Leading with dysphagia An unusual view of a common symptom.

Plummer-Vinson syndrome (PVS) is characterized by the classic triad of post-cricoid dysphagia, iron-deficiency anemia and esophageal webs. PVS is commonly found in women of middle age especially in the fourth and fifth decade of life. The prevalence of PVS has decreased due to early detection of iron deficiency and repletion of iron stores. We report a case of a 81-year-old female patient who had a classic presentation of PVS, treated successfully with endoscopic procedure. To our knowledge, the current case is the fourth case of dysphagia related to Plummer-Vinson syndrome reported in an octogenarian in the literature so far. Iron supplementation can resolve dysphagia in many patients, but dilation of esophageal webs may sometimes be required. PVS should be part of the differential diagnosis of sideropenic dysphagia, especially due the risk of pharyngeal and esophageal epidermoid neoplasia.

Integrating decision modeling and machine learning to inform treatment stratification.

There is increasing interest in moving away from "one size fits all (OSFA)" approaches toward stratifying treatment decisions. Understanding how expected effectiveness and cost-effectiveness varies with patient covariates is a key aspect of stratified decision making. Recently proposed machine learning (ML) methods can learn heterogeneity in outcomes without pre-specifying subgroups or functional forms, enabling the construction of decision rules ('policies') that map individual covariates into a treatment decision. However, these methods do not yet integrate ML estimates into a decision modeling framework in order to reflect long-term policy-relevant outcomes and synthesize information from multiple sources. In this paper, we propose a method to integrate ML and decision modeling, when individual patient data is available to estimate treatment-specific survival time. We also propose a novel implementation of policy tree algorithms to define subgroups using decision model output. We demonstrate these methods using the SPRINT (Systolic Blood Pressure Intervention Trial), comparing outcomes for "standard" and "intensive" blood pressure targets. We find that including ML into a decision model can impact the estimate of incremental net health benefit (INHB) for OSFA policies. We also find evidence that stratifying treatment using subgroups defined by a tree-based algorithm can increase the estimates of the INHB.

A randomised controlled trial of Pre-Operative Oncotype DX testing in early-stage breast cancer (PRE-DX study) - Study protocol.

BACKGROUND: The Oncotype DX® Breast Recurrence Score assay can guide recommendations made to patients with oestrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer regarding post-surgery adjuvant therapy. Standard practice is to order the test in the post-operative setting on a specimen from the excised invasive carcinoma. However, it has been shown to be technically possible to perform the test on the diagnostic core biopsy. By testing the diagnostic core biopsy in the pre-operative setting, the wait for excised invasive carcinoma Recurrence Score results could be reduced allowing patients to be more accurately counselled regarding their treatment pathway sooner with any adjuvant treatment recommendations expedited. This would allow for more efficient streaming of follow up appointments. The aim of this study is to compare the impact on the patient treatment pathway of performing the Oncotype DX® test on the diagnostic core biopsy pre-operatively (intervention) as opposed to the excised invasive carcinoma (control). METHODS AND ANALYSIS: This parallel group randomised controlled trial aims to recruit 330 newly diagnosed patients with grade 2 or grade 3, ER+, HER2-, invasive intermediate risk early-stage breast cancer. Participants will be randomised 2:1 to the preoperative testing of the diagnostic core biopsy compared to the post-operative testing of the excision specimen. The primary endpoint is number of clinical touchpoints between treating team and patient from initial approach until offer and prescription of the first adjuvant treatment. Secondary endpoints include time from diagnosis to offer and prescription of the first adjuvant treatment, patient-reported anxiety scores and health cost impact analysis collected at baseline, following the post-operative clinic and following the offer of adjuvant treatment, and number of alterations in treatment sequence from original planned surgical treatment to neoadjuvant therapy. TRIAL REGISTRATION: The study was registered on ISRCTN (ISRCTN14337451) on the 16th August 2022.

Unexpected cause of upper gastrointestinal bleeding: beyond the typical complications of gallstone disease.

