Relationship between diabetic peripheral neuropathy and adherence to the Mediterranean diet in patients with type 2 diabetes mellitus: an observational study.

PURPOSE: The main study goal is to assess the relationship between adherence to the mediterranean diet (MD) and the presence of diabetic peripheral neuropathy (DPN) in patients with type 2 diabetes mellitus (T2DM). METHODS: Observational pilot study of 174 patients diagnosed with T2DM. Sociodemographic and anthropometric variables, physical activity, smoking habits, blood biochemical parameters and comorbidities were recorded. The presence of alterations in sensitivity to pressure, pain, thermal and vibration was explored. Good MD adherence was a score ≥ 9 the 14-point MD adherence questionnaire (MEDAS-14). RESULTS: The study population consisted of 174 patients (61.5% men and 38.5% women), with a mean age of 69.56 ± 8.86 years; 19% of these patients adhered to the MD. The score obtained in the MEDAS-14 was higher in patients who did not present alterations in sensitivity to pressure (p = 0.047) or vibration (p = 0.021). The patients without diabetic peripheral neuropathy were more likely to comply with the MD and had a higher score on the MEDAS-14 (p = 0.047). However, multivariate analysis showed that only altered sensitivity to pressure was associated with adherence to the MD (altered sensitivity OR = 2.9; 95%CI 1.02-8.22; p = 0.045). CONCLUSIONS: Although the patients with DPN had lower scores on the MEDAS questionnaire and therefore poorer adherence to the mediterranean diet, the only parameter significantly associated with the MD was that of sensitivity to pressure (monofilament test).

Tropical tree foliage supplementation in ruminants improves rumen fermentation and the bacterial profile and decreases methane production.

The main of this study was to evaluate the effect of supplementation of tropical tree foliage in ruminant diets on the in vitro fermentation, bacterial population, volatile fatty acids (VFAs), and enteric CH4 production. Seven experimental diets were evaluated: a control treatment of Pennisetum purpureum (T7) and six treatments of P. purpureum supplemented (30%) with the foliage of Neomillspaughia emargiata (T1), Tabernaemontana amygdalifolia (T2), Caesalpinia gaumeri (T3), Piscidia piscipula (T4), Leucaena leucocephala (T5), and Havardia albicans (T6). The T2, T7, and T5 treatments had the highest (p < 0.05) digestibility of dry matter. Overall, supplementation increased (p < 0.05) the concentrations of propionic and butyric acid and decreased acetic acid. Methanogenic bacteria decreased (p < 0.05) in T1, T2, T5, and T6. Ruminococcus albus decreased in T1, T2, T3, and T5 and Selenomonas ruminiantum increased in T3. Fibrobacter succinogenes increased, except in T5. Methane production decreased (p < 0.05) in T1, T4, T5, and T6. The supplementation with Leucaena leucocephala, Tabernaemontana amygdalifolia, Neomillspaughia emargiata, Piscidia piscipula, Havardia albicans, and Caesalpinia gaumeri is a potential alternative nutritional strategy for ruminants that results in positive changes in VFAs profile, a decrease on CH4 production and methanogenic bacteria, and changes on fibrolytic and non-fibrolytic bacteria composition.HIGHLIGHTSTropical tree foliage supplementation increased propionic and butyric acid and decreased acetic acid concentrations.Fibrolytic, non-fibrolytic, and Methanogenic bacteria were selectively modulated with the supplementation of tropical tree foliage.The enteric methane (CH4) production decreased with the supplementation of tree foliage.The supplementation of Tabernaemontana amygdalifolia and Leucaena leucocephala had the highest digestibility and is a potential alternative nutritional strategy for ruminants.

Craniomaxillofacial morphology alterations in children, adolescents and adults with neurofibromatosis 1: A cone beam computed tomography analysis of a Brazilian sample.

