Low-Affinity Binding Sites and the Transcription Factor Specificity Paradox in Eukaryotes.

Eukaryotic transcription factors (TFs) from the same structural family tend to bind similar DNA sequences, despite the ability of these TFs to execute distinct functions in vivo. The cell partly resolves this specificity paradox through combinatorial strategies and the use of low-affinity binding sites, which are better able to distinguish between similar TFs. However, because these sites have low affinity, it is challenging to understand how TFs recognize them in vivo. Here, we summarize recent findings and technological advancements that allow for the quantification and mechanistic interpretation of TF recognition across a wide range of affinities. We propose a model that integrates insights from the fields of genetics and cell biology to provide further conceptual understanding of TF binding specificity. We argue that in eukaryotes, target specificity is driven by an inhomogeneous 3D nuclear distribution of TFs and by variation in DNA binding affinity such that locally elevated TF concentration allows low-affinity binding sites to be functional.

Parameters of clustered suboptimal miRNA biogenesis.

The nuclear cleavage of a suboptimal primary miRNA hairpin by the Drosha/DGCR8 complex ("Microprocessor") can be enhanced by an optimal miRNA neighbor, a phenomenon termed cluster assistance. Several features and biological impacts of this new layer of miRNA regulation are not fully known. Here, we elucidate the parameters of cluster assistance of a suboptimal miRNA and also reveal competitive interactions amongst optimal miRNAs within a cluster. We exploit cluster assistance as a functional assay for suboptimal processing and use this to invalidate putative suboptimal substrates, as well as identify a "solo" suboptimal miRNA. Finally, we report complexity in how specific mutations might affect the biogenesis of clustered miRNAs in disease contexts. This includes how an operon context can buffer the effect of a deleterious processing variant, but reciprocally how a point mutation can have a nonautonomous effect to impair the biogenesis of a clustered, suboptimal, neighbor. These data expand our knowledge regarding regulated miRNA biogenesis in humans and represent a functional assay for empirical definition of suboptimal Microprocessor substrates.

A feed-forward relay integrates the regulatory activities of Bicoid and Orthodenticle via sequential binding to suboptimal sites.

The K50 (lysine at amino acid position 50) homeodomain (HD) protein Orthodenticle (Otd) is critical for anterior patterning and brain and eye development in most metazoans. In Drosophila melanogaster, another K50HD protein, Bicoid (Bcd), has evolved to replace Otd's ancestral function in embryo patterning. Bcd is distributed as a long-range maternal gradient and activates transcription of a large number of target genes, including otd Otd and Bcd bind similar DNA sequences in vitro, but how their transcriptional activities are integrated to pattern anterior regions of the embryo is unknown. Here we define three major classes of enhancers that are differentially sensitive to binding and transcriptional activation by Bcd and Otd. Class 1 enhancers are initially activated by Bcd, and activation is transferred to Otd via a feed-forward relay (FFR) that involves sequential binding of the two proteins to the same DNA motif. Class 2 enhancers are activated by Bcd and maintained by an Otd-independent mechanism. Class 3 enhancers are never bound by Bcd, but Otd binds and activates them in a second wave of zygotic transcription. The specific activities of enhancers in each class are mediated by DNA motif variants preferentially bound by Bcd or Otd and the presence or absence of sites for cofactors that interact with these proteins. Our results define specific patterning roles for Bcd and Otd and provide mechanisms for coordinating the precise timing of gene expression patterns during embryonic development.

The Global Incident Gastrointestinal Cancers Attributable to Suboptimal Diets From 1990 to 2018.

