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ObjectivePatients with relapsed or metastatic head and neck squamous cell carcinoma (HNSCC) after primary local therapy have low response rates with cetuximab, systemic chemotherapy or check point inhibitor therapy. Novel combination therapies with the potential to improve outcomes for patients with HNSCC is an area of high unmet need.MethodsThis is a phase II single-arm clinical trial of locally advanced or metastatic HNSCC patients treated with a combination of soluble EphB4-human serum albumin (sEphB4-HSA) fusion protein and pembrolizumab after platinum-based chemotherapy with up to 2 prior lines of treatment. The primary endpoints were safety and tolerability and the primary efficacy endpoint was overall response rate (ORR). Secondary endpoints included progression free survival (PFS) and overall survival (OS). HPV status and EphrinB2 expression were evaluated for outcome.ResultsTwenty-five patients were enrolled. Median follow up was 40.4 months (range 9.8 - 40.4). There were 6 responders (ORR 24%). There were 5 responders in the 11 HPV-negative and EphrinB2 positive patients, (ORR 45%) with 2 of these patients achieving a complete response (CR). The median PFS in HPV-negative/EphrinB2 positive patients was 3.2 months (95% CI 1.1, 7.3). Median OS in HPV-negative/EphrinB2 positive patients was 10.9 months (95% CI 2.0, 13.7). Hypertension, transaminitis and fatigue were the most common toxicities.DiscussionThe combination of sEphB4-HSA and pembrolizumab has a favorable toxicity profile and favorable activity particularly among HPV-negative EphrinB2 positive patients with HNSCC.

As the microbiome field moves from descriptive and associative research to mechanistic and interventional studies, being able to account for all confounding variables in the experimental design, which includes the maternal effect1, cage effect2, facility differences3, as well as laboratory and sample handling protocols4, is critical for interpretability of results. Despite significant procedural and bioinformatic improvements, unexplained variability and lack of replicability still occur. One underexplored factor is that the microbiome is dynamic and exhibits diurnal oscillations that can change microbiome composition5-7. In this retrospective analysis of 16S amplicon sequencing studies in male mice, we show that sample collection time affects the conclusions drawn from microbiome studies and its effect size is larger than those of a daily experimental intervention or dietary changes. The timing of divergence of the microbiome composition between experimental and control groups is unique to each experiment. Sample collection times as short as only 4 hours apart can lead to vastly different conclusions. Lack of consistency in the time of sample collection may explain poor cross-study replicability in microbiome research. The impact of diurnal rhythms on the outcomes and study design of other fields is unknown but likely significant.

Next-generation sequencing technologies have enabled many advances across diverse areas of biology, with many benefiting from increased sample size. Although the cost of running next-generation sequencing instruments has dropped substantially over time, the cost of sample preparation methods has lagged behind. To counter this, researchers have adapted library miniaturization protocols and large sample pools to maximize the number of samples that can be prepared by a certain amount of reagents and sequenced in a single run. However, due to high variability of sample quality, over and underrepresentation of samples in a sequencing run has become a major issue in high-throughput sequencing. This leads to misinterpretation of results due to increased noise, and additional time and cost rerunning underrepresented samples. To overcome this problem, we present a normalization method that uses shallow iSeq sequencing to accurately inform pooling volumes based on read distribution. This method is superior to the widely used fluorometry methods, which cannot specifically target adapter-ligated molecules that contribute to sequencing output. Our normalization method not only quantifies adapter-ligated molecules but also allows normalization of feature space; for example, we can normalize to reads of interest such as non-ribosomal reads. As a result, this normalization method improves the efficiency of high-throughput next-generation sequencing by reducing noise and producing higher average reads per sample with more even sequencing depth. IMPORTANCE High-throughput next generation sequencing (NGS) has significantly contributed to the field of genomics; however, further improvements can maximize the potential of this important tool. Uneven sequencing of samples in a multiplexed run is a common issue that leads to unexpected extra costs or low-quality data. To mitigate this problem, we introduce a normalization method based on read counts rather than library concentration. This method allows for an even distribution of features of interest across samples, improving the statistical power of data sets and preventing the financial loss associated with resequencing libraries. This method optimizes NGS, which already has huge importance across many areas of biology.