BACKGROUND: Oral manifestations are common in neurofibromatosis 1 (NF1), and include jaws and teeth alterations. Our aim was to investigate the craniomaxillofacial morphology of Brazilian children, adolescents and adults with NF1 using cone beam computed tomography. MATERIAL AND METHODS: This study was conducted with 36 Brazilian individuals with NF1 with ages ranging from 4 to 75. The participants were submitted to anamnesis, extra and intraoral exam and cephalometric analysis using cone beam computed tomography. Height of the NF1 individuals was compared to the length of jaws and skull base. The results of the cephalometric measurements of the NF1 group were compared with a control group paired by age, gender and skin color. RESULTS: Individuals with NF1 had lower maxillary length (p<0.0001), lower mandibular length (p<0.0001), lower skull base length (p<0.0001). In children and adolescents, the mandible was more posteriorly positioned (p=0.01), when compared with the control group. There was no association between jaws and skull base length with the height of the individuals with NF1. CONCLUSIONS: Brazilian children, adolescents and adults with NF1 have short mandible, maxilla and skull base. Moreover, children and adolescents present mandibular retrusion.

Detection and Characterization of Xanthomonas vasicola pv. vasculorum (Cobb 1894) comb. nov. Causing Bacterial Leaf Streak of Corn in the United States.

Bacterial leaf streak of corn (Zea mays) recently reached epidemic levels in three corn-growing states, and has been detected in another six states in the central United States. Xanthomonas vasicola was identified as the causal agent of this disease. A multilocus sequence alignment of six housekeeping genes and comparison of average nucleotide identity from draft genome sequence were used to confirm phylogenetic relationships and classification of this bacteria relative to other X. vasicola strains. X. vasicola isolates from Nebraska and South Africa were highly virulent on corn and sugarcane and less virulent on sorghum but caused water-soaking symptoms that are typical of X. vasicola infection on the leaves of all three hosts. Based on host range and phylogenetic comparison, we propose the taxonomic designation of this organism to X. vasicola pv. vasculorum ( Cobb 1894 ) comb. nov. Polymerase chain reaction-based diagnostic assays were developed that distinguish X. vasicola pv. vasculorum and X. vasicola pv. holcicola from each other and from other Xanthomonas spp.

Pre-transplant shedding of BK virus in urine is unrelated to post-transplant viruria and viremia in kidney transplant recipients.

BK virus-(BKV) associated nephropathy (BKVN) is a major cause of allograft injury in kidney transplant recipients. In such patients, subclinical reactivation of latent BKV infection can occur in the pre-transplant period. The purpose of this study was to determine whether urinary BKV shedding in the immediate pre-transplant period is associated with a higher incidence of viruria and viremia during the first year after kidney transplantation. We examined urine samples from 34 kidney transplant recipients, using real-time quantitative polymerase chain reaction to detect BKV. Urine samples were obtained in the immediate pre-transplant period and during the first year after transplant on a monthly basis. If BKV viruria was detected, blood samples were collected and screened for BKV viremia. In the immediate pre-transplant period, we detected BKV viruria in 11 (32.3%) of the 34 recipients. During the first year after transplantation, we detected BKV viruria in all 34 patients and viremia in eight (23.5%). We found no correlation between pre-transplant viruria and post-transplant viruria or viremia (p = 0.2). Although reactivation of latent BKV infection in the pre-transplant period is fairly common among kidney transplant recipients, it is not a risk factor for post-transplant BKV viruria or viremia.

Spontaneous formation of three-dimensionally ordered Bi-rich nanostructures within GaAs1-x Bi x /GaAs quantum wells.

In this work, we report on the spontaneous formation of ordered arrays of nanometer-sized Bi-rich structures due to lateral composition modulations in Ga(As,Bi)/GaAs quantum wells grown by molecular beam epitaxy. The overall microstructure and chemical distribution is investigated using transmission electron microscopy. The information is complemented by synchrotron x-ray grazing incidence diffraction, which provides insight into the in-plane arrangement. Due to the vertical inheritance of the lateral modulation, the Bi-rich nanostructures eventually shape into a three-dimensional assembly. Whereas the Bi-rich nanostructures are created via two-dimensional phase separation at the growing surface, our results suggest that the process is assisted by Bi segregation which is demonstrated to be strong and more complex than expected, implying both lateral and vertical (surface segregation) mass transport. As demonstrated here, the inherent thermodynamic miscibility gap of Ga(As,Bi) alloys can be exploited to create highly uniform Bi-rich units embedded in a quantum confinement structure.