BACKGROUND & AIMS: The contribution of suboptimal diets to gastrointestinal (GI) cancer incidence globally remains unquantified, and we aimed to evaluate it. METHODS: Comprehensive meta-analyses and rigorous evidence-grading assessment identified the associations between suboptimal diets and 6 GI cancers and their subtypes. A comparative risk assessment model was used to estimate the proportional attributable burden and attributable rate of GI cancers to suboptimal diets by using the corroborative association estimates. In addition, correlation assessments with the Sociodemographic Index were carried out. RESULTS: In 2018, 21.5% (95% uncertainty interval, 19.1%-24.5%) of incident GI cancer cases globally were attributable to suboptimal diets, maintaining a relatively stable proportion since 1990 (22.4%; 19.7%-25.6%), whereas the absolute diet-attributable cases doubled from 580,862 (510,658-664,076) in 1990 to 1,039,877 (923,482-1,187,244) in 2018. Excessive processed meat consumption (5.9%; 4.2%-7.9%), insufficient fruit intake (4.8%; 3.8%-5.9%), and insufficient whole grain intake (3.6%; 2.8%-5.1%) were the most significant dietary risk factors in 2018, a shift from 1990 when the third major concern was insufficient nonstarchy vegetable intake. In addition, Central and Eastern Europe and Central Asia experienced the highest attributable burden across regions in both 1990 (31.6%; 27.0%-37.4%) and 2018 (31.6%; 27.3%-36.5%), and a positive correlation (P < .001) between the Sociodemographic Index and the attributable GI cancer incidence was observed. CONCLUSIONS: Although the proportional attributable GI incidence remains relatively stable, the doubling of absolute cases from 1990 to 2018, along with the discrepancies among urbanicity and countries/regions, informs dietary priorities and more targeted preventive measures.

Clinical factors associated with unexpected poor or suboptimal response in Poseidon criteria patients.

RESEARCH QUESTION: What clinical factors are associated with 'unexpected' poor or suboptimal responses to IVF ovarian stimulation per POSEIDON's criteria, and which AMH and AFC threshold values distinguish this population? DESIGN: Tri-centre retrospective cohort study (2015-2017) involving first-time IVF and ICSI cycles with conventional ovarian stimulation (≥150 IU/day of FSH). Eligibility criteria included sufficient ovarian reserve markers according to POSEIDON's classification (AMH ≥1.2 ng/ml; AFC ≥5). Ovarian response categories were poor (<4 oocytes), suboptimal (4-9 oocytes) and normal (≥9 oocytes). Primary outcomes included clinical factors associated with an unexpected poor or suboptimal response to conventional ovarian stimulation using logistic regression analyses, and the threshold values of AMH and AFC predicting increased risk of such responses using ROC curves. RESULTS: A total of 7625 patients met the inclusion criteria: 204 (9.3%) were poor and 1998 (90.7%) were suboptimal responders. Logistic regression identified significant clinical predictors for a poor or suboptimal response, including AFC, AMH, total gonadotrophin dose, gonadotrophin type and trigger type (P ≤ 0.02). The ROC curves indicated that AMH 2.87 ng/ml (AUC 0.740) and AFC 12 (AUC 0.826) were the threshold values predicting a poor or suboptimal response; AMH 2.17 ng/ml (AUC 0.741) and AFC 9 (AUC 0.835) predicted a poor response; and AMH 2.97 ng/ml (AUC 0.722) and AFC 12 (AUC 0.801) predicted a suboptimal response. CONCLUSIONS: The threshold values of AMH and AFC predicting 'unexpected' poor or suboptimal response were higher than expected. These findings have critical implications for tailoring IVF stimulation regimens and dosages.

Patterns of sub-optimal change following CBT for childhood anxiety.

BACKGROUND: Children and adolescents demonstrate diverse patterns of symptom change and disorder remission following cognitive behavioural therapy (CBT) for anxiety disorders. To better understand children who respond sub-optimally to CBT, this study investigated youths (N = 1,483) who continued to meet criteria for one or more clinical anxiety diagnosis immediately following treatment or at any point during the 12 months following treatment. METHODS: Data were collected from 10 clinical sites with assessments at pre-and post-treatment and at least once more at 3, 6 or 12-month follow-up. Participants were assigned to one of three groups based on diagnostic status for youths who: (a) retained an anxiety diagnosis from post to end point (minimal responders); (b) remitted anxiety diagnoses at post but relapsed by end point (relapsed responders); and (c) retained a diagnosis at post but remitted to be diagnosis free at end point (delayed responders). Growth curve models assessed patterns of change over time for the three groups and examined predictors associated with these patterns including demographic, clinical and parental factors, as well as treatment factors. RESULTS: Higher primary disorder severity, being older, having a greater number of anxiety disorders, having social anxiety disorder, as well as higher maternal psychopathology differentiated the minimal responders from the delayed and relapsed responders at the baseline. Results from the growth curve models showed that severity of the primary disorder and treatment modality differentiated patterns of linear change only. Higher severity was associated with significantly less improvement over time for the minimal and relapsed response groups, as was receiving group CBT, when compared to the delayed response group. CONCLUSIONS: Sub-optimal response patterns can be partially differentiated using variables assessed at pre-treatment. Increased understanding of different patterns of change following treatment may provide direction for clinical decision-making and for tailoring treatments to specific groups of clinically anxious youth. Future research may benefit from assessing progress during treatment to detect emerging response patterns earlier.

