An Analysis of 5 Years of Randomized Trials in Gastroenterology and Hepatology Reveals 52 Medical Reversals.

BACKGROUND AND AIMS: One manifestation of low-value medical practice is the medical reversal, a practice in widespread use that, once subjected to a randomized controlled trial (RCT), is found to be no better-or worse-than a prior established standard of care. We aimed to determine the prevalence of medical reversals in gastroenterology (GI) journals and characterize these reversals. METHODS: We searched the American Journal of Gastroenterology, Clinical Gastroenterology and Hepatology, Gastroenterology, Gut, Hepatology, and the Journal of Hepatology, reviewing studies published in 2015-2019. We identified RCTs that tested an established clinical practice and produced negative results, considered tentative reversals. Any systematic review or meta-analysis that included the article was categorized as confirming the reversal, refuting the reversal, or providing insufficient data. RESULTS: During the 5-year period, we identified 5,898 original articles, of which 212 tested an established practice and 52 were categorized as unrefuted medical reversals (25% of articles testing standard of care). Of the reversals, 21 (40%) tested procedures and devices, 15 (29%) tested medications, and 8 (15%) tested vitamins/supplements/diet. Twenty-three (44%) considered the alimentary tract, 12 (23%) considered the liver, pancreas, or biliary tract, and 17 (33%) considered endoscopy. Thirty-eight (73%) were funded exclusively by non-industry sources. CONCLUSION: This review reveals a total of 52 reversals across all subfields of GI and medical, procedural, screening, and diagnostic interventions, occurring in 25% of randomized trials testing an established practice. More research is needed to determine the optimal way to engage stakeholders and remove reversed practices from medical care.

Modelling the interplay between the CD4[Formula: see text]/CD8[Formula: see text] T-cell ratio and the expression of MHC-I in tumours.

Describing the anti-tumour immune response as a series of cellular kinetic reactions from known immunological mechanisms, we create a mathematical model that shows the CD4[Formula: see text]/CD8[Formula: see text] T-cell ratio, T-cell infiltration and the expression of MHC-I to be interacting factors in tumour elimination. Methods from dynamical systems theory and non-equilibrium statistical mechanics are used to model the T-cell dependent anti-tumour immune response. Our model predicts a critical level of MHC-I expression which determines whether or not the tumour escapes the immune response. This critical level of MHC-I depends on the helper/cytotoxic T-cell ratio. However, our model also suggests that the immune system is robust against small changes in this ratio. We also find that T-cell infiltration and the specificity of the intra-tumour TCR repertoire will affect the critical MHC-I expression. Our work suggests that the functional form of the time evolution of MHC-I expression may explain the qualitative behaviour of tumour growth seen in patients.

Exact results on high-dimensional linear regression via statistical physics.

It is clear that conventional statistical inference protocols need to be revised to deal correctly with the high-dimensional data that are now common. Most recent studies aimed at achieving this revision rely on powerful approximation techniques that call for rigorous results against which they can be tested. In this context, the simplest case of high-dimensional linear regression has acquired significant new relevance and attention. In this paper we use the statistical physics perspective on inference to derive several exact results for linear regression in the high-dimensional regime.

A review of the existing literature on buprenorphine pharmacogenomics.

Buprenorphine is an effective treatment for opioid dependence; however, it demonstrates individual variability in efficacy. Pharmacogenomics may explain this drug response variability and could allow for tailored therapy on an individual basis. The Food and Drug Administration and the Clinical Pharmacogenomics Implementation Consortium have guidelines on pharmacogenomic testing for some opioids (e.g., codeine); however, no guidelines exist for the partial opioid agonist buprenorphine. Pharmacogenomic testing targets for buprenorphine include pharmacodynamic genes like the mu-opioid receptor (MOP receptor) and catechol-O-methyltransferase (COMT), as well as the pharmacokinetic genes like the CYP enzymes. In this review we identified genotypes in patients with opioid addiction receiving buprenorphine that may result in altered therapeutic dosing and increased rate of relapse. The OPRM1 A118G single nucleotide polymorphism (SNP rs1799971) gene variant encoding the N40D MOP receptor has been associated with variable efficacy and response to treatment in both adult and neonatal patients receiving buprenorphine for treatment of opioid withdrawal. An SNP associated with rs678849 of OPRD1, coding for the delta opioid receptor, was associated with opioid relapse as indicated by opioid positive urine drug screens; there was also sex specific SNP identified at rs581111 and rs529520 in the European American population. COMT variability, particularly in rs4680, has been associated with length of stay and need for opioid treatment in patients with neonatal abstinence syndrome. Variations of the pharmacokinetic gene for CYP3A4 showed that the ultrarapid metabolizer phenotype required higher doses of buprenorphine. Genotyping of patients may allow us to appropriately tailor buprenorphine therapy to individual patients and lead to improved patient outcomes; however, further research on the pharmacogenomics of buprenorphine is needed.