Association between the CDH1-472delA and -160C>A polymorphisms and diffuse and intestinal gastric cancer in a Mexican population.

Gastric cancer (GC), the third leading cause of cancer-related deaths in Mexico and worldwide, can be classified into diffuse (DGC) or intestinal (IGC) types based on its histological characteristics. DGC is characterized by reduced expression of the cell adhesion protein E-cadherin, which is encoded by CDH1. The -472delA (rs5030625) and -160C>A (rs16260) polymorphisms in CDH1 induce a decrease in gene transcription; in fact, these mutated alleles have been associated with GC in some populations, with conflicting results. The aim of this study was to determine the association between the CDH1 -472delA and -160C>A polymorphisms and DGC and IGC in Mexican patients. The study was conducted in 24, 23, 48, and 93 individuals with DGC and IGC, without GC (control), and belonging to the general Mexican population (GMP), respectively. The genotypes were obtained by polymerase chain reaction - restriction fragment length polymorphism and the obtained data analyzed using Arlequin 3.1. The frequencies of the mutated allele (A) of -472delA were 0.326, 0.318, 0.284, and 0.296 in the DGC, IGC, control, and GMP groups, respectively, and those of the -160C>A polymorphism were 0.174, 0.318, 0.313, and 0.280, respectively. The genotype and allele frequencies of the two polymorphisms did not differ significantly (P > 0.05) among DGC, IGC, and control subjects. Therefore, we concluded that the CDH1 -472delA and -160C>A polymorphisms are not associated with DGC or IGC in patients from western Mexico.

EGFR gene polymorphisms -216G>T and -191C>A are risk markers for gastric cancer in Mexican population.

Epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein with tyrosine-kinase activity that plays an important role in multiple cellular functions. EGFR overexpression has been observed in several types of tumors and it is significantly associated with disease stage, survival, prognosis, and progression of cancer. The polymorphisms -216G>T, -191C>A, and (CA)n first intervening sequence (IVS1) have been related to EGFR overexpression and have been studied in several types of cancer, but not in gastric cancer (GC). The aim of this study was to determine the association of these 3 polymorphisms and GC. Genomic DNA from 68 GC patients and 102 healthy blood donors were analyzed. Polymorphisms were identified by DNA-sequencing (-216G>T and -191C>A) and GeneScan (CA)n IVS1. The results showed that the distribution of the -216G>T and -191C>A genotypes differed between groups (P < 0.05). The odds ratio for the -216TT genotype was 4.59 (95% confidence interval = 1.55-13.54, P < 0.05) and 10.71 (95% confidence interval = 2.31-49.59, P < 0.05) for the -191AA genotype, both in a recessive model. The genotype and allele distributions of the (CA)n IVS1 repeat was similar in both groups. In conclusion, the -216TT and -191AA genotypes and GA haplotype of the EGFR gene were found to be associated with an increased risk of gastric cancer in a Mexican population.

Evaluation of the sensitivity of IgG and IgM ELISA in detecting Schistosoma mansoni infections in a low endemicity setting.