Effect of delay in treatment intensification in people with type 2 diabetes and suboptimal glycaemia after basal insulin initiation: A real-world observational study.

AIM: Despite global recommendations for type 2 diabetes mellitus treatment to maintain optimal glycaemic targets, a significant proportion of people remain in suboptimal glycaemic control. Our objective was to investigate the impact of intensification delay after basal insulin (BI) initiation on long-term complications in people with suboptimal glycaemia. MATERIALS AND METHODS: We conducted a retrospective cohort study in individuals with type 2 diabetes mellitus initiated on BI. Those with suboptimal glycaemia (glycated haemoglobin ≥7% or ≥53 mmol/mol) within 12 months of BI initiation were divided into early (treatment intensified within 5 years), or late (≥5 years) intensification groups. We estimated the age-stratified risks of micro- and macrovascular complications among these groups compared with those with optimal glycaemia (glycated haemoglobin <7%). RESULTS: Of the 13 916 people with suboptimal glycaemia, 52.5% (n = 7304) did not receive any treatment intensification. In those aged <65 years, compared with the optimal glycaemia group late intensification was associated with a 56% higher risk of macrovascular complications (adjusted hazard ratio 1.56; 95% confidence intervals 1.08, 2.26). In elderly people (≥65 years), late intensification was associated with a higher risk of cardiovascular-related death (1.62; 1.03, 2.54) and a lower risk of microvascular complications (0.26; 0.08, 0.83). CONCLUSIONS: Those who had late intensification were at an increased risk of cardiovascular death if they were ≥65 years and an increased risk of macrovascular complications if they were <65 years. These findings highlight the critical need for earlier intensification of treatment and adopting personalized treatment strategies to improve patient outcomes.

Intention and preference to use long-acting injectable PrEP among MSM in the Netherlands: a diffusion of innovation approach.

Long-acting injectable pre-exposure prophylaxis (LAI-PrEP) is efficacious in preventing HIV among men-who-have-sex-with-men (MSM) and will be soon available in Europe. This study investigated the intention and preference to use LAI-PrEP among MSM in the Netherlands by employing a diffusion of innovation approach. This study had a cross-sectional design nested within a cohort study established in 2017 to understand oral PrEP use among MSM. 309 MSM completed the survey on their awareness, interest, intention, and preference for LAI-PrEP in June 2022. Among them, 83% showed high/very-high interest in, and 63% showed high/very-high intention to use LAI-PrEP. A repeated innovator effect from the early adopters to LAI-PrEP was not observed. Early adopters did not show increased intention to use LAI-PrEP compared to other MSM subgroups, but neither did PrEP-naïve nor PrEP-discontinued MSM. However, among the 218 current oral PrEP users, suboptimal adherence was associated with preference for LAI-PrEP but not with intention to use it. In conclusion, our findings indicated that an effective, available, and affordable LAI-PrEP would be welcomed in the Netherlands, but that its introduction may not significantly expand PrEP coverage. However, the introduction of LAI-PrEP in the Netherlands could prove beneficial to MSM with suboptimal adherence to oral PrEP.

Recipients of public assistance with advanced chronic kidney disease: insights into receiving a presentation of kidney replacement therapy options and polypharmacy from Japanese investigators with innovative network about kidney disease study.