Space of Functions Computed by Deep-Layered Machines.

We study the space of functions computed by random-layered machines, including deep neural networks and Boolean circuits. Investigating the distribution of Boolean functions computed on the recurrent and layer-dependent architectures, we find that it is the same in both models. Depending on the initial conditions and computing elements used, we characterize the space of functions computed at the large depth limit and show that the macroscopic entropy of Boolean functions is either monotonically increasing or decreasing with the growing depth.

Severe Gastrointestinal Mucositis Following Concurrent Palbociclib and Palliative Radiation Therapy.

BACKGROUND/AIM: Palbociclib is an FDA-approved cyclin-dependent kinase inhibitor for the treatment of advanced breast cancer. Limited information is available regarding the toxicity of palbociclib and concurrent radiation therapy. CASE REPORT: Herein, we report a case of esophageal toxicity in a patient treated with palbociclib and radiation therapy. A 63-year-old woman was treated with palbociclib followed by palliative radiation therapy. The patient presented three days after completing radiation therapy with severe odynophagia, and dysphagia and was found to have grade 2-3 esophageal ulcers. Palbociclib and radiation therapy was held on admission, and a resolution of her symptoms and improvement in her oral intake was noted at which time she was restarted on palbociclib with no further radiation treatment. CONCLUSION: Caution is advised when patients are undergoing concurrent palbociclib and even low-dose palliative radiation treatment. In these patients, providers should maintain a high index of suspicion for toxicities such as dermatitis or mucositis.

Pharmacology, Pharmacotherapy, and Pharmacopolicy Through an Evidence-Based Medicine: A Novel Approach for First-Year Medical Students.

Introduction: As evidenced by student performance on various assessments, pharmacotherapy remains a comparative weakness in undergraduate medical education, with several institutions developing novel strategies for students to apply these principles in a practical setting. Medical curricula have recently prioritized group-learning modalities and evidence-based medicine education. However, these principles have yet to impact pharmacology education. We developed and implemented an evidence-based, group-learning exercise for first-year medical students focusing on pharmacology through the practical lens of pharmacotherapy and pharmacopolicy. Methods: First-year medical students in different groups were assigned a particular medication and, during an in-class session, were encouraged to meet with other representatives assigned the same drug to interpret the provided package insert and any online information. Students then reconvened with their groups to engage in collaborative teaching about each assigned drug before completing a group quiz using online resources. Facilitators reviewed the group quiz and allowed time for student questions. Results: For 180 participants, the average group-quiz score was 86%, ranging from 68% to 100%. Student-reported satisfaction with the activity in meeting its preset objectives averaged 3.7 on a 5-point scale, with 5 being most positive. Discussion: Overall, this activity effectively integrates principles of pharmacotherapy and pharmacopolicy into a group-based, evidence-based exercise. Limitations of the activity include the number of possible example drugs and the amount of material covered in a given time frame. However, the activity lends itself to the role of an introductory session in a longer curriculum centered on clinical-applied pharmacology and evidence-based practice.

Opioid-Associated Hearing Loss: A 20-Year Review from the New Jersey Poison Center.