Schistosomiasis is a major public health concern, with 200 million people infected worldwide. In Brazil, this disease has been reported in 19 states, and its prevalence in the city of Barra Mansa in Rio de Janeiro State is 1 %. The parasitological diagnostic methods currently available in these areas lack sensitivity; however, enzyme-linked immunosorbent assays (ELISAs) have been employed successfully for the diagnosis of schistosomiasis by using antibodies against antigens of Schistosoma mansoni adult worms and eggs, and for the detection of circulating antigens. The objective of this study was to determine systematically the prevalence of S. mansoni infection in the peripheral areas of Barra Mansa. A cross-sectional study was conducted from April to December 2011 by using probabilistic sampling that collected 610 fecal samples and 612 serum samples. ELISA-IgG with total extracts and ELISA-IgM with trichloroacetic acid-soluble fractions were employed to detect antibodies against S. mansoni and were compared with the Kato-Katz and Hoffman parasitological techniques. Among the individuals studied, anti-S. mansoni antibodies were detected in 11.16 % (n = 71) by ELISA-IgG and in 20.75 % (n = 132) by ELISA-IgM, while the parasitological techniques showed 0.82 % (n = 5) positivity. The agreement between the two ELISA tests was 85.38 % (n = 543), and 8.65 % (n = 55) of the serum samples showed positive results in both tests. The higher positivity of the ELISA-IgM test corroborates the results of previous reports and indicates that the test may be a useful tool in epidemiological studies, particularly in areas of low endemicity for S. mansoni.

Macular optical coherence tomography findings and GPR143 mutations in patients with ocular albinism.

The aim of this study was to describe macular findings using spectral-domain optical coherence tomography (SD-OCT) in patients with ocular albinism (OA) and their carrier mothers, and to identify the frequency of GPR143 gene mutations in these patients. The study included five patients with a clinical diagnosis of OA. SD-OCT of the macular area was performed in both patients and their mothers. The anatomical characteristics of the macula and retinal pigment epithelium (RPE), patterns of autofluorescence and infrared imaging were analyzed. Polymerase chain reaction amplification of the complete coding sequence of GPR 143 was performed and subsequently analyzed by direct sequencing in patients and their possible carrier mothers. SD-OCT images revealed the presence of inner retinal layers in the fovea, an abnormal disposition of the Henle layer and a lack of thickening in the perifoveal area. We found increased thickness in the RPE to the outer segment and in the outer segment to the outer nuclear layer that is associated with increased visual acuity. Autofluorescence images revealed an absence of normal hipoautofluorescence in the fovea. No changes were observed in the images of their carrier mothers. Mutation screening and sequence analysis of the GPR 143 gene revealed a novel pathological mutation in two patients. Abnormalities in the macula were observed in all patients. SD-OCT is a useful tool for the assessment of patients with OA. No changes were observed in the SD-OCT of carrier mothers. Only two patients had the GPR143 gene mutation.

[Genetic factors associated with long COVID]. / Factores genéticos asociados a long COVID.

INTRODUCTION: The variability in expression and evolution of COVID is not completely explained by clinical factors. In fact, genetic factors play an important role. Moreover, it is unknown whether the genetic factor that contribute to susceptibility and severity are also involved in the onset and evolution of long-COVID. The objective of this review is to gather information from literature to understand which genetic factors are involved in the onset of persistent COVID. MATERIAL AND METHODS: Systematic review in PubMed and bioRxiv and medRxiv repositories based on MeSH-descriptors and MeSH-terms related to COVID and genetic factors. Using these terms 2715 articles were pooled. An initial screening performed by authors independently, selected 205 articles of interest. A final deeper screening a total of 85 articles were chosen for complete reading and summarized in this review. RESULTS: Although ACE2 and TMPSS6 are involved in COVID susceptibility, their involvement in long-COVID has not been found. On the other hand, the severity of the disease and the onset of long-COVID has been associated with different genes involved in the inflammatory and immune response. Particularly interesting has been the association found with the FOXP4 locus. CONCLUSIONS: Although studies on long-COVID are insufficient to fully comprehend the cause, it is clear that the current identified genetic factors do not fully explain the progression and onset of long-COVID. Other factors such as polygenic action, pleiotropic genes, the microbiota and epigenetic changes must be considered and studied.

Interevaluator reliability of a tool for measuring body height in adult intensive care patients.

