Feasibility of this method was established by evaluating the percentage of total dose delivered to the target volume when the CW was sufficiently visible for monitoring. Geometric accuracy of the approach was quantified by applying known displacements to an anthropomorphic thorax phantom. The software was used to evaluate (offline) the geometric treatment accuracy for ten patients treated using real-time position management (RPM)-guided DIBH. Results: The CW could be monitored within the tangential sub-arcs which delivered a median 89% (range 73% to 97%) of the dose to target volume. The phantom measurements showed a geometric accuracy within 1 mm, with visual inspection showing good agreement between the software-derived and user-determined CW positions. For the RPM-guided DIBH treatments, the CW was found to be within ±5 mm of the planned position in 97% of EPID frames in which the CW was visible. Conclusion: An intrafraction monitoring method with sub-millimetre accuracy was successfully developed to validate target positioning during breast VMAT DIBH.

A systematic review of breast milk microbiota composition and the evidence for transfer to and colonisation of the infant gut.

The intestinal microbiota plays a major role in infant health and development. However, the role of the breastmilk microbiota in infant gut colonisation remains unclear. A systematic review was performed to evaluate the composition of the breastmilk microbiota and evidence for transfer to/colonisation of the infant gut. Searches were performed using PUBMED, OVID, LILACS and PROQUEST from inception until 18th March 2020 with a PUBMED update to December 2021. 88 full texts were evaluated before final critique based on study power, sample contamination avoidance, storage, purification process, DNA extraction/analysis, and consideration of maternal health and other potential confounders. Risk of skin contamination was reduced mainly by breast cleaning and rejecting the first milk drops. Sample storage, DNA extraction and bioinformatics varied. Several studies stored samples under conditions that may selectively impact bacterial DNA preservation, others used preculture reducing reliability. Only 15 studies, with acceptable sample size, handling, extraction, and bacterial analysis, considered transfer of bacteria to the infant. Three reported bacterial transfer from infant to breastmilk. Despite consistent evidence for the breastmilk microbiota, and recent studies using improved methods to investigate factors affecting its composition, few studies adequately considered transfer to the infant gut providing very little evidence for effective impact on gut colonisation.

Lactation time influences the composition of Bifidobacterium and Lactobacillus at species level in human breast milk.

Human breast milk is a source of microorganisms for infants that play an important role in building infant gut health and immunity. The bacterial composition in human breast milk is influenced by lactation time. This study aimed to investigate the influence of lactation time on bacteria in breast milk at the genus level and the species levels of Bifidobacterium and Lactobacillus on days 2-4, 8, 14, and 30. Eighteen individuals were recruited and 60 milk samples were collected. The 16S rRNA gene, and the bifidobacterial groEL and lactobacilli groEL genes were used for amplicon sequencing. The results revealed that the alpha diversities of colostrum and transition 1 (day 8) milk were lower than that of transition 2 (day 14) and mature milk. PCoA analysis showed that bacterial composition in colostrum and transition 1 milk differed from transition 2 and mature milk. A lower relative abundance of Blautia was found in colostrum and transition 1 milk compared with mature milk and lower abundances of Ruminococcus, Dorea, and Escherichia-Shigella were found in transition 1 compared with mature milk. Bifidobacterium ruminantium, Limosilactobacillus mucosae, and Ligilactobacillus ruminis were the predominant species across all four lactation stages, while Bifidobacterium bifidum was lower in transition 1, and Bifidobacterium pseudocatenulatum and Bifidobacterium pseudolongum were higher in transition 1 milk. This study indicated that the bacterial composition in colostrum was more similar to that of transition 1 milk, whereas the bacterial community in transition 2 milk was similar to that of mature milk which suggests that bacterial composition in human breast milk shows stage-specific signatures even within a short period at both genus level and Bifidobacterium and Lactobacillus species levels, providing insights into probiotic supplementation for the nursing mother.

Modulation, microbiota and inflammation in the adult CF gut: A prospective study.

BACKGROUND: Cystic Fibrosis (CF) has prominent gastrointestinal and pancreatic manifestations. The aim of this study was to determine the effect of Cystic fibrosis transmembrane conductance regulator (CFTR) modulation on, gastrointestinal inflammation, pancreatic function and gut microbiota composition in people with cystic fibrosis (CF) and the G551D-CFTR mutation. METHODS: Fourteen adult patients with the G551D-CFTR mutation were assessed clinically at baseline and for up to 1 year after treatment with ivacaftor. The change in gut inflammatory markers (calprotectin and lactoferrin), exocrine pancreatic status and gut microbiota composition and structure were assessed in stool samples. RESULTS: There was no significant change in faecal calprotectin nor lactoferrin in patients with treatment while all patients remained severely pancreatic insufficient. There was no significant change in gut microbiota diversity and richness following treatment. CONCLUSION: There was no significant change in gut inflammation after partial restoration of CFTR function with ivacaftor, suggesting that excess gut inflammation in CF is multi-factorial in aetiology. In this adult cohort, exocrine pancreatic function was irreversibly lost. Longer term follow-up may reveal more dynamic changes in the gut microbiota and possible restoration of CFTR function.