Abstract Background The diagnosis of primary aldosteronism (PA) is comprehensive, which includes case-detection testing, case confirmation followed by subtype classification. In certain instances, such as in the setting of spontaneous hypokalemia, suppressed renin activity (PRA) plus plasma aldosterone concentration (PAC) of > 15 ng/dL, one may not proceed with confirmatory tests. However, the quality of evidence behind this approach is very low. This study sought to evaluate the proposed “simplified confirmatory pathway” that can spare confirmatory testing for primary aldosteronism by evaluating the diagnostic performances of the various pre-specified PAC thresholds in combination with findings of suppressed renin and spontaneous hypokalemia. Methods This is a multi-center, retrospective diagnostic accuracy cohort-selected cross-sectional study. A total of 133 participants aged 18 years and above underwent saline infusion test between January 2010 to March 2024. The outcome measures comprise of the diagnostic performances of the different index test combinations (baseline PAC, baseline PRA and presence of spontaneous hypokalemia): sensitivity, specificity, negative predictive value, positive predictive value, positive likelihood ratio, negative likelihood ratio, and diagnostic accuracy. Data analysis was performed using SPSS 29.0.1.0 & MedCalc 20.218. Results Of the 133 patients who underwent saline infusion test, 88 (66.17%) were diagnosed with PA. A PAC of > 25 ng/dL plus PRA < 1.0 ng/dL/hr with spontaneous hypokalemia showed the highest specificity at 100% (95% CI 90.51%, 100.00%) and positive predictive value at 100% (85.18 – 100.00%). The minimum acceptable combination criteria were determined to be a PAC of > 20 ng/dL plus PRA < 0.6 ng/dL/hr, and presence of spontaneous hypokalemia. It has high specificity (94.59%; 95% CI 81.81%, 99.34%), positive predictive value (93.55%, 95% CI 78.49%, 98.29%), and moderate positive likelihood ratio (LR+) (6.39, 95% CI 1.61, 25.38) Conclusion A hypertensive patient with spontaneous hypokalemia and screening findings of PAC > 20 ng/dL and suppressed PRA of < 0.6 ng/ml/hr, may be classified as “overt primary aldosteronism confirmed” and may not need to proceed with dynamic confirmatory testing. Protocol registration number SRCTN34186253

Abstract Passively harmonic mode-locking has been experimentally demonstrated in an erbium-doped fiber laser with large normal dispersion using single-multi-single mode structure as artificial saturable absorber. By increasing the pump power under the same polarization setting, the mode-locking operation can switch from fundamental mode-locked to 5th order harmonic mode-locked. Highest repetition rate of 4.26 MHz (5th order harmonic) is observed, with pulse width and pulse energy ascertained at 290 fs and 3.0 nJ, respectively. Excellent signal-to-noise ratio (SNR) of above 50 dB is observed for all harmonic orders. The findings validated that SMS structure can be used to generate stable and switchable high order of harmonic mode-locked. The low-cost SMS fiber for harmonic mode-locked generation technique could lay the groundwork for future sustainable industrial growth.

Background: The school environment, consisting of the physical environment and social-emotional climate (SEC), plays a crucial role in both student and employee health; however, there is a lack of recent literature synthesizing school environment interventions in K-12 settings. We describe updated evidence about school environment interventions to support K-12 student and employee health in the United States. Methods: A 2-phase search included a review of reviews (2010-2018), followed by a search for individual articles (2010-2020) that targeted school physical environment and/or SEC to address physical activity (PA) and/or nutrition. We also investigated how nutrition and PA interventions with an SEC component improves social-emotional and/or mental health outcomes. Because research on dietary and PA behaviors for school employees is limited; we included studies on other worksites (eg, hospitals and offices) to provide insight for school employees. Findings: We identified 40 articles describing 40 unique studies and 45 interventions and grouped them by intervention type. Physical environment interventions demonstrated significant and positive nutrition and PA behavioral outcomes for students; outcomes among employees were mixed. Interventions with SEC components reported improvements in some mental health outcomes. Implications: The school environment can affect dietary and PA behaviors as well as mental health for students and employees. Conclusions: Establishing healthy school environments can support student and employee PA, dietary behaviors, and mental health.