BACKGROUND: The calculation of body height in the intensive care unit is essential for obtaining the ideal body weight, which is used to program the tidal volume and establish objective and effective pulmonary ventilation. The objective of the study was to determine the interrater reliability of a tool for measuring body height in adult patients in an intensive care unit (ICU) in southwestern Colombia. METHODS: This cross-sectional observational study was conducted between January and May 2021, following the recommendations of the COSMIN protocol. Two physiotherapists in the roles of observer/evaluator measured the heights of 106 patients upon admission to the ICU with a previously designed. The sample size was calculated based on Pearson's correlation coefficient. For interrater reliability, the intraclass correlation coefficient (ICC) was used, and Bland-Altman analysis was used to assess concordance. The 95% confidence interval was established, and a P value <0.05 indicated statistical significance. RESULTS: A total of 106 individuals with a mean age of 59.3 years were included; the mean body height was 158.5 cm for women. The interrater reliability of the measurement of height was excellent (global ICC of 0.99, P = 0.000), and an almost perfect positive correlation was obtained between the raters for both women and men (R = 0.99). CONCLUSIONS: Excellent interrater/interobserver reliability was obtained for the measurement of body height in the ICU. This research highlights the importance of protocolizing the measurement of height in critical patients with valid and reliable instruments.

Prevalence, risk factors, and impact of long COVID in a socially vulnerable community in Brazil: a prospective cohort study.

Background: Long COVID is an emerging global public health issue. Socially vulnerable communities in low- and-middle-income countries were severely impacted by the pandemic and are underrepresented in research. This prospective study aimed to determine the prevalence of long COVID, its impact on health, and associated risk factors in one such community in Rio de Janeiro, Brazil. Methods: A total of 710 individuals aged 18 and older, with confirmed SARS-CoV-2 infection at least three months prior, were enrolled between November 25, 2021, and May 5, 2022. Participants were assessed via telephone or in person using a standardized questionnaire to evaluate their perception of recovery, symptoms, quality of life, and functional status. Findings: Twenty percent of participants did not feel fully recovered, 22% experienced new or persistent symptoms, 26% had worsened functional status, 18% had increased dyspnoea, and 32% reported a worse quality of life. Persistent symptoms included headache, cough, fatigue, muscle pain, and shortness of breath. Dyspnoea during the acute phase was the strongest independent predictor of worsening outcomes. Females and individuals with comorbidities were more likely to report worse recovery, functioning, dyspnoea, and quality of life. Interpretation: Our findings reveal a high burden of severe and persistent physical and mental health sequelae in a socially vulnerable community following COVID-19. Funding: UK Foreign, Commonwealth and Development Office and Wellcome Trust Grant (222048/Z/20/Z), Fundação Oswaldo Cruz (FIOCRUZ), Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), and the Centers for Disease Control and Prevention (CDC).

HyDRa: control of parameters for deterministic polishing.

Deterministic hydrodynamic polishing with HyDRa requires a precise control of polishing parameters, such as propelling air pressure, slurry density, slurry flux and tool height. We describe the HyDRa polishing system and prove how precise, deterministic polishing can be achieved in terms of the control of these parameters. The polishing results of an 84 cm hyperbolic mirror are presented to illustrate how the stability of these parameters is important to obtain high-quality surfaces.

Anti-cardiolipin and anti-ß2-glycoprotein I antibodies: normal reference ranges in northwestern Italy.

Laboratory tests for anticardiolipin antibodies (aCL) and anti-ß2glycoprotein I antibodies (a-ß2GPI) face problems common to many autoantibody assays: the lack of a reference standard and the need for each laboratory to assess assay-specific cut-off values. The aims of the study were to evaluate the reference range upper limits (99th percentile) used for aCL and a-ß2GPI in the northwest of Italy and to investigate the analytical performances of these assays with the newly obtained reference ranges. We assayed aCL and a-ß2GPI in 104 serum samples from patients without a history of thrombosis, pregnancy morbidity, tumours, infections and/or autoimmune diseases (30 males and 74 non-pregnant females). We tested all the commercial assays available in our regions (i.e. Orgentec Diagnostika, Aesku Diagnostics and Inova Diagnostics ELISA; CliA Zenit-RA and EliA Phadia Laboratory Systems). A further 30 serum samples, including 10 from healthy subjects, 10 from antiphospholipid syndrome (APS) patients and 10 from septic patients were assessed to investigate the analytical performance of the obtained cut-off limits. Reference range upper limits obtained with the commercial kits differ among assays and from the values reported by the manufacturer. Moreover, normal reference ranges calculated for IgG and IgM aCL differed from the arbitrary selected laboratory classification values suggested in the guidelines of 40 GPL and MPL.