Fatty acid concentration of plasma, muscle, adipose and liver from beef heifers fed an encapsulated n-3 polyunsaturated fatty acid supplement.

Increasing the content of polyunsaturated fat in the human diet is a priority for reducing cardiovascular disease and cancer risks. Beef has the potential to contribute to the polyunsaturated fat content in the human diet; however, ruminants cannot synthesise many long-chain fatty acids de novo; they require dietary supplementation. The objectives of the current study were to evaluate (i) the effect of a partially rumen protected n-3 long-chain polyunsaturated fatty acid (LC-PUFA) dietary supplement on the fatty acid composition of muscle (Longissimus dorsi), adipose and liver tissues of beef heifers and (ii) the usefulness of blood plasma as a predictor of tissue concentrations of specific fatty acids. Charolais crossbred heifers (n = 20) were assigned to one of two isolipid dietary treatments namely palmitic acid (control) or an n-3 LC-PUFA supplement for a 91-day period. Blood plasma and adipose tissue samples were taken to determine the temporal effect of these diets on fatty acid composition (days 0, 10, 35 and 91), while liver and muscle samples were taken following slaughter. Dietary lipid source did not influence animal growth rate or body condition score. At day 91, the percentage differences between control and n-3 LC-PUFA heifers in concentrations of eicosapentaenoic acid were +61, +176 and +133 % in liver, muscle and adipose, respectively. For docosahexaenoic acid, at the same time point, the percentage differences were +57, +73 and +138 % for liver, muscle and adipose, respectively. Medium-to-strong positive correlation coefficients were evident for liver and plasma fatty acids, in particular, there were positive relationships with concentrations of total saturated fatty acid (SFA), total n-6 PUFA and total n-3 PUFA. This trend also extended to both the ratio of PUFA to SFA (slope (ß1) = 0.56 ±â€¯0.167, intercept (ß0) = 0.56, R2 = 0.61, P < 0.05) and the ratio of n-6 to n-3 PUFA (ß1 = 0.15 ±â€¯0.054, ß0 = 0.24, R2 = 0.52, P < 0.05). A strong correlation was also detected in the ratio of n-6 to n-3 in plasma and muscle tissue of heifers fed the n-3 LC-PUFA diet (ß1 = 0.53 ±â€¯0.089, ß0 = -0.31, R2 = 0.83, P < 0.001). The results of this study show that the n-3 LC-PUFA can be readily increased through targeted supplementation and that plasma concentrations of n-3 LC-PUFA are useful predictors of their concentrations in a number of economically important tissues.

Mixed Phenotype Acute Leukemia, B/Myeloid (Bilineal and Biphenotypic), With t(2;22)(q35;q12);EWSR1-FEV.

BACKGROUND: Ewing sarcoma breakpoint region 1 gene (EWSR1) rearrangements are largely associated with the Ewing sarcoma family of tumors. OBSERVATIONS: We report the first case of infantile, mixed phenotype acute leukemia, B/myeloid (bilineal and biphenotypic [B-lymphoid and B-lymphoid/myeloid]), with a t(2;22)(q35;q12). The EWSR1-fifth Ewing variant gene fusion and nonsense mutation in STAG2 were detected by next-generation sequencing and markedly high expression of fifth Ewing sarcoma variant mRNA detected by quantitative reverse transcription polymerase chain reaction. The patient was treated with a combined myeloid/lymphoid leukemia regimen followed by allogeneic stem cell transplant and was in complete remission at 3.8-year follow-up. CONCLUSIONS: Our case study underscores the importance of a comprehensive evaluation of acute leukemia and provides insights into the phenotype of EWSR1 rearranged neoplasms in the context of partner genes and cell type.

Histamine and cholesterol lowering abilities of lactic acid bacteria isolated from artisanal Pico cheese.

