Evaluating physiochemical properties of FDA-approved orally administered drugs.

INTRODUCTION: Analyses of orally administered FDA-approved drugs from 1990 to 1993 enabled the identification of a set of physiochemical properties known as Lipinski's Rule of Five (Ro5). The original Ro5 and extended versions still remain the reference criteria for drug development programs. Since many bioactive compounds do not conform to the Ro5, we validated the relevance of and adherence to these rulesets in a contemporary cohort of FDA-approved drugs. AREAS COVERED: The authors noted that a significant proportion of FDA-approved orally administered parent compounds from 2011 to 2022 deviate from the original Ro5 criteria (~38%) or the Ro5 with extensions (~53%). They then evaluated if a contemporary Ro5 criteria (cRo5) could be devised to better predict oral bioavailability. Furthermore, they discuss many case studies showcasing the need for and benefit of increasing the size of certain compounds and cover several evolving strategies for improving oral bioavailability. EXPERT OPINION: Despite many revisions to the Ro5, the authors find that no single proposed physiochemical rule has universal concordance with absolute oral bioavailability. Innovations in drug delivery and formulation have dramatically expanded the range of physicochemical properties and the chemical diversity for oral administration.

BoatNet: automated small boat composition detection using deep learning on satellite imagery.

Tracking and measuring national carbon footprints is key to achieving the ambitious goals set by the Paris Agreement on carbon emissions. According to statistics, more than 10% of global transportation carbon emissions result from shipping. However, accurate tracking of the emissions of the small boat segment is not well established. Past research looked into the role played by small boat fleets in terms of greenhouse gases, but this has relied either on high-level technological and operational assumptions or the installation of global navigation satellite system sensors to understand how this vessel class behaves. This research is undertaken mainly in relation to fishing and recreational boats. With the advent of open-access satellite imagery and its ever-increasing resolution, it can support innovative methodologies that could eventually lead to the quantification of greenhouse gas emissions. Our work used deep learning algorithms to detect small boats in three cities in the Gulf of California in Mexico. The work produced a methodology named BoatNet that can detect, measure and classify small boats with leisure boats and fishing boats even under low-resolution and blurry satellite images, achieving an accuracy of 93.9% with a precision of 74.0%. Future work should focus on attributing a boat activity to fuel consumption and operational profile to estimate small boat greenhouse gas emissions in any given region.

Therapeutic targeting of histone lysine demethylase KDM4B blocks the growth of castration-resistant prostate cancer.

Epigenetics is an emerging mechanism for tumorigenesis. Treatment that targets epigenetic regulators is becoming an attractive strategy for cancer therapy. The role of epigenetic therapy in prostate cancer (PCa) remains elusive. Previously we demonstrated that upregulation of histone lysine demethylase KDM4B correlated with the appearance of castration resistant prostate cancer (CRPC) and identified a small molecular inhibitor of KDM4B, B3. In this study, we further investigated the role of KDM4B in promoting PCa progression and tested the efficacy of B3 using clinically relevant PCa models including PCa cell line LNCaP and 22Rv1 and xenografts derived from these cell lines. In loss and gain-functional studies of KDM4B in PCa cells, we found that overexpression of KDM4B in LNCaP cells enhanced its tumorigenicity whereas knockdown of KDM4B in 22Rv1 cells reduced tumor growth in castrated mice. B3 suppressed the growth of 22Rv1 xenografts and sensitized tumor to anti-androgen receptor (AR) antagonist enzalutamide inhibition. B3 also inhibited 22Rv1 tumor growth synergistically with rapamycin, leading to cell apoptosis. Comparative transcriptomic analysis performed on KDM4B knockdown and B3-treated 22Rv1 cells revealed that B3 inhibited both H3K9me3 and H3K27me3 demethylase activities. Our studies establish KDM4B as a target for CRPC and B3 as a potential therapeutic agent. B3 as monotherapy or in combination with other anti-PCa therapeutics offers proof of principle for the clinical translation of epigenetic therapy targeting KDMs for CRPC patients.

Tensiomyographic Responses to Warm-Up Protocols in Collegiate Male Soccer Athletes.