[Celiac disease: descriptive study at the Anglo American clinic]. / Enfermedad celiaca: estudio descriptivo en la clínica Anglo Americana.

BACKGROUND: Celiac disease (CD) is a condition in which gluten intake develops an autoimmune response generating intestinal villous atrophy, causing malabsorption. Prevalence worldwide is approximately 1%, in our country it is not known. MATERIAL AND METHODS: Retrospective, descriptive, observational study in Anglo American Clinic between September 2004 and February 2012. We reviewed the medical charts, upper GI endoscopy reports and duodenal biopsy reports of all patients with positive anti TTG results, who were older than 18 years of age. RESULTS: We studied 39 cases, 26 (66.7%) women and 13 (33.3%) men. Mean age was 61.25 years. The symptoms were chronic diarrhea in 32 (82.1%), abdominal pain in 22 (56.4%), abdominal distention in 14 (35.9%), and others in lower frequency. Eight (20.5%) patients had anemia. Just 5 (12.8%) had upper endoscopy findings consistent with CD, and Marsh classification was: 0: 5 (12.7%), I: 1 (2.6%), II: 0 (0%), IIII A: 20 (51.3%), III B: 12 (30.8%) y III C: 1 (2.6%). CONCLUSIONS: CD should be considered as a differential diagnosis of patients with non-specific long-term gastrointestinal symptoms, extraintestinal symptoms should also be taken into account. Diagnosis should be made with anti TTG as the initial test and posteriorly with a duodenal biopsy for staging.

The role of vagus nerve stimulation in the treatment of refractory epilepsy: clinical outcomes and impact on quality of life.

BACKGROUND: Vagus nerve stimulation (VNS) is used as a complementary therapy to pharmacological treatment in patients with refractory epilepsy. This study aims to evaluate the efficacy of VNS in reducing seizure frequency, severity, and duration; reducing the number of antiepileptic drugs administered; and improving patients' quality of life. MATERIAL AND METHODS: We analysed the clinical progression of 70 patients with refractory epilepsy treated with VNS at Hospital Universitario de Alicante and Hospital Clínico de Valencia. Data were collected before and after the procedure. The difference in seizure frequency pre- and post-VNS was classified using the McHugh scale. Data were also collected on seizure duration and severity, the number of drugs administered, and quality of life. RESULTS: According to the McHugh classification, 12.86% of the patients were Class I, 44.29% were Class II, 40% were Class III, and the remaining 2.86% of patients were Class IV-V. A ≥ 50% reduction in seizure frequency was observed in 57.15% of patients. Improvements were observed in seizure duration in 88% of patients and in seizure severity in 68%; the number of drugs administered was reduced in 66% of patients, and 93% reported better quality of life. CONCLUSIONS: VNS is effective for reducing seizure frequency, duration, and severity and the number of antiepileptic drugs administered. It also enables an improvement in patients' quality of life.

Inter-rater reliability of the measurement of diaphragmatic excursion and fraction of diaphragmatic thickening by ultrasonography in healthy volunteers.