AIMS: This study was designed to select lactic acid bacteria with histamine- and cholesterol-reducing abilities to be used as potential probiotics. METHODS AND RESULTS: Thirty strains of lactic acid bacteria isolated from an artisanal raw milk cheese were screened for their abilities to degrade histamine, reduce cholesterol and hydrolyse bile salts. Strains were also screened for safety and probiotic traits, such as resistance to gastrointestinal conditions, adhesion to Caco-2 cells, resistance to antibiotics and presence of virulence genes. Two Lactobacillus paracasei strains presented high cholesterol- and histamine-lowering abilities, tested negative for the presence of virulence genes and showed susceptibility to most important antibiotics. These strains were also shown to possess desirable in vitro probiotic properties, revealed by tolerance to gastrointestinal conditions and high adhesion to intestinal cells. CONCLUSIONS: Among the screened strains, Lb. paracasei L3C21M6 revealed the best cholesterol and histamine reducing abilities together with desirable probiotic and safety features to be used in food applications. SIGNIFICANCE AND IMPACT OF THE STUDY: The strain L3C21M6 is a good candidate for use as a probiotic with histamine-degrading activity and cholesterol lowering effect. In addition, this strain could be use in dairy foods to prevent histamine food poisoning.

Replacing fishmeal with plant protein in Atlantic salmon (Salmo salar) diets by supplementation with fish protein hydrolysate.

The effects of feeding an 80% plant protein diet, with and without fish protein hydrolysate (FPH) supplementation, on the growth and gut health of Atlantic salmon were investigated. Fish were fed either (A) a control diet containing 35% fishmeal, (B) an 80% plant protein diet with 15% fishmeal, (C) an 80% plant protein diet with 5% fishmeal and 10% partly hydrolysed protein, or (D) an 80% plant protein diet with 5% fishmeal and 10% soluble protein hydrolysate. Fish on the 80% plant- 15% fishmeal diet were significantly smaller than fish in the other dietary groups. However, partly-hydrolysed protein supplementation allowed fish to grow as well as fish fed the control 35% fishmeal diet. Fish fed the FPH diets (diets C and D) had significantly higher levels of amino acids in their blood, including 48% and 27% more branched chain amino acids compared to fish on the 35% fishmeal diet, respectively. Plant protein significantly altered gut microbial composition, significantly decreasing α-diversity. Spirochaetes and the families Moritellaceae, Psychromonadaceae, Helicobacteraceae and Bacteroidaceae were all found at significantly lower abundances in the groups fed 80% plant protein diets compared to the control fishmeal diet.

Multicenter investigation on the influence of climate in penile prosthesis infection.

The purpose of this study is to investigate the relationship between inflatable penile prosthesis (IPP) infection, time of year, climate, temperature and humidity. This is a retrospective IRB-approved analysis of 211 patients at 25 institutions who underwent salvage procedure or device explant between 2001 and 2016. Patient data were compiled after an extensive review of all aspects of their electronic medical records. Climate data were compiled from monthly norms based on location, as well as specific data regarding temperature, dew point, and humidity from dates of surgery. Rigorous statistical analysis was performed. We found that penile prosthesis infections occurred more commonly in June (n = 24) and less frequently during the winter months (n = 39), with the lowest number occurring in March (n = 11). One-hundred thirty-nine infections occurred at average daily temperatures greater than 55 °F, compared to 72 infections at less than 55 °F. The incidence rate ratio for this trend was 1.93, with a p-value of <0.001. Humidity results were similar, and fungal infections correlate with daily humidity. Infected implants performed in the fall and summer were over 3 and 2.3 times, respectively, more likely to grow Gram-positive bacteria compared to implants performed in spring (p = 0.004; p = 0.039). This was consistent across geographic location, including in the Southern hemisphere. We found trends between climate factors and IPP infection like those seen and proven in other surgical literature. To our knowledge these data represent the first exploration of the relationship between temperature and infection in prosthetic urology.

Gamma-aminobutyric acid-producing lactobacilli positively affect metabolism and depressive-like behaviour in a mouse model of metabolic syndrome.

Metabolic and neuroactive metabolite production represents one of the mechanisms through which the gut microbiota can impact health. One such metabolite, gamma-aminobutyric acid (GABA), can modulate glucose homeostasis and alter behavioural patterns in the host. We previously demonstrated that oral administration of GABA-producing Lactobacillus brevis DPC6108 has the potential to increase levels of circulating insulin in healthy rats. Therefore, the objective of this study was to assess the efficacy of endogenous microbial GABA production in improving metabolic and behavioural outcomes in a mouse model of metabolic dysfunction. Diet-induced obese and metabolically dysfunctional mice received one of two GABA-producing strains, L. brevis DPC6108 or L. brevis DSM32386, daily for 12 weeks. After 8 and 10 weeks of intervention, the behavioural and metabolic profiles of the mice were respectively assessed. Intervention with both L. brevis strains attenuated several abnormalities associated with metabolic dysfunction, causing a reduction in the accumulation of mesenteric adipose tissue, increased insulin secretion following glucose challenge, improved plasma cholesterol clearance and reduced despair-like behaviour and basal corticosterone production during the forced swim test. Taken together, this exploratory dataset indicates that intervention with GABA-producing lactobacilli has the potential to improve metabolic and depressive- like behavioural abnormalities associated with metabolic syndrome in mice.

