Miracle-dz/UniFAR-FTUs huggingface dataset:
Results of a Phase 1/2 Trial of Chemoradiotherapy With Simultaneous Integrated Boost of Radiotherapy Dose in Unresectable Locally Advanced Esophageal Cancer.

Importance Effective treatment options for locally advanced esophageal cancer are limited, and rates of local recurrence after standard chemoradiotherapy remain high. Objective To evaluate toxic effects, local control, and overall survival rates after chemoradiotherapy with a simultaneous integrated boost of radiotherapy dose to the gross tumor and nodal disease for patients with unresectable locally advanced esophageal cancer. Design, Setting, and Participants A phase 1/2, single-arm trial was conducted in 46 patients from April 28, 2010, to April 9, 2015 (median follow-up, 52 months [range, 2-86 months]), at a tertiary academic cancer center. Outcomes of the study patients were compared with those of 97 similar patients treated at the same institution from January 10, 2010, to December 5, 2014, as part of the interim analysis. Statistical analysis was performed from December 15, 2018, to February 12, 2019. Interventions Chemoradiotherapy with a simultaneous integrated boost of radiotherapy dose (50.4 Gy to subclinical areas at risk and 63.0 Gy to the gross tumor and involved nodes, all given in 28 fractions) with concurrent docetaxel and capecitabine or fluorouracil. Main Outcomes and Measures Toxic effects, local (in-field) control, and overall survival rates. Results All 46 patients (11 women and 35 men; median age, 65.5 years [range, 37.3-84.4 years]) received per-protocol therapy, as intensity-modulated photon therapy (39 [85%]) or intensity-modulated proton therapy (7 [15%]); 11 patients (24%) ultimately underwent resection. No patients experienced grade 4 or 5 toxic effects; the 10 acute grade 3 toxic events were esophagitis (4), dysphagia (3), and anorexia (3) and the 3 late grade 3 toxic events were all esophageal strictures. The actuarial local recurrence rates were 22% (95% CI, 11%-35%) at 6 months, 30% (95% CI, 18%-44%) at 1 year, and 33% (95% CI, 20%-46%) at 2 years. Overall, 15 patients (33%) experienced local failure, at a median interval of 5 months (range, 1-24 months). The median overall survival time was 21.5 months (range, 2.3-86.4 months). Exploratory comparison with a 97-patient contemporaneous institutional cohort receiving standard-dose (non-simultaneous integrated boost) chemoradiotherapy showed superior local control (hazard ratio, 0.49; 95% CI, 0.26-0.92; P = .03) and overall survival (hazard ratio, 0.66; 95% CI, 0.47-0.94; P = .02) in the group that received chemoradiotherapy with a simultaneous integrated boost. Conclusions and Relevance These findings suggest that chemoradiotherapy with a simultaneous integrated boost of radiotherapy dose for locally advanced esophageal cancer is well tolerated, with encouraging local control, and thus warrants further study. Trial Registration ClinicalTrials.gov identifier: NCT01102088.
ACL Size and Notch Width Between ACLR and Healthy Individuals: A Pilot Study

Background: Given the relatively high risk of contralateral anterior cruciate ligament (ACL) injury in patients with ACL reconstruction (ACLR), there is a need to understand intrinsic risk factors that may contribute to contralateral injury. Hypothesis: The ACLR group would have smaller ACL volume and a narrower femoral notch width than healthy individuals after accounting for relevant anthropometrics. Study Design: Cross-sectional study. Level of Evidence: Level 3. Methods: Magnetic resonance imaging data of the left knee were obtained from uninjured (N = 11) and unilateral ACL-reconstructed (N = 10) active, female, collegiate-level recreational athletes. ACL volume was obtained from T2-weighted images. Femoral notch width and notch width index were measured from T1-weighted images. Independent-samples t tests examined differences in all measures between healthy and ACLR participants. Results: The ACLR group had a smaller notch width index (0.22 ± 0.02 vs 0.25 ± 0.01; P = 0.004; effect size, 1.41) and ACL volume (25.6 ± 4.0 vs 32.6 ± 8.2 mm3/(kg·m)−1; P = 0.025; effect size, 1.08) after normalizing by body size. Conclusion: Only after normalizing for relevant anthropometrics, the contralateral ACLR limb had smaller ACL size and narrower relative femoral notch size than healthy individuals. These findings suggest that risk factor studies of ACL size and femoral notch size should account for relevant body size when determining their association with contralateral ACL injury. Clinical Relevance: The present study shows that the method of the identified intrinsic risk factors for contralateral ACL injury could be used in future clinical screening settings.
Lens Connexin Channels Have Differential Permeability to the Second Messenger cAMP

