Development and validation of an interpretable machine learning-based calculator for predicting 5-year weight trajectories after bariatric surgery: a multinational retrospective cohort SOPHIA study.

BACKGROUND: Weight loss trajectories after bariatric surgery vary widely between individuals, and predicting weight loss before the operation remains challenging. We aimed to develop a model using machine learning to provide individual preoperative prediction of 5-year weight loss trajectories after surgery. METHODS: In this multinational retrospective observational study we enrolled adult participants (aged ≥18 years) from ten prospective cohorts (including ABOS [NCT01129297], BAREVAL [NCT02310178], the Swedish Obese Subjects study, and a large cohort from the Dutch Obesity Clinic [Nederlandse Obesitas Kliniek]) and two randomised trials (SleevePass [NCT00793143] and SM-BOSS [NCT00356213]) in Europe, the Americas, and Asia, with a 5 year follow-up after Roux-en-Y gastric bypass, sleeve gastrectomy, or gastric band. Patients with a previous history of bariatric surgery or large delays between scheduled and actual visits were excluded. The training cohort comprised patients from two centres in France (ABOS and BAREVAL). The primary outcome was BMI at 5 years. A model was developed using least absolute shrinkage and selection operator to select variables and the classification and regression trees algorithm to build interpretable regression trees. The performances of the model were assessed through the median absolute deviation (MAD) and root mean squared error (RMSE) of BMI. FINDINGS: 10 231 patients from 12 centres in ten countries were included in the analysis, corresponding to 30 602 patient-years. Among participants in all 12 cohorts, 7701 (75·3%) were female, 2530 (24·7%) were male. Among 434 baseline attributes available in the training cohort, seven variables were selected: height, weight, intervention type, age, diabetes status, diabetes duration, and smoking status. At 5 years, across external testing cohorts the overall mean MAD BMI was 2·8 kg/m2 (95% CI 2·6-3·0) and mean RMSE BMI was 4·7 kg/m2 (4·4-5·0), and the mean difference between predicted and observed BMI was -0·3 kg/m2 (SD 4·7). This model is incorporated in an easy to use and interpretable web-based prediction tool to help inform clinical decision before surgery. INTERPRETATION: We developed a machine learning-based model, which is internationally validated, for predicting individual 5-year weight loss trajectories after three common bariatric interventions. FUNDING: SOPHIA Innovative Medicines Initiative 2 Joint Undertaking, supported by the EU's Horizon 2020 research and innovation programme, the European Federation of Pharmaceutical Industries and Associations, Type 1 Diabetes Exchange, and the Juvenile Diabetes Research Foundation and Obesity Action Coalition; Métropole Européenne de Lille; Agence Nationale de la Recherche; Institut national de recherche en sciences et technologies du numérique through the Artificial Intelligence chair Apprenf; Université de Lille Nord Europe's I-SITE EXPAND as part of the Bandits For Health project; Laboratoire d'excellence European Genomic Institute for Diabetes; Soutien aux Travaux Interdisciplinaires, Multi-établissements et Exploratoires programme by Conseil Régional Hauts-de-France (volet partenarial phase 2, project PERSO-SURG).

Effect of Allogeneic Oral Mucosa Mesenchymal Stromal Cells on Equine Wound Repair.

OBJECTIVE: To assess the clinical value and safety of the application of allogeneic equine oral mucosa mesenchymal stromal cells (OM-MSCs) to wounds. Animals. 8 healthy adult horses without front limb skin lesions or musculoskeletal disease. Procedures. Stem cells were isolated from the oral mucosa of a donor horse. Horses were subjected to the creation of eight full-thickness cutaneous wounds, two on each distal forelimb (FL) and two on both sides of the thorax (TH). Each wound was subjected to one out of four treatments: no medication (T1), hyaluronic acid- (HA-) gel containing OM-MSC (T2), HA-gel containing OM-MSC secretome (T3), and HA-gel alone (T4). Gross macroscopic evaluation and laser digital photographic documentation were regularly performed to allow wound assessment including wound surface area. Full-thickness skin punch biopsy was performed at each site before wound induction (D0, normal skin) and after complete wound healing (D62, repaired skin). RESULTS: All wounds healed without adverse effect at D62. Distal limb wounds are slower to heal than body wounds. OM-MSC and its secretome have a positive impact on TH wound contraction. OM-MSC has a positive impact on the contraction and epithelialization of FL wounds. No significant difference between wound sites before and after treatment was noted at histological examination. Conclusion and Clinical Relevance. Using horse cells harvested from oral mucosa is a feasible technique to produce OM-MSC or its secretome. The gel produced by the combination of these biologic components with HA shows a positive impact when applied during the early stage of wound healing.