Background: We introduce the Whole School, Whole Community, Whole Child approach to supporting student and school staff physical activity and nutrition and describe the methods used to generate the evidence synthesized across the special issue articles. Methods: A 2-phase literature review search included a search of systematic reviews (2010-2018) for individual qualifying articles (Phase 1) and a search for individual articles on topics not addressed by a review (2010-2020) or that needed an update because they were in a review that was older (2010-2016) or showed insufficient evidence (Phase 2). Research librarians developed search strategies. In each phase, pairs of subject matter experts applied criteria to review abstracts and full-text articles and extracted data using standardized forms. We included 314 articles, describing 293 studies. Findings: Most of the included studies looked at elementary or secondary school level interventions; 51% were rated poor quality, and few took place in a rural setting. Implications for School Health Policy, Practice, and Equity: Most of the identified studies engaged majority minority or racially/ethnically diverse schools, suggesting that these interventions are feasible in a variety of settings. Conclusions: This collection of 10 articles identifies evidence-based interventions, gaps in research, and implications for health equity.

The fms-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib improved the survival of patients with relapsed or refractory (R/R) FLT3-mutated acute myelogenous leukemia (AML) in the phase 3 ADMIRAL trial. In this study, we assessed survival and relapse rates of patients in the ADMIRAL trial who underwent hematopoietic stem cell transplantation (HSCT), as well as safety outcomes in patients who received post-transplantation gilteritinib maintenance therapy. ADMIRAL was a global phase 3 randomized controlled trial that enrolled adult patients with FLT3-mutated R/R AML. Patients with R/R AML who harbored FLT3 internal tandem duplication mutations in the juxtamembrane domain or D835/I836 point mutations in the tyrosine kinase domain were randomized (2:1) to gilteritinib (120 mg/day) or to preselected high- or low-intensity salvage chemotherapy (1 or 2 cycles). Patients in the gilteritinib arm who proceeded to HSCT could receive post-transplantation gilteritinib maintenance therapy if they were within 30 to 90 days post-transplantation and had achieved composite complete remission (CRc) with successful engraftment and no post-transplantation complications. Adverse events (AEs) during HSCT were recorded in the gilteritinib arm only. Survival outcomes and the cumulative incidence of relapse were assessed in patients who underwent HSCT during the trial. Treatment-emergent AEs were evaluated in patients who restarted gilteritinib as post-transplantation maintenance therapy. Patients in the gilteritinib arm underwent HSCT more frequently than those in the chemotherapy arm (26% [n = 64] versus 15% [n = 19]). For all transplantation recipients, 12- and 24-month overall survival (OS) rates were 68% and 47%, respectively. Despite a trend toward longer OS after pretransplantation CRc, post-transplantation survival was comparable in the 2 arms. Patients who resumed gilteritinib after HSCT had a low relapse rate after pretransplantation CRc (20%) or CR (0%). The most common AEs observed with post-transplantation gilteritinib therapy were increased alanine aminotransferase level (45%), pyrexia (43%), and diarrhea (40%); grade ≥3 AEs were related primarily to myelosuppression. The incidences of grade ≥III acute graft-versus-host disease and related mortality were low. Post-transplantation survival was similar across the 2 study arms in the ADMIRAL trial, but higher remission rates with gilteritinib facilitated receipt of HSCT. Gilteritinib as post-transplantation maintenance therapy had a stable safety and tolerability profile and was associated with low relapse rates. Taken together, these data support a preference for bridging therapy with gilteritinib over chemotherapy in transplantation-eligible patients.

Pancreatic ductal adenocarcinoma (PDAC) has been left behind in the evolution of personalized medicine. Predictive markers of response to therapy are lacking in PDAC despite various histological and transcriptional classification schemes. We report an artificial intelligence (AI) approach to histologic feature examination that extracts a signature predictive of disease-specific survival (DSS) in patients with PDAC receiving adjuvant gemcitabine. We demonstrate that this AI-generated histologic signature is associated with outcomes following adjuvant gemcitabine, while three previously developed transcriptomic classification systems are not (n = 47). We externally validate this signature in an independent cohort of patients treated with adjuvant gemcitabine (n = 46). Finally, we demonstrate that the signature does not stratify survival outcomes in a third cohort of untreated patients (n = 161), suggesting that the signature is specifically predictive of treatment-related outcomes but is not generally prognostic. This imaging analysis pipeline has promise in the development of actionable markers in other clinical settings where few biomarkers currently exist.