An 88-year-old man presented with haematemesis with haemodynamic stability requiring transfusion of 5 units of blood. Physical examination was unremarkable. Upper endoscopy identified a fistulous opening in the proximal second part of the duodenum (D2) with an oozing bleed and blood clots. A computed tomography (CT)-angiogram revealed a 18mm cystic artery pseudoaneurysm next to a fistulous communication between the gallbladder and D2, allowing the passage of a large stone (Bouveret syndrome). The patient successfully underwent emergent arterial embolization guided by a clip endoscopically-placed near the duodenal fistulous orifice. There were no intercurrences or bleeding recurrence.

Impact of weather and climate advisories on agricultural outcomes in Pakistan.

The earth is warming, and the frequency of extreme weather events have been rapidly growing globally with unprecedented consequences to farming communities. In principle, weather and climate information services (WCIS) can help farmers better manage their activities and farm level outcomes by supporting their decision-making with relevant and usable information to address the potential impacts of expected changing climate conditions. But, in practice, can the availability and use of WCIS help improve agricultural outcomes given the weather and climate related uncertainties? To understand the use and impact of WCIS in the cotton-wheat cropping areas of Pakistan, we conducted a multistage stratified clustered random sample of 612 farm households in the provinces of Punjab and Sindh. Over 55% of the farm households in the sample indicated that they used WCIS provided by the Pakistan Meteorological Department and other sources for making their agricultural decisions. Our analysis, however, suggests that the impact of using WCIS on major farm outcomes (i.e. farm revenue, costs, profits, and input usage) is not statistically significant when compared with those farm households not using WCIS (null result). This result is robust to different estimation techniques (i.e. ordinary least squares, instrumental variable approach, and propensity score matching method). From the focus group discussions, we gathered that farmers perceived WCIS as less reliable, often unclear, and difficult to understand as this information is not translated and transmitted in local languages. Addressing these issues can help reduce the impact of climate and weather variability on farm outcomes in those provinces as well as in Pakistan more generally. Our study suggests that, under uncertainty, emphasis should be on WCIS that farmers can rely on for making farming related decisions.

Uniparental Disomy as a Mechanism for Combined Oxidative Phosphorylation Deficiency Associated with MRPS34 Gene.

INTRODUCTION: Mitochondrial oxidative phosphorylation (OXPHOS) is a cellular process that generates most of the cellular energy required by the body. Disorders affecting OXPHOS are multisystem diseases caused by pathogenic variants in more than 50 genes. In 2017, biallelic variants in the MRPS34 gene were shown to cause combined oxidative phosphorylation deficiency type 32 (COPD32) (OMIM#617664); however, only 7 patients have been reported in the literature up to this moment. COPD32 is characterized mainly by a severe Leigh-like syndrome. METHODS: Whole-exome sequencing identified a homozygous pathogenic variant in the MRPS34 gene, c.322-10G>A. Only the mother was heterozygous for this variant. SNP-array analysis was performed, which revealed a region of absence of heterozygosity in variant 16q with 9.8Mb, compatible with maternal uniparental disomy. RESULTS/CASE REPORT: We report the case of an 18-year-old female with unremarkable family history. The pregnancy was complicated by oligohydramnios, and the neonatal period was unremarkable. She evolved with low weight, mild-moderate developmental delay/intellectual disability, and hypogonadotropic hypogonadism. On examination, she had slender habitus, joint laxity, and kyphoscoliosis. The cardiac evaluation was normal, and the head MRI showed bilateral olivary nucleus degeneration that was not confirmed subsequently. Extensive metabolic studies documented only mild lactate and pyruvate elevation, and the chromosomal microarray was normal. CONCLUSION: We have reported the case of the first patient with COPD32 due to partial maternal uniparental disomy of chromosome 16, being first in Portugal and seventh in the literature. Contrarily to previous patients, who died in the first months of life or survived with severe DD/ID, and had a Leigh-like syndrome, this case is significantly milder, contributing to a better characterization of the phenotypic spectrum. Recurrence risk is unexpectedly low in this instance. This case illustrates the importance of segregation analysis in patients with homozygous recessive mutations.

First record of intraspecific cleaning behavior by the threatened Leuciscidae Squalius alburnoides (Steindachner, 1866) at the Guadiana River basin (Portugal).