Scientific and Regulatory Policy Committee Points to Consider*: Approaches to the Conduct and Interpretation of Vaccine Safety Studies for Clinical and Anatomic Pathologists.

The design and execution of toxicology studies supporting vaccine development have some unique considerations relative to those supporting traditional small molecules and biologics. A working group of the Society of Toxicologic Pathology Scientific and Regulatory Policy Committee conducted a review of the scientific, technical, and regulatory considerations for veterinary pathologists and toxicologists related to the design and evaluation of regulatory toxicology studies supporting vaccine clinical trials. Much of the information in this document focuses on the development of prophylactic vaccines for infectious agents. Many of these considerations also apply to therapeutic vaccine development (such as vaccines directed against cancer epitopes); important differences will be identified in various sections as appropriate. The topics addressed in this Points to Consider article include regulatory guidelines for nonclinical vaccine studies, study design (including species selection), technical considerations in dosing and injection site collection, study end point evaluation, and data interpretation. The intent of this publication is to share learnings related to nonclinical studies to support vaccine development to help others as they move into this therapeutic area. [Box: see text].

An Effective Intervention for Diabetic Lipohypertrophy: Results of a Randomized, Controlled, Prospective Multicenter Study in France.

BACKGROUND: Lipohypertrophy (LH) is highly prevalent and is potentially harmful to insulin-injecting patients. METHODS: In this study, we assessed the impact of injection technique (IT) education, including use of a 4-mm pen needle on insulin-treated patients with clinically observed LH in a randomized, controlled, prospective multicenter study in France with follow-up of 6 months. Intensive education and between-visit reinforcement were given to the intervention group. Control patients received similar messages at study outset. RESULTS: A total of 123 patients were recruited (age 52.1 ± 15.7 years; men 70.7%; body mass index >30 kg/m2: 34.2%; type 1: 53.7%; years with diabetes mellitus: 18.1 ± 10.5), of which 109 patients were included in the final analysis. The intervention group (n = 53) showed a significant decrease of total daily dose of insulin (average at baseline: 54.1 IU) at 3 months (T-3) and 6 months (T-6), reaching just over 5 IU versus baseline (P = 0.035). Corresponding, although not significant, decreases occurred in controls (n = 56); between-group differences were not significant. There were significant decreases in HbA1c (up to 0.5%) at T-3 and T-6 in both groups, with no significant differences between groups. A significant number of intervention patients improved their IT habits; about half achieved ideal IT habits by T-3 versus a quarter of control patients. By T-6, 2/3 of intervention patients achieved either ideal or acceptable IT habits, while only 1/3 of control patients did. CONCLUSIONS: Our intervention was effective in both study arms, however, to a greater degree and more rapidly in the intervention group. Widespread application of this intervention could be highly cost-effective.

Pre- and Postnatal Development of the Eye: A Species Comparison.

In this review paper, literature data on pre- and postnatal eye development are compared between humans and nonclinical species that are commonly used for human safety assessment, namely, mouse, rat, rabbit, dog, minipig, and nonhuman primates. Some new data on rat and minipig ocular development are also included. This compiled information can be helpful for species selection in juvenile toxicity studies or assist in the interpretation of (non)clinical data during pediatric drug development. Despite some differences in developmental windows and anatomical peculiarities, such as the lack of a fovea centralis in nonprimate species or the presence of a nictitating membrane in some nonclinical species, the functioning and development of the eye is strikingly similar between humans and other mammals. As such, all commonly used nonclinical species appear to be relatively good models for human eye development, although some practical constraints such as size may be a limiting factor. Birth Defects Research 109:1540-1567, 2017. © 2017 Wiley Periodicals, Inc.