Risk Factors for Perceptual-versus-Interpretative Errors in Diagnostic Neuroradiology.

BACKGROUND AND PURPOSE: Diagnostic errors in radiology are classified as perception or interpretation errors. This study determined whether specific conditions differed when perception or interpretation errors occurred during neuroradiology image interpretation. MATERIALS AND METHODS: In a sample of 254 clinical error cases in diagnostic neuroradiology, we classified errors as perception or interpretation errors, then characterized imaging technique, interpreting radiologist's experience, anatomic location of the abnormality, disease etiology, time of day, and day of the week. Interpretation and perception errors were compared with hours worked per shift, cases read per shift, average cases read per shift hour, and the order of case during the shift when the error occurred. RESULTS: Perception and interpretation errors were 74.8% (n = 190) and 25.2% (n = 64) of errors, respectively. Logistic regression analyses showed that the odds of an interpretation error were 2 times greater (OR, 2.09; 95% CI, 1.05-4.15; P = .04) for neuroradiology attending physicians with ≤5 years of experience. Interpretation errors were more likely with MR imaging compared with CT (OR, 2.10; 95% CI, 1.09-4.01; P = .03). Infectious/inflammatory/autoimmune diseases were more frequently associated with interpretation errors (P = .04). Perception errors were associated with faster reading rates (6.01 versus 5.03 cases read per hour; P = .004) and occurred later during the shift (24th-versus-18th case; P = .04). CONCLUSIONS: Among diagnostic neuroradiology error cases, interpretation-versus-perception errors are affected by the neuroradiologist's experience, technique, and the volume and rate of cases read. Recognition of these risk factors may help guide programs for error reduction in clinical neuroradiology services.

Multicenter Investigation of Fungal Infections of Inflatable Penile Prostheses.

BACKGROUND: Fungal infections of inflatable penile prostheses (IPPs) are inadequately understood in the literature. AIM: To review a multi-institution database of IPP infections to examine for common patient and surgical factors related to IPP fungal infections. METHODS: This is a retrospective Institutional Review Board-approved analysis of 217 patients at 26 institutions who underwent salvage or device explant between 2001 and 2018. Patient data were compiled after an extensive record review. OUTCOMES: 26 patients (12%) with fungal infections were identified. RESULTS: 23 of 26 patients (83%) with a fungal IPP infection were either diabetic or overweight. 15 patients had undergone primary IPP implantation, and the other 11 had previously undergone an average of 1.7 IPP-related surgeries (range 1-3; median 2). The average age at implantation was 63 years (range 31-92; median 63). 18 of the 26 patients with fungal infection had diabetes (69%), with a mean hemoglobin A1c (HbA1c) value of 8.4 (range 5.8-13.3; median 7.5). Twenty-two patients (85%) were overweight or obese. The mean body mass index for all patients was 30.1 kg/m2 (range 23.7-45 kg/m2; median 28.4 kg/m2), and that for diabetic patients was 30.8 kg/m2 (range 24.1-45 kg/m2, median 29.7 kg/m2). Ninety-one percent of implants were placed with intravenous antibiotics, consistent with current American Urological Association guidelines: an aminoglycoside plus first- or second-generation cephalosporin or vancomycin or ampicillin/sulbactam or piperacillin/tazobactam. 65% (17 of 26) of infected IPPs had only fungal growth in culture. No patient had concomitant immunosuppressive disease or recent antibiotic exposure before IPP implantation. CLINICAL IMPLICATIONS: More than two-thirds of the fungal infections occurred in diabetic patients and 85% occurred in overweight or obese patients, suggesting that antifungal prophylaxis may be appropriate in these patients. STRENGTHS & LIMITATIONS: This is the largest series of fungal infections reported to date in the penile prosthesis literature. The overall number of such cases, however, remains small. CONCLUSION: Fungal infections represent 12% of all penile prosthesis infections in our series and were seen mostly in diabetic or overweight patients, who may benefit from antifungal prophylaxis. Gross MS, Reinstatler L, Henry GD, et al. Multicenter Investigation of Fungal Infections of Inflatable Penile Prostheses. J Sex Med 2019;16:1100-1105.