Squalius alburnoides (Steindachner, 1866) is an endemic threatened species from the Iberian Peninsula. Here, we report the first observations of intraspecific cleaning behavior in isolated summer pools in the Guadiana River Basin (Portugal). We found that focal S. alburnoides solicited cleaning by adopting an immobile tail-stand position known as "posing," which immediately signaled a response to a few conspecifics that approached and inspect them. Our study expands the list of cleanerfish species in freshwaters, giving emphasis to the importance of mutual positive behavior within an endangered species, particularly when facing seasonal disturbance.

European value-based healthcare benchmarking: moving from theory to practice.

BACKGROUND: Value-based healthcare (VBHC) is a conceptual framework to improve the value of healthcare by health, care-process and economic outcomes. Benchmarking should provide useful information to identify best practices and therefore a good instrument to improve quality across healthcare organizations. This paper aims to provide a proof-of-concept of the feasibility of an international VBHC benchmarking in breast cancer, with the ultimate aim of being used to share best practices with a data-driven approach among healthcare organizations from different health systems. METHODS: In the VOICE community-a European healthcare centre cluster intending to address VBHC from theory to practice-information on patient-reported, clinical-related, care-process-related and economic-related outcomes were collected. Patient archetypes were identified using clustering techniques and an indicator set following a modified Delphi was defined. Benchmarking was performed using regression models controlling for patient archetypes and socio-demographic characteristics. RESULTS: Six hundred and ninety patients from six healthcare centres were included. A set of 50 health, care-process and economic indicators was distilled for benchmarking. Statistically significant differences across sites have been found in most health outcomes, half of the care-process indicators, and all economic indicators, allowing for identifying the best and worst performers. CONCLUSIONS: To the best of our knowledge, this is the first international experience providing evidence to be used with VBHC benchmarking intention. Differences in indicators across healthcare centres should be used to identify best practices and improve healthcare quality following further research. Applied methods might help to move forward with VBHC benchmarking in other medical conditions.

Effect of Tryptophan Dietary Content on Meagre, Argyrosomus regius, Juveniles Stress and Behavioral Response.

There are a high number of stressors present in aquaculture that can affect fish welfare and quality. One way of mitigating stress response is by increasing dietary tryptophan. In this study, three diets containing 0.5% (Tript1), 0.6% (Tript2), and 0.8% (Tript3) of tryptophan were tested in 32 g juvenile meagre for 56 days. At the end of the trial, survival, growth, and proximate composition were similar between treatments. Significant differences were found in the plasma parameters before and after a stress test consisting of 30 s of air exposure. Blood glucose levels were higher in the post-stress for all treatments (e.g., 63.9 and 76.7 mg/dL for Tript1 before and after the stress test), and the hemoglobin values were lower in the post-stress of Tript1 (1.9 g/dL compared to 3.0 and 2.4 g/dL for Tript2 and Tript3, respectively). In terms of behavior, three tests were carried out (novel tank diving and shoaling assays, and lateralization test), but no significant differences were found, except for the number of freezing episodes during the anxiety test (1.4 for Tript3 compared to 3.5 and 4.2 for the other treatments). This study suggests that supplementation with dietary tryptophan, particularly in higher dosage (0.8%), can reduce anxiety-like behavior in meagre exposure to acute stress (novel tank). Although the remaining results showed mild effects, they provide some clues as to the potential of this amino acid as a stress mitigator in aquaculture.

Amivantamab Compared with Real-World Physician's Choice after Platinum-Based Therapy from a Pan-European Chart Review of Patients with Lung Cancer and Activating EGFR Exon 20 Insertion Mutations.

Patients with advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor gene (EGFR) Exon 20 insertions (Exon20ins) at the second line and beyond (2L+) have an unmet need for new treatment. Amivantamab, a bispecific EGFR- and MET-targeted antibody, demonstrated efficacy in this setting in the phase 1b, open-label CHRYSALIS trial (NCT02609776). The primary objective was to compare the efficacy of amivantamab to the choices made by real-world physicians (RWPC) using an external control cohort from the real-world evidence (RWE) chart review study, CATERPILLAR-RWE. Adjustment was conducted to address differences in prognostic variables between cohorts using inverse probability weighting (IPW) and covariate adjustments based on multivariable regression. In total, 114 patients from CHRYSALIS were compared for 55 lines of therapy from CATERPILLAR-RWE. Baseline characteristics were comparable between the amivantamab and IPW-weighted RWPC cohorts. For amivantamab versus RWPC using IPW adjustment, the response rate ratio for the overall response was 2.14 (p = 0.0181), and the progression-free survival (PFS), time-to-next-treatment (TTNT) and overall survival (OS) hazard ratios (HRs) were 0.42 (p < 0.0001), 0.47 (p = 0.0063) and 0.48 (p = 0.0207), respectively. These analyses provide evidence of clinical and statistical benefits across multiple outcomes and adjustment methods, of amivantamab in platinum pre-treated patients with advanced NSCLC harboring EGFR Exon20ins. These results confirm earlier comparisons versus pooled national registry data.