BACKGROUND: The characteristics of patients with advanced chronic kidney disease (CKD) who are recipients of public assistance in Japan, and the adequacy of their medical care have not been reported previously. METHODS: The records of patients with CKD stage G5 who visited nine facilities in Japan from April to June 2013 were retrospectively reviewed to compare the characteristics and care of recipients of public assistance with those of non-recipients. Receiving a presentation of kidney replacement therapy (KRT) options and polypharmacy were used as indicators of suboptimal medical care. RESULTS: Of the 592 patients included in this analysis (mean age, 69.6 years; male, 59.3%), 56 (9.5%) were recipients of public assistance and 536 (90.5%) were non-recipients of public assistance. The prevalence of diabetes mellitus, unmarried status, and living alone were higher in recipients of public assistance. In multivariable logistic regression analysis, compared with non-recipients of public assistance, recipients of public assistance were less likely to receive a presentation of KRT options (adjusted odds ratio [aOR], 0.31; 95% confidence interval [CI], 0.17-0.56), and were more likely to receive ≥ 10 (aOR, 1.92; 95% CI, 1.05-3.51), and ≥ 15 (aOR, 2.78; 95% CI, 1.23-6.26) types of medication. CONCLUSIONS: Patients with advanced CKD receiving public assistance were less likely to receive a presentation of KRT options and more likely to receive ≥ 10 and ≥ 15 types of medication, suggesting that recipients of public assistance are more likely to receive suboptimal medical care.

One-Anastomosis Gastric Bypass (OABG) vs. Single Anastomosis Duodeno-Ileal Bypass (SADI) as revisional procedure following Sleeve Gastrectomy: results of a multicenter study.

PURPOSE: Sleeve Gastrectomy (SG) is the most performed bariatric surgery, but a considerable number of patients may require revisional procedures for suboptimal clinical response/recurrence of weight (SCR/RoW). Conversion options include One-Anastomosis Gastric Bypass (OAGB) and Single Anastomosis Duodeno-Ileal Bypass (SADI). The study aims to compare SADI vs. OAGB as revisional procedures in terms of early and mid-term complications, operative time, postoperative hospital stay and clinical outcomes. METHODS: All patients who underwent OAGB or SADI as revisional procedures following SG for SCR/RoW at three high-volume bariatric centers between January 2014 and April 2021 were included. Propensity score matching (PSM) analysis was performed. Demographic, operative, and postoperative outcomes of the two groups were compared. RESULTS: One hundred and sixty-eight patients were identified. After PSM, the two groups included 42 OAGB and 42 SADI patients. Early (≤ 30 days) postoperative complications rate did not differ significantly between OAGB and SADI groups (3 bleedings vs. 0, p = 0.241). Mid-term (within 2 years) complications rate was significantly higher in the OAGB group (21.4% vs. 2.4%, p = 0.007), mainly anastomotic complications and reflux disease (12% of OAGBs). Seven OAGB patients required conversion to another procedure (Roux-en-Y Gastric Bypass-RYGB) vs. none among the SADI patients (p = 0.006). CONCLUSIONS: SADI and OAGB are both effective as revisional procedures for SCR/RoW after SG. OAGB is associated with a significantly higher rate of mid-term complications and a not negligible rate of conversion (RYGB). Larger studies are necessary to draw definitive conclusions.

Medications and cognitive risk in Aboriginal primary care: a cross-sectional study.

BACKGROUND: Aboriginal and Torres Strait Islander people are ageing with high rates of comorbidity, yet little is known about suboptimal prescribing in this population. AIM: The prevalence of potentially suboptimal prescribing and associated risk factors were investigated among older patients attending primary care through Aboriginal Community Controlled Health Services (ACCHSs). METHODS: Medical records of 420 systematically selected patients aged ≥50 years attending urban, rural and remote health services were audited. Polypharmacy (≥ 5 prescribed medications), potentially inappropriate medications (PIMs) as per Beers Criteria and anticholinergic burden (ACB) were estimated and associated risk factors were explored with logistic regression. RESULTS: The prevalence of polypharmacy, PIMs and ACB score ≥3 was 43%, 18% and 12% respectively. In multivariable logistic regression analyses, polypharmacy was less likely in rural (odds ratio (OR) = 0.43, 95% confidence interval (CI) = 0.24-0.77) compared to urban patients, and more likely in those with heart disease (OR = 2.62, 95% CI = 1.62-4.25), atrial fibrillation (OR = 4.25, 95% CI = 1.08-16.81), hypertension (OR = 2.14, 95% CI = 1.34-3.44), diabetes (OR = 2.72, 95% CI = 1.69-4.39) or depression (OR = 1.91, 95% CI = 1.19-3.06). PIMs were more frequent in females (OR = 1.88, 95% CI = 1.03-3.42) and less frequent in rural (OR = 0.41, 95% CI = 0.19-0.85) and remote (OR = 0.58, 95% CI = 0.29-1.18) patients. Factors associated with PIMs were kidney disease (OR = 2.60, 95% CI = 1.37-4.92), urinary incontinence (OR = 3.00, 95% CI = 1.02-8.83), depression (OR = 2.67, 95% CI = 1.50-4.77), heavy alcohol use (OR = 2.83, 95% CI = 1.39-5.75) and subjective cognitive concerns (OR = 2.69, 95% CI = 1.31-5.52). High ACB was less common in rural (OR = 0.10, 95% CI = 0.03-0.34) and remote (OR = 0.51, 95% CI = 0.25-1.04) patients and more common in those with kidney disease (OR = 3.07, 95% CI = 1.50-6.30) or depression (OR = 3.32, 95% CI = 1.70-6.47). CONCLUSION: Associations between potentially suboptimal prescribing and depression or cognitive concerns highlight the importance of considering medication review and deprescribing for these patients.