Spontaneous testicular tubular hypoplasia/atrophy in the Göttingen minipig: a retrospective study.

The aim of this retrospective study was to assess the incidence and severity of tubular atrophy/hypoplasia in the testes of 104 control Göttingen minipigs aged 4.5 to 15 months. The finding was termed "tubular hypoplasia/atrophy" according to published descriptions for the dog. It included different microscopic changes that were considered part of a continuum, namely seminiferous epithelium vacuolation, presence of multinucleated germ cells in the tubular lumen, and decreased numbers (hypospermatogenesis) or absence of germ cells. This retrospective study demonstrates that tubular hypoplasia/atrophy is present in more than 70% of Göttingen minipigs and can occur at a marked severity in control animals. It correlated with a higher level of cell debris and a decrease in sperm content in the epididymides and with lower absolute and relative testes weights. There was no correlation with the weight of other sexual organs, total bodyweight, or age, which demonstrates that this change was not related to sexual immaturity. The distinction between this background finding and a compound-related effect could be challenging for the pathologist.

Presurgical Weight Is Associated with Pain, Functional Impairment, and Anxiety among Gastric Bypass Surgery Patients.

Chronic pain and obesity are significant public health concerns in the United States associated with significant levels of health-care expenses and lost productivity. Previous research suggests that obesity is a risk factor for chronic pain, mainly due to excessive weight placed on the joints. However, the obesity-pain relationship appears to be complex and reciprocal. Little work to date has focused on the relationship between weight and pain among patients undergoing gastric bypass surgery for weight loss. Patients scheduled to undergo bariatric surgery for weight loss at a large southeastern academic medical center (N = 115) completed the Brief Pain Inventory (BPI), the Center for Epidemiological Studies 10-item Depression scale (CESD-10), and the Beck Anxiety Inventory (BAI). Higher presurgical weight was associated with higher pain-on-average ratings, higher functional impairment due to pain across the domains of physical activity, mood, walking ability, relationships, and enjoyment of life. Higher presurgical weight was associated with higher BAI scores, but weight was not related to depression. Findings suggest that bariatric surgery candidates report a moderate amount of pain prior to surgery and that presurgical weight is associated with higher pain, increased functional impairment due to pain, and increased anxiety. Anxiety was found to mediate the relationship between increased weight and pain.

The Food Craving Questionnaire-Trait in a bariatric surgery seeking population and ability to predict post-surgery weight loss at six months.

Food cravings have been understudied in bariatric surgery patients and the Food Craving Questionnaire-Trait has not been validated in this population. Reliability and validity of the FCQ-T were examined and a regression analysis was run to determine whether or not preoperative scores on individual subscales of the instrument could predict weight loss at 6 months. The FCQ-T demonstrated excellent internal consistency in bariatric surgery-seeking patients, and individual subscales measuring emotion and mood were correlated with other measures of depression and anxiety. Endorsement of binge eating or emotional eating behaviors during a clinical interview was correlated with similar subscales on the FCQ-T. Higher scores on the subscale 'cues that may trigger food cravings' were associated with greater weight loss at 6 months post-surgery and higher scores on the subscale 'guilt from cravings and/or giving into them' was associated with less weight loss. Management of external cues may predict successful outcomes while emotional impact of cravings may indicate the need for further intervention to help manage specific food craving traits.

The effect of exercise absence on affect and body dissatisfaction as moderated by obligatory exercise beliefs and eating disordered beliefs and behaviors.