BACKGROUND: Opioid-associated ototoxicity is a known complication of opioid exposure, although the mechanism remains unclear. While historically most closely linked to heroin and oxycodone, evolving reports suggest that it may be a class effect of opioids. However, the evidence is limited to case reports. METHODS: A retrospective review of the New Jersey Poison Center records (ToxiCALL®) identified cases that included both hearing loss and recent opioid exposure between January 1, 1999, and September 21, 2018. RESULTS: Forty-one cases were identified, mean age 29.4 years, 51% (n = 21) were male. Reported heroin exposures comprised 51% (n = 22), 18 of which were heroin alone. The next most commonly cited opioids were oxycodone (n = 7), methadone, (n = 4), and tramadol (n = 3). Hearing loss was described as tinnitus in 24% of cases, hypoacusis in 37% of cases, deafness in 29% of cases, and mixed tinnitus/hypoacusis in 10% of cases. Only 34% (n = 14) of cases were associated with a potential hypoxic event. Of the cases that documented resolution data, 21% (n = 4 of 19) reported no improvement at time of hospital discharge. DISCUSSION: Opioid-associated ototoxicity appears to be a hypoxia-independent adverse effect since most of the reported cases did not involve a known contributory hypoxic event. It occurs with a wide array of opioids, which supports an opioid receptor-mediated mechanism. The ototoxic effect may be self-limited in many patients. CONCLUSION: Opioid-associated ototoxicity was most commonly associated with heroin exposure and appeared independent of hypoxic events. Further investigation that clarifies the risk factors and long-term outcomes is needed.

Sociological and Medical Factors Influence Outcomes in Facial Trauma Malpractice.

PURPOSE: Medical error in the United States carries substantial economic and safety costs, which manifest in a large number of malpractice suits filed each year. The aim of this study was to characterize the various sociologic and medical factors that influence malpractice suits occurring from cases of facial trauma. MATERIALS AND METHODS: This retrospective cohort study examined defendant data from facial trauma malpractice cases extracted from the Westlaw database, a database composed of representative federal litigations. Study variables of interest included geographic region, type of trial, injury category, and provider specialty, which were analyzed for impact on initial and final legal decisions. Descriptive statistics, Pearson χ2 test, and Fisher t test were performed using SPSS. RESULTS: Of the 69 defendants (76.8% men and 23.2% women; age range, 17 to 57 yr), which resulted from 53 claims, 12 (17.4%) involved plastic surgeons and 10 (14.5%) involved emergency physicians. Most complaints consisted of inadequate care that deviated from treatment standards (32 [46.4%]) and delayed diagnosis (24 [34.8%]). Of delayed diagnosis cases, 14 patients had radiographic imaging performed. Geographic location of the claim was statistically significant-the Midwest upheld 40% of complaints (P = .007) and the South dismissed 91.4% (P = .027). CONCLUSIONS: The impact of sociologic factors, including geographic region, informed consent, and cosmesis, and medical factors, such as delayed diagnosis and deviation from standard of care, in facial trauma litigation were found to be incongruent with previous studies describing the medicolegal influences in facial plastic procedures. This analysis provides greater insight to surgical practitioners across subspecialty disciplines regarding the potential legal implications of malpractice.

Impact of Body Mass Index on Operative Outcomes in Head and Neck Free Flap Surgery.

OBJECTIVE: Analyze the risk for perioperative complications associated with body mass index (BMI) class in patients undergoing head and neck free flap reconstruction. STUDY DESIGN AND SETTING: Retrospective cohort study. SUBJECTS AND METHODS: The National Surgical Quality Improvement Program (NSQIP) database was queried for all cases of head and neck free flaps between 2005 and 2014 (N = 2187). This population was stratified into underweight, normal-weight, overweight, and obese BMI cohorts. Groups were compared for demographics, comorbidities, and procedure-related variables. Rates of postoperative complications were compared between groups using χ2 and binary logistic regression analyses. RESULTS: Underweight patients (n = 160) had significantly higher rates of numerous comorbidities, including disseminated cancer, preoperative chemotherapy, and anemia, while obese patients (n = 447) had higher rates of diabetes and hypertension. Rates of overall surgical complications, medical complications, and flap loss were insignificantly different between BMI groups. Following regression, obese BMI was protective for perioperative transfusion requirement (odds ratio [OR] = 0.63, P = .001), while underweight status conferred increased risk (OR = 2.43, P < .001). Recent weight loss was found to be an independent predictor of perioperative cardiac arrest (OR = 3.16, P = .006) while underweight BMI was not (OR = 1.21, P = .763). However, both weight loss and underweight status were associated with significantly increased risk for 30-day mortality (OR = 4.48, P = .032; OR = 4.02, P = .010, respectively). CONCLUSION: Obesity does not increase the risk for postoperative complications in head and neck free flap surgery and may be protective in some cases. When assessing a patient's fitness for surgery, underweight status or recent weight loss may suggest a reduced ability to tolerate extensive free flap reconstruction.