Prevalence of and factors associated with suboptimal glycemic control among patients with type 2 diabetes mellitus attending public hospitals in the Greater Male' Region, Maldives: a hospital-based cross-sectional study.

BACKGROUND: Suboptimal glycemic control of type 2 diabetes mellitus (T2DM) which is defined as having HbA1c greater than 7% is a major public health problem in several countries, including the Maldives. The study aimed to estimate the prevalence and determine factors associated with suboptimal glycemic control among T2DM patients. METHODS: A hospital-based cross-sectional was applied to collect data from T2DM patients who attended public hospitals in the Greater Male' Region, Maldives where were one of the highest reports of T2DM and suboptimal glycemic control cases in the country between January to March 2023 by a validated questionnaire and anthropometric measurements. Five (5) ml blood specimens were collected to measure the glycated hemoglobin (HbA1c) level. Univariable and multivariable logistic regressions were employed to determine factors associated with suboptimal glycemic control of T2DM at a significant level of α = 0.05. RESULTS: A total of 341 participants were recruited for the study: 65.7% were female, 42.5% were aged 40-60 years, and 42.2% were married. The overall prevalence of suboptimal glycemic control was 50.7%. Ten variables were found to be associated with suboptimal glycemic control in multivariable logistic regression. Those aged 40-60 years (AOR = 3.35, 95% CI = 1.78-6.30), being single (AOR = 2.53, 95% CI = 1.21-5.30), preparation of food using more than three tablespoons of cooking oil (AOR = 2.78, 95% CI = 1.46-5.28), preparation of food with more than three tablespoons of sugar (AOR = 2.55, 95% CI = 1.31-4.93), no exercise (AOR = 2.04, 95% CI = 1.15-3.61), DM diagnosed with more than twenty years prior (AOR = 2.59, 95% CI = 1.34-4.99), obese body mass index (BMI) (AOR = 3.82, 95% CI = 1.75-8.32), high total cholesterol (AOR = 2.43, 95% CI = 1.36-4.35), high triglycerides (AOR = 3.43, 95% CI = 1.93-6.11), and high-level stress (AOR = 2.97, 95% CI = 1.48-5.93) were having a greater odds of having suboptimal glycemic control than those who did not have these characteristics. CONCLUSION: A large proportion of T2DM patients in the Greater Male' Region fail to control their blood glucose. Effective public health interventions should be introduced, especially interventions focused on reducing cooking oil and sugar in daily cooking practices, encouraging regular exercise, and maintaining cholesterol levels, particularly for those diagnosed with diabetes mellitus for more than 20 years prior.

The mediating effect of lifestyle behaviors on the relationship between self-perceived work stress and suboptimal health status: a cross-sectional study involving Chinese urban workers.