AIM: Research suggests that exercise absence is frequently associated with greater guilt and negative affect, particularly when obligatory exercise beliefs and eating disordered psychopathology are considered. Two separate studies used ecological momentary assessment (EMA) to examine differences in mood on exercise and non-exercise days and the moderating impact of obligatory exercise beliefs and eating disordered beliefs and behaviors. METHOD: Both studies recruited female university students who endorsed frequent exercise behavior and study two also recruited based on level of eating disordered psychopathology. Participants completed the Obligatory Exercise Questionnaire at baseline and EMA measures of affect and exercise behavior for approximately one week. Study two participants also completed measures of body dissatisfaction and cognitions. RESULTS: Results of study one suggest that obligation to exercise appears to have a greater impact on general level of affect than does exercise absence or the interaction of these two. In addition, in study two, eating disorder symptomatology was significantly associated with affect and cognition while exercise absence and obligatory exercise beliefs were not. CONCLUSIONS: The present studies suggest that the absence of exercise is not associated with significant changes in affect or cognitions. However, obligation to exercise and eating disorder symptomatology do impact affect and cognitions.

The effects of exercise on body satisfaction and affect.

This research used ecological momentary assessment to examine the effects of exercise on state body dissatisfaction and affect in 33 undergraduate females with high trait body dissatisfaction and 28 with low trait body dissatisfaction who exercised at least three times weekly. Trait body dissatisfaction was investigated as a moderator of the effects of exercise as well as different motivations for exercise. Results indicated all participants experienced lower state body dissatisfaction and negative affect and greater positive affect post-exercise. Trait body dissatisfaction moderated the association between motivations and exercise effects. Appearance and weight motivations were related to higher state body dissatisfaction for all individuals. Fitness and health motivations were related to higher state body dissatisfaction for high trait body dissatisfied individuals and lower state body dissatisfaction for low trait body dissatisfied individuals. Thus, although exercise has positive effects on body dissatisfaction and affect for high frequency exercisers, their exercise motivations impact these effects.

Psychological correlates of fasting and vigorous exercise as compensatory strategies in undergraduate women.

Vigorous exercise and fasting are commonly used compensatory behaviors. However, it is unknown how non-clinical individuals who engage in one or both of these compensatory behaviors differ from one another. This research compared women who engaged in both fasting and vigorous exercise as compensatory strategies (n=76) with women who engaged in either fasting (n=56) or excessive exercise (n=82) and women who employed no compensatory strategies (n=113) on body image/eating and psychological symptomatology. Participants completed questionnaires assessing body dissatisfaction, restrained eating, thin-ideal internalization, depression, self-esteem, and general psychological distress. Women who utilize any compensatory strategies report significantly greater body dissatisfaction and restrained eating than women who use no compensatory strategies at all. Moreover, fasting as a compensatory behavior is associated with more significant psychological and behavioral symptoms than vigorous exercise as a compensatory behavior. Implications of these findings for clinical intervention and research are discussed.

A review of background findings in cynomolgus monkeys (Macaca fascicularis) from three different geographical origins.

This review was performed to assess variations in background observations in cynomolgus macaques (Macaca fascicularis) originating from three breeding centres located in Mauritius, The Philippines and Vietnam. The data and tissue samples from 90 cynomolgus monkeys (approximately evenly distributed between the three sources) comprising the control groups from 11 regulatory toxicology studies were used for this investigation. Clinical data--age, body weight, organ weights, haematology and serum biochemistry--were analyzed. Samples of stomach, colon, kidney, heart, liver, spleen and lung were examined microscopically and graded to characterize the degree of lymphoplasmacytic cell infiltration. The main microscopic origin-related variations concerned the digestive tract, where the lymphoplasmacytic cell infiltration grade was significantly lower (p0.001) in cynomolgus monkeys from Mauritius when compared with those from Asia. Generally, only the antral mucosa of the stomach was infiltrated in cynomolgus monkeys from The Philippines, whereas both the fundic and antral regions were infiltrated in those from Vietnam. The digestive tract infiltration grade was strongly correlated with the mean white blood cell count in monkeys from all three sources. Spiral-shaped bacteria were observed in the stomach of monkeys from all three sources, but their presence did not correlate with the severity of the gastric infiltrate. Helicobacter heilmannii-type bacteria were almost always seen in the fundus, Helicobacter pylori-type bacteria were only occasionally seen in the antral region. The incidences of other microscopic findings, such as urothelial cytoplasmic inclusions or Balantidium coli in the caecum, also varied according to the source of the monkeys. Some variations in relative organ weights, haematology and serum biochemistry were also related to the origin of the monkeys, but these did not correlate with the microscopic findings.