Transitional B Cells in Early Human B Cell Development - Time to Revisit the Paradigm?

The B cell repertoire is generated in the adult bone marrow by an ordered series of gene rearrangement processes that result in massive diversity of immunoglobulin (Ig) genes and consequently an equally large number of potential specificities for antigen. As the process is essentially random, the cells exhibiting excess reactivity with self-antigens are generated and need to be removed from the repertoire before the cells are fully mature. Some of the cells are deleted, and some will undergo receptor editing to see if changing the light chain can rescue an autoreactive antibody. As a consequence, the binding properties of the B cell receptor are changed as development progresses through pre-B ≫ immature ≫ transitional ≫ naïve phenotypes. Using long-read, high-throughput, sequencing we have produced a unique set of sequences from these four cell types in human bone marrow and matched peripheral blood, and our results describe the effects of tolerance selection on the B cell repertoire at the Ig gene level. Most strong effects of selection are seen within the heavy chain repertoire and can be seen both in gene usage and in CDRH3 characteristics. Age-related changes are small, and only the size of the CDRH3 shows constant and significant change in these data. The paucity of significant changes in either kappa or lambda light chain repertoires implies that either the heavy chain has more influence over autoreactivity than light chain and/or that switching between kappa and lambda light chains, as opposed to switching within the light chain loci, may effect a more successful autoreactive rescue by receptor editing. Our results show that the transitional cell population contains cells other than those that are part of the pre-B ≫ immature ≫ transitional ≫ naïve development pathway, since the population often shows a repertoire that is outside the trajectory of gene loss/gain between pre-B and naïve stages.

Consistent inference of a general model using the pseudolikelihood method.

Recently, a maximum pseudolikelihood (MPL) inference method has been successfully applied to statistical physics models with intractable likelihoods. We use information theory to derive a relation between the pseudolikelihood and likelihood functions. Furthermore, we show the consistency of the pseudolikelihood method for a general model.

Dynamics of Boolean networks: an exact solution.

The dynamics of Boolean networks (BN) with quenched disorder and thermal noise is studied via the generating functional method. A general formulation, suitable for BN with any distribution of Boolean functions, is developed. It provides exact solutions and insight into the evolution of order parameters and properties of the stationary states, which are inaccessible via existing methodology. We identify cases where the commonly used annealed approximation is valid and others where it breaks down. Broader links between BN and general Boolean formulas are highlighted.

Noisy random Boolean formulae: a statistical physics perspective.

Properties of computing Boolean circuits composed of noisy logical gates are studied using the statistical physics methodology. A formula-growth model that gives rise to random Boolean functions is mapped onto a spin system, which facilitates the study of their typical behavior in the presence of noise. Bounds on their performance, derived in the information theory literature for specific gates, are straightforwardly retrieved, generalized and identified as the corresponding macroscopic phase transitions. The framework is employed for deriving results on error-rates at various function-depths and function sensitivity, and their dependence on the gate-type and noise model used. These are difficult to obtain via the traditional methods used in this field.

Computing with noise: phase transitions in boolean formulas.

Computing circuits composed of noisy logical gates and their ability to represent arbitrary boolean functions with a given level of error are investigated within a statistical mechanics setting. Existing bounds on their performance are straightforwardly retrieved, generalized, and identified as the corresponding typical-case phase transitions. Results on error rates, function depth, and sensitivity, and their dependence on the gate-type and noise model used are also obtained.