When eating becomes a real nightmare.

.We present the case of a 46-year-old female with dysphagia to solids and retrosternal pain that worsened after eating. Due to mediastinal lymphadenopathies, she underwent endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) 3 weeks before, mentioning the complaints started afterwards. On physical examination she had fever (38.3ºC). Gastroscopy revealed three 10-20mm fistulous orifices with purulent discharge at 26-32cm from the incisors and another four partially covered by fibrin in the distal esophagus. EBUS-TBNA report was reviewed, mentioning 6 needle passes through the esophagus, due to failed endotracheal intubation, without immediate complications. A cervicothoracic CT scan identified 2 mediastinal abscesses, the largest with 9cm, communicating with the esophageal fistulas. She was admitted, underwent intravenous antibiotics and endoscopy-guided nasogastric tube placement. The histopathological analysis diagnosed Castleman's disease. There was clinical and imagological improvement during admission. After 16 days she was released. Upper endoscopy was repeated one month later showing complete closure of the fistulous orifices.

Chronic Obstructive Pulmonary Disease Self-Management in Three Low- and Middle-Income Countries: A Pilot Randomized Trial.

Objectives: Chronic obstructive pulmonary disease (COPD) disproportionately affects low- and middle-income countries. Health systems are ill prepared to manage the increase in COPD cases. Methods: We performed a pilot effectiveness-implementation randomized field trial of a community health worker (CHW)-supported, 1-year self-management intervention in individuals with COPD grades B-D. The study took place in low-resource settings of Nepal, Peru, and Uganda. The primary outcome was the St. George's Respiratory Questionnaire (SGRQ) score at 1 year. We evaluated differences in moderate to severe exacerbations, all-cause hospitalizations, and the EuroQol score (EQ-5D-3 L) at 12 months. Measurements and Main Results: We randomly assigned 239 participants (119 control arm, 120 intervention arm) with grades B-D COPD to a multicomponent, CHW-supported intervention or standard of care and COPD education. Twenty-five participants (21%) died or were lost to follow-up in the control arm compared with 11 (9%) in the intervention arm. At 12 months, there was no difference in mean total SGRQ score between the intervention and control arms (34.7 vs. 34.0 points; adjusted mean difference, 1.0; 95% confidence interval, -4.2, 6.1; P = 0.71). The intervention arm had a higher proportion of hospitalizations than the control arm (10% vs. 5.2%; adjusted odds ratio, 2.2; 95% confidence interval, 0.8, 7.5; P = 0.15) at 12 months. Conclusions: A CHW-based intervention to support self-management of acute exacerbations of COPD in three resource-poor settings did not result in differences in SGRQ scores at 1 year. Fidelity was high, and intervention engagement was moderate. Although these results cannot differentiate between a failed intervention or implementation, they nonetheless suggest that we need to revisit our strategy. Clinical trial registered with www.clinicaltrials.gov (NCT03359915).

Effects of mesotocin manipulation on the behavior of male and female common waxbills.

The oxytocin family of neuropeptides is implicated in the regulation of sociality across vertebrates. Non-mammalian homologs of oxytocin, such as isotocin in fish and mesotocin in amphibians, reptiles and birds, all play crucial roles modulating social and reproductive behavior. In this study, we exogenously manipulated the mesotocinergic system in a highly social bird, the common waxbill Estrild astrild, and tested the effects on affiliative and aggressive behavior by performing tests of competition over food. Birds treated with mesotocin decreased almost all the behaviors we studied (movement, feeding, allopreening), while birds treated with an oxytocin antagonist showed a reduction only in social behaviors (aggressions and allopreening). We also found two sex-specific effects: mesotocin reduced allopreening more in males than females, and the oxytocin antagonist reduced aggressiveness only in females. Our results suggest sex-specific effects in the modulation of affiliative and aggressive behaviors via mesotocinergic pathways.