Purpose Gap junction channels exhibit connexin specific biophysical properties, including the selective intercellular passage of larger solutes, such as second messengers. Here, we have examined the cyclic nucleotide permeability of the lens connexins, which could influence events like epithelial cell division and differentiation. Methods We compared the cAMP permeability through channels composed of Cx43, Cx46, or Cx50 using simultaneous measurements of junctional conductance and intercellular transfer. For cAMP detection, the recipient cells were transfected with a cAMP sensor gene, the cyclic nucleotide-modulated channel from sea urchin sperm (SpIH). cAMP was introduced via patch pipette into the cell of the pair that did not express SpIH. SpIH-derived currents were recorded from the other cell of a pair that expressed SpIH. cAMP permeability was also directly visualized in transfected cells using a chemically modified fluorescent form of the molecule. Results cAMP transfer was observed for homotypic Cx43 channels over a wide range of junctional conductance. Homotypic Cx46 channels also transferred cAMP, but permeability was reduced compared with Cx43. In contrast, homotypic Cx50 channels exhibited extremely low permeability to cAMP, when compared with either Cx43, or Cx46. Conclusions These data show that channels made from Cx43 and Cx46 result in the intercellular delivery of cAMP in sufficient quantity to activate cyclic nucleotide-modulated channels. The data also suggest that the greatly reduced cAMP permeability of Cx50 channels could play a role in the regulation of cell division in the lens.
Association Between Post-Resuscitation Coronary Angiography With and Without Intervention and Neurological Outcomes After Out-of-Hospital Cardiac Arrest

Abstract Objective: This study aimed to investigate the association between coronary angiography (CAG) with and without percutaneous coronary intervention (PCI) after out-of-hospital cardiac arrest (OHCA) and neurological recovery and to determine the influence of primary electrocardiogram or patient age on the effects of CAG. Methods: Adult patients with OHCA with cardiac etiology who were admitted to PCI-capable hospitals from 2016 to 2017 were enrolled in this study from the nationwide OHCA registry of Korea. Coronary intervention was categorized into three groups: No CAG, CAG without PCI, and CAG with PCI. The endpoint was good neurological recovery. Multivariable logistic regression and interaction analyses (intervention × electrocardiogram and intervention × age) were conducted by calculating adjusted odds ratios (aORs) and 95% confidence intervals (CI). Results: Of a total of 6,802 eligible OHCA patients, 1,218 (17.9%) underwent CAG without PCI and 1,136 (16.7%) underwent CAG with PCI. The CAG without PCI and CAG with PCI groups were more likely to have good neurological recovery than the No CAG group (57.4% vs. 61.6% vs. 16.3%; 3.39 [2.83–4.06] for CAG without PCI and 3.32 [2.74–4.01] for CAG with PCI). Interaction analysis showed that although the effect size differed according to patient characteristics, both CAG groups were associated with an increased likelihood of good neurological recovery, regardless of primary electrocardiogram and age group. In younger patients, CAG with PCI had greater outcome benefits than CAG without PCI (8.54 [4.31–16.95] vs. 4.10 [2.69–6.24]), whereas CAG without PCI had a larger effect size than CAG with PCI in elderly patients (4.46 [2.59–7.68] vs. 2.92 [1.80–4.73]) (p value for interaction 0.02). Conclusions: Post-resuscitation CAG with and without PCI are associated with better neurological recovery in patients with OHCA, regardless of primary electrocardiogram and patient age.
Effects of total sleep deprivation on endurance cycling performance and heart rate indices used for monitoring athlete readiness