Subcutaneous microchip-associated tumours in B6C3F1 mice: a retrospective study to attempt to determine their histogenesis.

Fifty-two subcutaneous tumours associated with microchip were collected from three carcinogenicity B6C3F1 mice studies. Two of these 52 tumours were adenocarcinoma of the mammary gland located on the dorsal region forming around the chip. All the other 50 were mesenchymal in origin and were difficult to classify on morphological grounds with haematoxylin-eosin. These sarcomas were investigated using a panel of immunohistochemistry and special stains consisting of desmin, smooth muscle actin (SMA), myogenin, S100, mouse macrophages, phosphotungstic acid haematoxylin (PTAH) and Masson's trichrome (MT). All the sarcomas displayed the same histochemical characteristics and a close immunophenotype, characterized by desmin +/-, SMA+, myogenin--, S100--, mouse macrophages + and PTAH-. These tumours thus appear to have similar histologic-type lineage and designation as sarcomas not otherwise specified (NOS) with a large myofibroblastic component appears today to be more appropriate and it is likely to clarify them in the future with the emergence of new markers.

Trichloroethylene Does Not Accelerate Autoimmune Diabetes in NOD Mice.

Pre-existing or contributing risk factors, including genetic predisposition and environmental influences, are largely thought to play a crucial (though ill-elucidated) role in the development of autoimmunity. Trichloroethylene (TCE) is a widely used organic solvent, which has been suspected of increasing the prevalence of autoimmune diseases, e.g., lupus, following environmental contamination. Although few epidemiological data are available, several studies reported an accelerated and more severe disease in TCE-exposed autoimmunity-prone MRL(+/+) mice. To test whether TCE can exert similar deleterious effects on organ-specific autoimmune diseases, non obese diabetic (NOD) mice were given 5 mg/ml TCE via the drinking water for 12 weeks. TCE administration induced a decrease in CD44(+) splenic T-cells and CD45RB(high), CD54(+) blood and splenic T-cells. Conversely, the number of CD45RB(low) splenocytes was increased. Interestingly, the progressive increase in serum TNF-alpha and IFN-gamma levels normally seen with age in these mice was inhibited by TCE. There was also a relative lower incidence of histological changes in the pancreas of TCE-exposed NOD mice than in unexposed mice. Contrary to what has been found in systemic models of autoimmunity, TCE did not accelerate the diabetes of NOD mice and may have a protective effect. This finding suggests that comparative studies using different genetically related autoimmune-prone models are needed to investigate the role of xenobiotics in the precipitation of autoimmunity, particularly in sensitive populations.

What do Québec children eat during their first six months?

Study objectives were to describe the introduction of foods and beverages and the use of vitamin and/or mineral supplements among infants aged six months, and to identify factors associated with following Québec recommendations on introducing foods and beverages. Study subjects were primiparous women interviewed by phone when their infants were approximately six months old. Data were gathered on foods and beverages offered to infants, the age at which these were introduced, and supplements. The use of each food, beverage, and supplement was evaluated according to recommendations. Mean age at which foods were introduced and proportions of women who followed recommendations were calculated. Multivariate logistic regression models were used to identify the factors associated with following recommendations. Results indicated that among the 1,937 interviewed mothers, 212 (10.9%) exclusively breast-fed their infants before age four months, 1,073 (55.4%) breast-fed their infants at birth but gave them formula or foods before age four months, and 652 (33.7%) formula-fed their infants at birth. Factors associated with adherence to recommendations were breast-feeding exclusively, being older than 30 years, an annual family income of at least 60,000 dollars, and being a non-smoker. Few mothers followed all the recommendations.