Comparison of different measuring methods in the assessment of the ISNT rule and its variants in a normal population: A cross-sectional study.

PURPOSE: The aim of this study was to compare five different neuroretinal rim (NRR) measurement methods, based on quadrants and NRR widths, in the assessment of the ISNT (inferior (I) > superior (S) > nasal (N) > temporal (T)) rule, and its variants IST (inferior (I) > superior (S) > temporal (S)) rule, IS (inferior (I) > superior (S)) rule and T (temporal is the thinnest) rule in a normal population. Factors influencing compliance with this rule and its variants were also evaluated. METHODS: Stereoscopic fundus images were analysed through a dichoptic viewing system. Two graders labelled the optic disc and cup, as well as the fovea. Custom-made software automatically determined the limits of the optic disc and cup and examined the ISNT rule and its variants using several NRR measurement methods. RESULTS: Sixty-nine subjects with normal eyes were enrolled. For the various NRR measuring methods, the percentage of eyes following the rules, that is, validity ranges were 0.0%-15.9% for the ISNT rule, 31.9%-59.4% for the IST rule, 46.4%-59.4% for the IS rule and 50.7%-100.0% for the T rule. Significant intra-measurement agreement ranges were IST (κ = 0.50-0.85), IS (κ = 0.68-1.00) and T (κ = 0.24-0.77). Only the IST and IS rules achieved significant inter-measurement agreement (κ = 0.47-1.00). After multivariate and receiver operating characteristic (ROC) curve analyses, the vertical cup position cupy (area under the ROC curve (AUROC) = 0.60-0.96; cut-off = |0.005|) was the most important predictor for virtually all NRR measurement agreements for the ISNT, IST and IS rules. The horizontal cup position (AUROC = 0.50-0.92; cut-off = -0.028 to 0.05) was the most important predictive factor for the majority of the NRR measurement agreements for the T rule. CONCLUSIONS: Only the IST and IS rules are valid for the same normal subjects. The most important factor affecting the validity of the ISNT rule and its variants was the anatomical cup position. NRR measurement agreements based on NRR quadrants exhibited larger validity and better agreement. The IST and IS rules can be combined with the alternative SIT (superior (S) > inferior (I) > temporal (T)) and SI (superior (S) > inferior (I)) rules to detect almost all normal subjects.

The role of Graves' disease in the development of thyroid nodules and thyroid cancer.

Aim: The prevalence of thyroid nodules and the risk of thyroid cancer in patients with Graves' disease is uncertain. We aimed to evaluate the prevalence of thyroid nodules and cancer in patients with Graves' disease. Methods: Retrospective observational study of adult subjects with Graves' disease (positive autoantibodies thyrotropin receptor antibodies (TRAbs)) between 2017 and 2021 at our center was done. We evaluated the prevalence of thyroid nodules and cancer in this population and characterized the predictive factors for thyroid malignancy using linear and logistic regression models. Results: We evaluated a total of 539 patients with Graves' disease during a median follow-up of 3.3 years (25th-75th percentiles 1.5-5.2 years). Fifty-three percent had thyroid nodules and 18 (3.3%) were diagnosed with thyroid cancer (12 papillary microcarcinomas). All tumors were classified using TNM classification as T1, and only one had lymph node metastasis; there were no recordings of distant metastasis. Sex, age, body mass index, smoking, TSH, and TRAbs levels were not significantly different between patients with and without thyroid cancer. Patients with multiple nodules on ultrasound (OR 1.61, 95%CI 1.04-2.49) and with larger nodules (OR 2.96, 95%CI 1.08-8.14, for 10 mm increase in size) had a greater risk of thyroid cancer diagnosis. Conclusion: Patients with Graves' disease had a high prevalence of thyroid nodules and their nodules had a significant risk of thyroid cancer. The risk was higher in those with multiple and larger nodules. Most had low-grade papillary thyroid cancer. More studies are needed to clarify the clinical relevance of these findings.