ABSTRACT This study investigated effects of total sleep deprivation on self-paced endurance performance, and heart rate (HR) indices of athletes' “readiness to perform”. Endurance athletes (n = 13) completed a crossover experiment comprising a normal sleep (NS) and sleep deprivation (SD) condition. Each required completion of an endurance time-trial (TT) on consecutive days (D1, D2) separated by normal sleep or total sleep deprivation. Finishing time, perceived exertion (RPE), mood, psychomotor vigilance (PVT), and HR responses were assessed. Time on D2 of SD was 10% slower than D2 of NS (64 ± 7 vs 59 ± 4 min, P < 0.01), and 11% slower than D1 of SD (58 ± 5 min, P < 0.01). Subjective to objective (RPE:mean HR) intensity ratio was higher on D2 of SD compared with D2 of NS and D1 of SD (P < 0.01). Mood disturbance and PVT mean response time increased on D2 of SD compared with D2 of NS and D1 of SD. Anaerobic threshold and change in TT time were correlated (R = −0.73, P < 0.01). Sleep helps to optimise endurance performance. Subjective to objective intensity ratios appear sensitive to effects of sleep on athletes’ readiness. Research examining more subtle sleep manipulation is required.
Using DNA barcoding to improve invasive pest identification at U.S. ports-of-entry

Interception of potential invasive species at ports-of-entry is essential for effective biosecurity and biosurveillance programs. However, taxonomic assessment of the immature stages of most arthropods is challenging; characters for identification are often dependent on adult morphology and reproductive structures. This study aims to strengthen the identification of such specimens through DNA barcoding, with a focus on microlepidoptera. A sample of 241 primarily immature microlepidoptera specimens intercepted at U.S. ports-of-entry from 2007 to 2011 were selected for analysis. From this sample, 201 COI-5P sequences were generated and analyzed for concordance between morphology-based and DNA-based identifications. The retrospective analysis of the data over 10 years (2009 to 2019) using the Barcode of Life Data (BOLD) system demonstrates the importance of establishing and growing DNA barcode reference libraries for use in specimen identification. Additionally, analysis of specimen identification using public data (43.3% specimens identified) vs. non-public data (78.6% specimens identified) highlights the need to encourage researchers to make data publicly accessible. DNA barcoding surpassed morphological identification with 42.3% (public) and 66.7% (non-public) of the sampled specimens achieving a species-level identification, compared to 38.3% species-level identification by morphology. Whilst DNA barcoding was not able to identify all specimens in our dataset, its incorporation into border security programs as an adjunct to morphological identification can provide secondary lines of evidence and lower taxonomic resolution in many cases. Furthermore, with increased globalization, database records need to be clearly annotated for suspected specimen origin versus interception location.
Immunogenicity and safety of a quadrivalent inactivated influenza vaccine in pregnant women: a randomized, observer-blind trial

ABSTRACT Vaccination against influenza during pregnancy provides direct protection to pregnant women and indirect protection to their infants. Trivalent inactivated influenza vaccines (IIV3s) are safe and effective during pregnancy, but quadrivalent inactivated influenza vaccines (IIV4s) have not been evaluated in pregnant women and their infants. Here, we report the results of a randomized phase IV study to evaluate the immunogenicity and safety of IIV4 vs. IIV3 in pregnant women. Participants aged ≥18 years at weeks 20 to 32 of gestation were randomly assigned in a 2:1 ratio to receive a single dose of IIV4 (n = 230) or IIV3 (n = 116). Between baseline and 21 days after vaccination, hemagglutination inhibition (HAI) antibody titers increased in both groups by similar magnitudes for the two influenza A strains and single B strain common to IIV4 and IIV3. For the additional B strain in IIV4, HAI titers were higher in IIV4 recipients than IIV3 recipients (post-/pre-vaccination geometric mean titer ratio, 6.3 [95% CI: 5.1 − 7.7] vs. 3.4 [95% CI: 2.7 − 4.3]). At delivery, in both groups, HAI antibody titers for all strains were 1.5 − 1.9-fold higher in umbilical cord blood than in maternal blood, confirming active transplacental antibody transfer. Rates of solicited and unsolicited vaccine-related adverse events in mothers were similar between the two groups. Live births were reported for all participants and there were no vaccine-related adverse events in newborns. These results suggest IIV4 is as safe and immunogenic as IIV3 in pregnant women, and that maternal immunization with IIV4 should protect newborns against influenza via passively acquired antibodies.
Discovery, Validation, and Application of Novel Methylated DNA Markers for Detection of Esophageal Cancer in Plasma