Naphthol Green B (NGB) is a synthetic azo dye widely used in various industries, including textiles and leathers. NGB poses significant environmental and ecological concerns when released into natural water systems. This paper investigates the decolorization of NGB using UV/sulfite system. The % decolorization of NGB was optimized using 32 Full Factorial Design (FFD), and the ANOVA results show that the model has a good fit for the data (R2 = 99.54 %, R2(adj) = 98.76 %) and the significant factors contributing to the % decolorization are A, B, A2, and B2 where A = mM sulfite and B = pH. The model predicted ≥100 % decolorization with the optimum conditions 12 mM sulfite and pH 10. An actual experiment was conducted to verify the response, resulting in 96.2 % decolorization which is in good agreement with the model.

PurposeThe FMS-related tyrosine kinase 3 (FLT3) inhibitor gilteritinib is standard therapy for relapsed/refractory FLT3-mutated (FLT3mut) acute myeloid leukemia (AML) but seldom reduces FLT3mut burden or induces sustained efficacy. Gilteritinib combines synergistically with the BCL-2 inhibitor venetoclax in preclinical models of FLT3mut AML.MethodsThis phase Ib open-label, dose-escalation/dose-expansion study (ClinicalTrials.gov identifier: NCT03625505) enrolled patients with FLT3 wild-type and FLT3mut (escalation) or FLT3mut (expansion) relapsed/refractory AML. Patients received 400 mg oral venetoclax once daily and 80 mg or 120 mg oral gilteritinib once daily. The primary objectives were safety, identification of the recommended phase II dose, and the modified composite complete response (mCRc) rate (complete response [CR] + CR with incomplete blood count recovery + CR with incomplete platelet recovery + morphologic leukemia-free state) using ADMIRAL phase III-defined response criteria.ResultsSixty-one patients were enrolled (n = 56 FLT3mut); 64% (n = 36 of 56) of FLT3mut patients had received prior FLT3 inhibitor therapy. The recommended phase II dose was 400 mg venetoclax once daily and 120 mg gilteritinib once daily. The most common grade 3/4 adverse events were cytopenias (n = 49; 80%). Adverse events prompted venetoclax and gilteritinib dose interruptions in 51% and 48%, respectively. The mCRc rate for FLT3mut patients was 75% (CR, 18%; CR with incomplete blood count recovery, 4%; CR with incomplete platelet recovery, 18%; and morphologic leukemia-free state, 36%) and was similar among patients with or without prior FLT3 inhibitor therapy (80% v 67%, respectively). The median follow-up was 17.5 months. The median time to response was 0.9 months, and the median remission duration was 4.9 months (95% CI, 3.4 to 6.6). FLT3 molecular response (< 10-2) was achieved in 60% of evaluable mCRc patients (n = 15 of 25). The median overall survival for FLT3mut patients was 10.0 months.ConclusionThe combination of venetoclax and gilteritinib was associated with high mCRc and FLT3 molecular response rates regardless of prior FLT3 inhibitor exposure. Dose interruptions were needed to mitigate myelosuppression.

Background and purposePrevious studies suggest that mechanisms and outcomes in patients with COVID-19-associated stroke differ from those in patients with non-COVID-19-associated strokes, but there is limited comparative evidence focusing on these populations. The aim of this study, therefore, was to determine if a significant association exists between COVID-19 status with revascularization and functional outcomes following thrombectomy for large vessel occlusion (LVO), after adjustment for potential confounding factors.MethodsA cross-sectional, international multicenter retrospective study was conducted in consecutively admitted COVID-19 patients with concomitant acute LVO, compared to a control group without COVID-19. Data collected included age, gender, comorbidities, clinical characteristics, details of the involved vessels, procedural technique, and various outcomes. A multivariable-adjusted analysis was conducted.ResultsIn this cohort of 697 patients with acute LVO, 302 had COVID-19 while 395 patients did not. There was a significant difference (p