BACKGROUND AND OBJECTIVE: To determine the inter-rater reliability in the ultrasonographic (US) measurement of the diaphragmatic excursion (DE) and the diaphragm thickness fraction (DTF) performed by non-medical health professionals in healthy people. PARTICIPANTS AND METHODS: Prospective observational study in a third level hospital in Cali, Colombia. Measurements were made to 30 healthy volunteers chosen by convenience sampling, without a history of lung diseases, with ages between 18-60 years. A pilot test was previously carried out with 8 healthy volunteers. US measurements of DE, and DTF were based on previously published protocols. Each assessor independently observed several cycles of normal quiet breathing for 3min to establish a baseline. The Intraclass Correlation Index (ICC) was used to evaluate the inter-rater reliability in the measurements of DE and DTF, with 95% confidence intervals and a p<0.05. RESULTS: Substantial agreement was identified in the measurement of DE in the splenic and hepatic windows because the ICC was greater than 0.6 (p<0.05). The measurement of the DTF in the hepatic window showed slight agreement in both 2D and M modes (p>0.05). In the splenic window, the measurement of the DTF in the 2D mode was found to be moderate agreement and for the M mode a slight agreement was found (p>0.05). CONCLUSIONS: The diaphragmatic US constitutes a reproducible method with acceptable inter-rater reliability for the measurement of inspiratory/expiratory thickness, and with little reliability for the measurement of DTF.

Quantitative systems pharmacology modeling sheds light into the dose response relationship of a trispecific T cell engager in multiple myeloma.

In relapsed and refractory multiple myeloma (RRMM), there are few treatment options once patients progress from the established standard of care. Several bispecific T-cell engagers (TCE) are in clinical development for multiple myeloma (MM), designed to promote T-cell activation and tumor killing by binding a T-cell receptor and a myeloma target. In this study we employ both computational and experimental tools to investigate how a novel trispecific TCE improves activation, proliferation, and cytolytic activity of T-cells against MM cells. In addition to binding CD3 on T-cells and CD38 on tumor cells, the trispecific binds CD28, which serves as both co-stimulation for T-cell activation and an additional tumor target. We have established a robust rule-based quantitative systems pharmacology (QSP) model trained against T-cell activation, cytotoxicity, and cytokine data, and used it to gain insight into the complex dose response of this drug. We predict that CD3-CD28-CD38 killing capacity increases rapidly in low dose levels, and with higher doses, killing plateaus rather than following the bell-shaped curve typical of bispecific TCEs. We further predict that dose-response curves are driven by the ability of tumor cells to form synapses with activated T-cells. When competition between cells limits tumor engagement with active T-cells, response to therapy may be diminished. We finally suggest a metric related to drug efficacy in our analysis-"effective" receptor occupancy, or the proportion of receptors engaged in synapses. Overall, this study predicts that the CD28 arm on the trispecific antibody improves efficacy, and identifies metrics to inform potency of novel TCEs.

Is there a therapeutic potential in combining bupropion and naltrexone in schizophrenia?

INTRODUCTION: A sustained-release tablet composed of a combination of the dopamine and norepinephrine reuptake inhibitor bupropion (BUP) and the µ-opioid receptor antagonist naltrexone (NAT) is marketed under the brand name Contrave by Orexigen Therapeutics for appetite control. Minimal literature is available regarding the use of combination bupropion and naltrexone (BUPNAT) in individuals with schizophrenia. AREAS COVERED: In this review, we propose a theoretical model where BUPNAT may have a therapeutic effect in the treatment of schizophrenia. We explore the pathways targeted by the constituent drugs BUP and NAT and summarize the literature on their efficacy and possible adverse effects. We then look at the potential use of BUPNAT in schizophrenia. EXPERT OPINION: Research has hinted that BUP's dopaminergic properties affect the same striatal pathways involved in schizophrenia. NAT, via opioid receptor antagonism, indirectly increases striatal dopamine release by disinhibiting nicotinic acetylcholine receptors. As such, we hypothesize that BUPNAT can have a therapeutic effect in schizophrenia, particularly on negative symptoms. We also suggest that it may ameliorate comorbidities frequently seen in this group of patients, including obesity, smoking, and substance use. Further research and clinical data are needed to elucidate the potential clinical benefits of BUPNAT in the treatment of schizophrenia.