Purpose: The burden of esophageal cancer continues to rise, and noninvasive screening tools are needed. Methylated DNA markers (MDM) assayed from plasma show promise in detection of other cancers. For esophageal cancer detection, we aimed to discover and validate MDMs in tissue, and determine their feasibility when assayed from plasma. Experimental Design: Whole-methylome sequencing was performed on DNA extracted from 37 tissues (28 EC; 9 normal esophagus) and 8 buffy coat samples. Top MDMs were validated by methylation specific PCR on tissue from 76 EC (41 adeno, 35 squamous cell) and 17 normal esophagus. Quantitative allele-specific real-time target and signal amplification was used to assay MDMs in plasma from 183 patients (85 EC, 98 controls). Recursive partitioning (rPART) identified MDM combinations predictive of esophageal cancer. Validation was performed in silico by bootstrapping. Results: From discovery, 23 candidate MDMs were selected for independent tissue validation; median area under the receiver operating curve (AUC) for individual MDMs was 0.93. Among 12 MDMs advanced to plasma testing, rPART modeling selected a 5 MDM panel (FER1L4, ZNF671, ST8SIA1, TBX15, ARHGEF4) which achieved an AUC of 0.93 (95% CI, 0.89–0.96) on best-fit and 0.81 (95% CI, 0.75–0.88) on cross-validation. At 91% specificity, the panel detected 74% of esophageal cancer overall, and 43%, 64%, 77%, and 92% of stages I, II, III, and IV, respectively. Discrimination was not affected by age, sex, smoking, or body mass index. Conclusions: Novel MDMs assayed from plasma detect esophageal cancer with moderate accuracy. Further optimization and clinical testing are warranted.
When does an advantage become unfair? Empirical and normative concerns in Semenya’s case

There is a fundamental tension in many sports: human sex is not binary, but there are only two categories in which people can compete: male and female. Over the past 10 years, the International Association of Athletics Federations (IAAF) regulations have been at the centre of two notable legal disputes. The Court of Arbitration for Sport (CAS) reached two contradictory rulings: in the first case (Dutee Chand vs Athletics Federation India and IAAF), the IAAF regulations for the eligibility of athletes to compete in the female category were suspended (24 July 2015) on grounds of "discrimination against the female category"; in the latter (Caster Semenya and Athletics South Africa vs IAAF), the regulations were reaffirmed (1 May 2019) on grounds that although discriminatory, they are necessary to maintain a "level playing field" and to “protect” the female category. Although Semenya’s case has paved the way for questioning existing gender norms in sport, a new stable norm has yet to emerge from her case. The pharmacological solution put forward by IAAF to the tension between fairness and inclusivity of bodies non-conforming to two sexes is not, however, the only possible solution/resolution to the case, as I aim to show in this paper. Here I present some reflections on this topic and suggest how CAS should approach the case if it hopes to resolve it.
Digital Design of a Universal Rat Intraoral Device for Therapeutic Evaluation of a Topical Formulation against Candida-Associated Denture Stomatitis

Candida-associated denture stomatitis (DS) is a persistent and chronic oral infection of the denture-bearing palatal mucosa. DS stems from the ability of the fungal opportunistic pathogen Candida albicans to adhere to denture material and invade palatal tissue. Although DS is the most prevalent form of oral candidiasis, there are currently no feasible therapeutic strategies for the prevention of this recurrent condition. ABSTRACT Candida-associated denture stomatitis (DS) is a persistent and chronic oral infection of the denture-bearing palatal mucosa. DS stems from the ability of the fungal opportunistic pathogen Candida albicans to adhere to denture material and invade palatal tissue. Although DS is the most prevalent form of oral candidiasis, there are currently no feasible therapeutic strategies for the prevention of this recurrent condition. We developed a peptide-based antimicrobial bioadhesive formulation specifically designed for oral topical formulation. In this study, we aimed to evaluate the applicability of the novel formulation for the prevention of C. albicans colonization on denture material and development of clinical disease. To that end, using the latest technological advances in dental digital design and three-dimensional (3D) printing, we fabricated an intraoral device for rats with universal fit. The device was successfully installed and used to develop clinical DS. Importantly, by taking a preventative therapeutic approach, we demonstrated the potential clinical utility of the novel formulation as a safe and feasible prophylactic agent against DS.
Physiological stress reactivity and recovery related to behavioral traits in dogs (Canis familiaris)