STUDY DESIGN: Cross-sectional study. OBJECTIVES: Suboptimal health status (SHS) is a third state between health and disease. Long-term being SHS will be detrimental to one's ability development. Previous studies have demonstrated the associations of lifestyle behaviors or work stress with SHS, but few studies have comprehensively analyzed the underlying factors and mechanisms between the three. This study aimed to investigate whether lifestyle behaviors mediated the relationship between self-perceived work stress and SHS. METHODS: A total of 4238 urban workers, who participated in a cross-sectional survey conducted from December 2018 to October 2019, were included. A general linear model was used to explore the associations between lifestyle behaviors and self-perceived work stress with SHS after adjusting for demographic variables. Structural equation modeling was performed to examine the mediation by lifestyle behaviors. RESULTS: The mean transformed scores of physical, mental, and social SHS were 70.98, 67.17, and 61.72, respectively. Unhealthy lifestyle behaviors and high self-perceived work stress positively affected SHS (P < 0.001). Self-perceived work stress imposed negative effects on physical SHS (ß = -0.228, P < 0.001), mental SHS (ß = -0.237, P < 0.001), and social SHS (ß = -0.092, P < 0.001). The indirect effects of self-perceived work stress on physical SHS (ß = -0.139, 95% CI: -0.178 to -0.106), mental SHS (ß = -0.106, 95% CI: -0.134 to -0.082), and social SHS (ß = -0.121, 95% CI: -0.154 to -0.092) were statistically significant. CONCLUSIONS: Lifestyle behaviors and self-perceived work stress were significantly associated with SHS among Chinese urban workers. The mediating effects of unhealthy lifestyle behaviors were found in the relationship between high self-perceived work stress and SHS. Future longitudinal research may verify these associations and elucidate the underlying mechanisms.

A One-Step RPA-CRISPR Assay Using crRNA Based on Suboptimal Protospacer Adjacent Motif for Vibrio vulnificus Detection.

Vibrio vulnificus is a hazardous foodborne pathogen responsible for approximately 95% of seafood-related deaths. This highlights the urgent requirement for specialized detection tools to be developed and used by food enterprises and food safety authorities. The DETECTR (DNA endonuclease targeted CRISPR trans reporter) system that combines CRISPR/Cas and recombinase polymerase amplification (RPA) has been utilized to develop a molecular detection assay for V. vulnificus. However, because the incompatibility between RPA and Cas12a cleavage has not been addressed, it is a two-step assay that lacks convenience and presents contamination risk. Here, we developed a one-step RPA-CRISPR assay for V. vulnificus using a special crRNA targeting a sequence with a suboptimal protospacer adjacent motif (PAM). The entire assay, conducted at 37°C, takes only 40-60 min, yields results visualized under blue light, and exhibits exceptional specificity and sensitivity (detecting 4 pathogen genome copies per reaction). This study offers a valuable tool for detecting V. vulnificus, aiding in foodborne infection prevention, and exemplifies one-step RPA-CRISPR assays managing Cas-cleavage activity through PAM adjustments.

Mitigation of cold stress in Nile tilapia (Oreochromis niloticus) through dietary lipids supplementation: a preliminary network meta-analysis.

There is a growing body of evidence suggesting that water temperature can significantly impact the dietary fatty acid requirements of Nile tilapia (Oreochromis niloticus). Therefore, this study assessed the effectiveness of different dietary lipid sources on the growth performance of Nile tilapia reared at suboptimal temperatures. A network meta-analysis was performed, including searches of PubMed and Scopus from inception to January 2022, for trials that evaluated the effects of lipid sources on cold-stressed Nile tilapia. The Bayesian hierarchical framework was used to pool and compare the effect sizes of growth parameters such as weight gain, feed intake, and feed conversion ratio (FCR). Furthermore, the surface under the cumulative ranking curve (SUCRA) was obtained to calculate the probability that each lipid source was the most effective against cold stress. All subsequent numbers refer to comparisons with diets containing only fish oil. Dietary Aurantiochytrium significantly increased weight gain (SMD = 2.00, CrI: 0.70 to 3.40). In contrast, diets containing coconut oil led to significantly lower weight gain (SMD = - 3.30, CrI: - 6.00 to - 0.63) and higher FCR (SMD = 17.0, CrI: 6.70 to 27.0). Additionally, dietary corn oil was associated with a decrease in feed intake (SMD = - 2.32, CrI: - 3.91 to - 0.80), while a combination of fish and corn oil reduced FCR (SMD = - 5.70, CrI: - 11.0 to - 0.81). In general, the analysis of SUCRA values revealed that in cold-stressed Nile tilapia, Aurantiochytrium, sunflower oil, and the combination of fish and corn oil were the most effective lipid sources for improving growth at suboptimal temperatures. The results of the current study can serve as a basis for future studies that focus on the use of dietary lipid sources to mitigate cold stress in Nile tilapia.