Genitourinary Complications of Gender-Affirming Surgery.

PURPOSE OF REVIEW: Gender-affirming surgery has become a more common procedure in the last 5 years. Feminizing genitoplasty typically involves inversion of penile skin as a neovagina, urethral shortening, and glans reduction to create a neoclitoris. Masculinizing genitoplasty is more complex, typically is performed in multiple stages, and has more inherent urologic risks. RECENT FINDINGS: The most common urologic complications involve voiding dysfunction, specifically meatal stenosis or fistula to the urinary tract. Urethral stricture, fistula, urinary retention, and voiding dysfunction are very common and require early recognition and intervention. This includes placement of catheter drainage, if necessary with the appropriate urologic instrumentation. Genital risks relating to phallus health are rare, but risks associated with placement of penile prosthesis for sexual function are common and require immediate attention. Urological complications after gender-affirming surgery are common, and the general urologist and urogynecologist should be able to identify and treat problems in this population after review of this chapter.

Meta-analysis of suicide rates among people discharged from non-psychiatric settings after presentation with suicidal thoughts or behaviours.

OBJECTIVE: To quantify the suicide rate among people discharged from non-psychiatric settings after presentations with suicidal thoughts or behaviours. METHOD: Meta-analysis of studies reporting suicide deaths among people with suicidal thoughts or behaviours after discharge from emergency departments or the medical or surgical wards of general hospitals. RESULTS: A total of 115 studies reported 167 cohorts and 3747 suicide deaths among 248 005 patients during 1 263 727 person-years. The pooled suicide rate postdischarge was 483 suicide deaths per 100 000 person-years (95% confidence interval (CI) 445-520, prediction interval (PI) 200-770) with high between-sample heterogeneity (I2  = 92). The suicide rate was highest in the first year postdischarge (851 per 100 000 person-years) but remained elevated in the long term. Suicide rates were elevated among samples of men (716 per 100 000 person-years) and older people (799 per 100 000 person-years) but were lower in samples of younger people (107 per 100 000 person-years) and among studies published between 2010 and 2018 (329 per 100 000 person-years). CONCLUSIONS: People with suicidal thoughts or behaviours who are discharged from non-psychiatric settings have highly elevated rates of suicide despite a clinically meaningful decline in these suicide rates in recent decades.

Potentially modifiable determinants of malnutrition in older adults: A systematic review.

BACKGROUND & AIMS: Malnutrition in older adults results in significant personal, social, and economic burden. To combat this complex, multifactorial issue, evidence-based knowledge is needed on the modifiable determinants of malnutrition. Systematic reviews of prospective studies are lacking in this area; therefore, the aim of this systematic review was to investigate the modifiable determinants of malnutrition in older adults. METHODS: A systematic approach was taken to conduct this review. Eight databases were searched. Prospective cohort studies with participants of a mean age of 65 years or over were included. Studies were required to measure at least one determinant at baseline and malnutrition as outcome at follow-up. Study quality was assessed using a modified version of the Quality in Prognosis Studies (QUIPS) tool. Pooling of data in a meta-analysis was not possible therefore the findings of each study were synthesized narratively. A descriptive synthesis of studies was used to present results due the heterogeneity of population source and setting, definitions of determinants and outcomes. Consistency of findings was assessed using the schema: strong evidence, moderate evidence, low evidence, and conflicting evidence. RESULTS: Twenty-three studies were included in the final review. Thirty potentially modifiable determinants across seven domains (oral, psychosocial, medication and care, health, physical function, lifestyle, eating) were included. The majority of studies had a high risk of bias and were of a low quality. There is moderate evidence that hospitalisation, eating dependency, poor self-perceived health, poor physical function and poor appetite are determinants of malnutrition. Moderate evidence suggests that chewing difficulties, mouth pain, gum issues co-morbidity, visual and hearing impairments, smoking status, alcohol consumption and physical activity levels, complaints about taste of food and specific nutrient intake are not determinants of malnutrition. There is low evidence that loss of interest in life, access to meals and wheels, and modified texture diets are determinants of malnutrition. Furthermore, there is low evidence that psychological distress, anxiety, loneliness, access to transport and wellbeing, hunger and thirst are not determinants of malnutrition. There appears to be conflicting evidence that dental status, swallowing, cognitive function, depression, residential status, medication intake and/or polypharmacy, constipation, periodontal disease are determinants of malnutrition. CONCLUSION: There are multiple potentially modifiable determinants of malnutrition however strong robust evidence is lacking for the majority of determinants. Better prospective cohort studies are required. With an increasingly ageing population, targeting modifiable factors will be crucial to the effective treatment and prevention of malnutrition.