This study investigated whether stress responsiveness (in one context) can be used to predict dog behavior in daily life. On two occasions (NT1 = 32 puppies; NT2 = 16 young adults), dogs’ physiological stress response after a behavioral test at home was measured in terms of reactivity (10 min post-test) and recovery (40 min post-test) for three salivary markers: cortisol, chromogranin A (CgA) and secretory immunoglobulin A (sIgA). For each marker, it was determined whether dogs with a strong physiological response displayed different behavior in daily life compared to dogs with a weaker physiological response. The results revealed three main findings: first, for CgA and cortisol, different patterns were identified according to sample time. High reactivity related to desirable traits, whereas slow recovery after the behavioral test related to undesirable traits. The findings suggest that increased levels of CgA and cortisol 10 minutes after the behavioral test reflected an adaptive stress response, whereas elevated levels 40 minutes after the test reflected unsuccessful coping. Second, patterns for sIgA differed from CgA and cortisol: significant associations were only found with behavioral traits at T2, mostly considered desirable and related to Trainability. Possibly, the delayed reaction pattern of sIgA caused this difference between markers, as sIgA reflects the (secondary) immune response to stress, due to immunosuppressive effects of cortisol. Third, predictive capacity of puppies’ physiological stress response (T1) was inconclusive, and contrary relations were found with behavioral traits at T2, suggesting that developmental factors play an important role. This study provides new insights about the relation between stress physiology and behavioral traits, and methodological advice is given to study these patterns further. In conclusion, physiological markers could provide additional insights in dogs’ tendencies to display certain behaviors, especially at the young adult stage. Further studies are needed to confirm these patterns.
Regrowth of Mycobacterium tuberculosis Populations Exposed to Antibiotic Combinations Is Due to the Presence of Isoniazid and Not Bacterial Growth Rate

Modulation of the growth rate in Mycobacterium tuberculosis is key to its survival in the host, particularly with regard to its adaptation during chronic infection, when the growth rate is very slow. The resulting physiological changes influence the way in which this pathogen interacts with the host and responds to antibiotics. Therefore, it is important that we understand how the growth rate impacts antibiotic efficacy, particularly with respect to recovery/relapse. ABSTRACT Modulation of the growth rate in Mycobacterium tuberculosis is key to its survival in the host, particularly with regard to its adaptation during chronic infection, when the growth rate is very slow. The resulting physiological changes influence the way in which this pathogen interacts with the host and responds to antibiotics. Therefore, it is important that we understand how the growth rate impacts antibiotic efficacy, particularly with respect to recovery/relapse. This is the first study that has asked how growth rates influence the mycobacterial responses to combinations of the frontline antimycobacterials, isoniazid (INH), rifampin (RIF), and pyrazinamide (PZA), using continuous cultures. The time course profiles of log-transformed total viable counts for cultures, controlled at either a fast growth rate (mean generation time [MGT], 23.1 h) or a slow growth rate (MGT, 69.3 h), were analyzed by the fitting of a mathematical model by nonlinear regression that accounted for the dilution rate in the chemostat and profiled the kill rates and recovery in culture. Using this approach, we show that populations growing more slowly were generally less susceptible to all treatments. We observed a faster kill rate associated with INH than with RIF or PZA and the appearance of regrowth. In line with this observation, regrowth was not observed with RIF exposure, which provided a slower bactericidal response. The sequential additions of RIF and PZA did not eliminate regrowth. We consider here that faster, early bactericidal activity is not what is required for the successful sterilization of M. tuberculosis, but instead, slower elimination of the bacilli followed by reduced recovery of the bacterial population is required.