Suboptimal response to tumor necrosis factor antagonists in inflammatory bowel disease in Latin America: EXPLORE LATAM study.

OBJECTIVE: Data on anti-tumor necrosis factor (anti-TNF) treatment and suboptimal response (SOR) among patients with inflammatory bowel diseases (IBD) in Latin America (LATAM) are scarce. This study evaluated the incidence and indicators of SOR to anti-TNF therapy in patients with ulcerative colitis (UC) and Crohn's disease (CD) from Argentina, Colombia and Mexico. PATIENTS AND METHODS: We performed retrospective analysis of data from LATAM patients of the EXPLORE study (NCT03090139) including adult patients with IBD who initiated anti-TNF therapy between March 2010 to March 2015. The cumulative incidence of SOR to first-line anti-TNF therapy was assessed. A physician survey to assess barriers to anti-TNF therapies was also carried out. RESULTS: We included 185 IBD patients (UC/CD: 99/86) treated with first-line anti-TNF from Argentina (38 UC; 40 CD), Colombia (21 UC; 25 CD) and Mexico (40 UC; 21 CD). 36.4% of patients with UC and 46.5% of patients with CD experienced SOR to anti-TNF therapy during the median (interquartile range) observational period: 49.0 months (37.2-60.1) in UC, and 50.0 months (40.9-60.1) in CD. The most common indicator of SOR among patients was augmentation of non-biologic therapy (UC: 41.7%; CD: 35.0%). Affordability and late referral to IBD specialist care centers were the most common barriers to anti-TNF therapies. CONCLUSIONS: SOR to anti-TNF therapy was common in LATAM IBD patients, where augmentation with non-biologic therapy represented the most frequent indicator of SOR across indications. Our findings contribute to the current evidence on the unmet needs associated with anti-TNF in LATAM.

Aesthetic grading causes food losses without financially benefiting farmers: Micro-level evidence from China's fresh apple supply chain.

International literature is lacking quantified information about the impact of raising demands for attractive appearances and the private standards on food loss and associated effects on the economy, the environment and social issues. Given the global scale and significance to food consumption and health, fresh apples were selected for researching the issues. By focusing on China, the major production region of fresh apple in the world where the effects of aesthetic preference and shape abnormality are substantial, the present study aims to gain insights into the on-farm grading processes and different marketing channels for fresh apples in China. It was discovered that 35% of the volume in China's major production areas of fresh apples were graded by aesthetic characteristics such as ripeness, colour, fragrance, bruising, intactness and appealing appearance. About 17.1% of production on average were considered as food losses mainly caused by such grading schemes. Favouring 'perfect' appearance; however, the grading did not yield economic benefits for smallholders. Lastly, direct procurement by supermarkets had a depressive effect on the price of fresh apples at the farm gate. The study has a unique value for global debates and actions against food loss and waste as it quantifies on-farm post-harvest losses of fresh apples by different agri-food chain organizations in China with respect to mass and economic value.

Paradoxical choice and the reinforcing value of information.

Signals that reduce uncertainty can be valuable because well-informed decision-makers can better align their preferences to opportunities. However, some birds and mammals display an appetite for informative signals that cannot be used to increase returns. We explore the role that reward-predictive stimuli have in fostering such preferences, aiming at distinguishing between two putative underlying mechanisms. The 'information hypothesis' proposes that reducing uncertainty is reinforcing per se, somewhat consistently with the concept of curiosity: a motivation to know in the absence of tractable extrinsic benefits. In contrast, the 'conditioned reinforcement hypothesis', an associative account, proposes asymmetries in secondarily acquired reinforcement: post-choice stimuli announcing forthcoming rewards (S+) reinforce responses more than stimuli signalling no rewards (S-) inhibit responses. In three treatments, rats faced two equally profitable options delivering food probabilistically after a fixed delay. In the informative option (Info), food or no food was signalled immediately after choice, whereas in the non-informative option (NoInfo) outcomes were uncertain until the delay lapsed. Subjects preferred Info when (1) both outcomes were explicitly signalled by salient auditory cues, (2) only forthcoming food delivery was explicitly signalled, and (3) only the absence of forthcoming reward was explicitly signalled. Acquisition was slower in (3), when food was not explicitly signalled, showing that signals for positive outcomes have a greater influence on the development of preference than signals for negative ones. Our results are consistent with an elaborated conditioned reinforcement account, and with the conjecture that both uncertainty reduction and conditioned reinforcement jointly act to generate preference.