The Rubiaceae family, comprising 550 species in the Philippines, is a significant source of bioactive components with ethnopharmacological uses. This study assessed the total phenolic content (TPC), total flavonoid content (TFC), and antioxidant activity of six Rubiaceae species, collected in Ilocos Norte, Philippines: Guettardella microphylla (Bartl. ex DC.) Merr., Timonius ternifolius (Bartl. ex DC.) Fern.-Vill., Kanapia monstrosa (A. Rich.) Arriola & Alejandro, Pyrostria triflora Arriola, Calaramo & Alejandro, Pyrostria subsessilifolia (Merr.) Arriola & Alejandro, and Psychotria luzoniensis (Cham. & Schltdl.) Fern.-Vill. Identification of the plant species was done using morphological characterization. The TFC results ranged between 1.86-3.81 mg quercetin equivalent/g dry weight (GAE/g DW), while TPC indicated 5.47-17.17 mg gallic acid equivalent/g dry weight (QE/g DW). G. microphylla showed the highest TFC (3.81±0.20 mg QE/g DW) while P. triflora exhibited the highest TPC (17.17±0.83 mg GAE/g DW). Antioxidant profiling showed P. luzoniensis exhibiting the highest activity in the NOS, ABTS, DPPH, and FRAP assays. G. microphylla showed the highest hydrogen peroxide scavenging activity, while T. ternifolius demonstrated the highest hydroxyl radical scavenging activity. Findings suggest that the crude methanolic extracts of the Rubiaceae species have relatively high TPC and TFC values and exhibit promising antioxidant capacities.

Abstract We experimentally demonstrated the generation of domain-wall dark pulse in an Erbium-doped fiber laser using the combination of a 10 cm graded index multimode fiber sandwiched by single mode fibers as artificial saturable absorber. The interaction of phase difference in grade index multimode fiber allowed the stable dual-wavelength oscillation in the cavity. The dual-wavelength centered at 1567.2 nm and 1569.4 nm produces the topological defect in temporal domain and achieved a dark pulse formation with repetition rate of 21.5 MHz. The highest average pulse energy is calculated as 769.6 pJ with pulse width of 5 ns. Throughout the operating pump power range, the average pulse energy and output power increase linearly, with R2 of 0.9999 and achieved the laser efficiency of 9.33%. From the measurement in frequency domain, the signal-to-noise ratio is measured as 49 dB. As compared to reported DW dark pulse works, the proposed structure only required a short length of multimode fiber, which allowed the domain-wall dark pulse to achieve higher pulse repetition rate. The venture of domain wall dark pulse is potentially to pave the foundation toward sustainable industrial growth.

Abstract We report a numerical evaluation of the impact of continuous helical baffle on the heat recovery efficiency of counterflow tube bundle heat exchangers. The baffle inclination angle has been varied from $$11^{\circ }$$ 11 ∘ to $$22^{\circ }$$ 22 ∘ . Since the fluid flows over the tube bundle at an angle due to helical flow inside the shell, the heat exchanger operates in cross counter mode. Fluent simulations with the k- $$\omega$$ ω transition shear stress transport turbulence model have been performed to investigate the thermal-hydraulic parameters of the system in terms of heat recovery efficiency, pressure loss, and overall heat transfer rate. Outside air temperature has been varied to mimic cold and warm weather. Pressure loss has been constrained to be less than 250 Pa, conforming to EU guidelines for energy labeling of residential ventilation units. At the maximum volume flow rate of 40 m $$^3$$ 3 /h, the device performed with over $$80\%$$ 80 % heat recovery efficiency for the considered temperature difference. Continuous helical baffles helped to improve convective heat transfer by reducing cross flow area and increasing velocity. Smaller angles result in greater pressure loss while having no discernible effect on heat recovery efficiency for the considered geometry. The analysis demonstrates the potential of a compact counterflowing recuperative heat exchanger with continuous helical baffles for decentralized ventilation systems and serves as a basis for further optimization.