BCR::ABL1 kinase domain mutation testing and clinical outcome in a nationwide chronic myeloid leukemia patient population.

OBJECTIVES: Acquired missense mutations in the BCR::ABL1 kinase domain (KD) may cause tyrosine kinase inhibitor (TKI) treatment failure. Based on mutation-specific in vitro derived IC50-values, alternative TKI may be selected. We assessed clinical practice of BCR::ABL1 KD mutation testing, clinical response in relation to IC50-values, and clinical outcome of tested patients. METHODS: Patients from six Dutch CML reference centers and a national registry were included once a mutational analysis was performed. Reasons for testing were categorized as suboptimal TKI response, and primary or secondary TKI resistance. RESULTS: Four hundred twenty analyses were performed in 275 patients. Sixty-nine patients harbored at least one mutation. Most analyses were performed because of suboptimal TKI response but with low mutation incidence (4%), while most mutations were found in primary and secondary resistant patients (21% and 51%, respectively). Harboring a BCR::ABL1 mutation was associated with inferior overall survival (HR 3.2 [95% CI, 1.7-6.1; p < .001]). Clinically observed responses to TKI usually corresponded with the predicted TKI sensitivity based on the IC50-values, but a high IC50-value did not preclude a good clinical response per se. CONCLUSIONS: We recommend BCR::ABL1 KD mutation testing in particular in the context of primary or secondary resistance. IC50-values can direct the TKI choice for CML patients, but clinical efficacy can be seen despite adverse in vitro resistance.

Advancing therapy in people with suboptimally controlled basal insulin-treated type 2 diabetes: Subanalysis of the SoliMix trial in participants in Latin American countries.

AIMS: This subanalysis of the SoliMix trial assessed the efficacy and safety of advancing basal insulin (BI) therapy with iGlarLixi versus BIAsp 30 in people with type 2 diabetes (T2D) living in Latin American (LATAM) countries, i.e. Argentina and Mexico (N = 160). MATERIALS AND METHODS: SoliMix (EudraCT: 2017-003370-13) was a 26-week, open-label, multicentre study, where adults with T2D suboptimally controlled with BI plus one or two oral glucose-lowering drugs and glycated haemoglobin (HbA1c) ≥7.5% to ≤10% were randomized to once-daily iGlarLixi or twice-daily BIAsp 30. Primary efficacy endpoints were non-inferiority in HbA1c reduction (margin 0.3%) or superiority in body weight change for iGlarLixi versus BIAsp 30. RESULTS: Both primary efficacy endpoints were met in the LATAM region. After 26 weeks, HbA1c was reduced by 1.8% with iGlarLixi and 1.4% with BIAsp 30, meeting non-inferiority [least squares mean difference -0.47% (95% confidence interval: -0.82, -0.11); p < .001]. iGlarLixi was superior to BIAsp 30 for body weight change [least squares mean difference -1.27% (95% confidence interval: -2.41, -0.14); p = .028]. iGlarLixi was also superior to BIAsp 30 for HbA1c reduction (p = .010). A greater proportion of participants achieved HbA1c <7% without weight gain and HbA1c <7% without weight gain and without hypoglycaemia with iGlarLixi versus BIAsp 30. Incidence and rates of American Diabetes Association Level 1 and 2 hypoglycaemia were lower with iGlarLixi versus BIAsp 30. CONCLUSIONS: Once-daily iGlarLixi provided better glycaemic control with weight benefit and less hypoglycaemia than twice-daily premix BIAsp 30. iGlarLixi may be a favourable alternative to premix BIAsp 30 in people with suboptimally controlled T2D to advance BI therapy in the LATAM region.