The mechanical properties of knee flexors and extensors in 15 collegiate male soccer players following different warm-up protocols [small-sided games (SSG), dynamic (DYN), and plyometric (PLY)] were evaluated. Tensiomyography (TMG) was used to assess contraction time (Tc), delay time (Td) and maximal displacement (Dm) of the rectus femoris (RF) and biceps femoris (BF) of both legs before and after each warm-up, while countermovement jump height variables, 20 m sprint, t-test and sit-and-reach were measured following the warm-ups. TMG was analyzed using a three-way [condition × time × leg] ANOVA, while performance variables were analyzed with a repeated measures ANOVA. Main effects of time were observed for BF-Tc (p = 0.035), RF-Td (p < 0.001), and BF-Td, (p = 0.008), and a main effect of condition was seen for RF-Tc (p = 0.038). Moreover, participants' 20 m sprint improved following SSG (p = 0.021) compared to DYN and PLY. Sit-and-reach was greater following PLY (p = 0.021). No significant interactions were noted for the measured TMG variables. Warm-up-specific improvements were demonstrated in sprint speed and flexibility following SSG and PLY, respectively. The present study revealed changes in certain TMG measures following the warm-ups that suggest enhanced response of lower leg muscles regardless of specific activities used.

TEVAR for complicated and uncomplicated type B aortic dissection-Systematic review and meta-analysis.

BACKGROUND: Type B aortic dissection (TBAD), is defined as a dissection involving the aorta distal to left subclavian artery with the ascending aorta and the aortic arch not affected. TBAD is classified due to the time frame and presence of complications. Complicated TBAD (co-TBAD) patients have a greater mortality rate than uncomplicated TBAD (un-TBAD) and thoracic endovascular aortic repair (TEVAR) is considered the gold-standard intervention for these clinical challenges. METHODS: We undertook a systematic review of the literature regarding TEVAR intervention in co-TBAD and un-TBAD. A comprehensive search was undertaken across four major databases and was evaluated and assessed until June 2020. RESULTS: A total of 16,104 patients were included in the study (7772 patients co-TBAD and 8352 un-TBAD). A significantly higher proportion of comorbidities were seen in co-TBAD patients compared with un-TBAD. Acute dissection was more frequent in the co-TBAD group (73.55% vs. 66.91%), while chronic dissection was more common in un-TBAD patients (33.8% vs. 70.73%). Postprocedure stroke was higher in co-TBAD (5.85% vs. 3.92%; p < .01), while postprocedural renal failure was higher in un-TBAD patients (7.23 vs. 11.38%; p < .01). No difference was observed in in-hospital mortality however the 30 days mortality was higher in the co-TBAD group. One-year survival was higher in the uncomplicated group but this difference was not observed in the 5-year survival. CONCLUSION: In our analysis we can appreciate that despite significantly higher comorbidities in the co-TBAD cohort, there was no difference in in-hospital mortality between the two groups and the 5-year survival did not have any difference.

The acute effects of thermogenic fitness drink formulas containing 140 mg and 100 mg of caffeine on energy expenditure and fat metabolism at rest and during exercise.

BACKGROUND: Thermogenic fitness drink formulas (TFD) have been shown to increase energy expenditure and markers of lipid metabolism. The purpose of the current study was to compare TFD formulas containing different caffeine concentrations versus a placebo drink on energy expenditure and lipid metabolism at rest and during exercise. METHODS: Thirty-two recreationally active participants (22.9 ± 0.7 y, 167.1 ± 1.4 cm, 68.8 ± 2.0 kg, 24.0 ± 1.2% fat) who were regular caffeine consumers, participated in this randomized, double-blind, crossover design study. Participants reported to the laboratory on three occasions, each of which required consumption of either a TFD containing 140 mg or 100 mg of caffeine or a placebo. Baseline measurements of resting energy expenditure (REE) and resting fat oxidation (RFO) were assessed using indirect calorimetry as well as measurements of serum glycerol concentration. Measurements were repeated at 30, 60, 90 min post-ingestion. Following resting measures, participants completed a graded exercise test to determine maximal oxygen uptake (V̇O2max), maximal fat oxidation (MFO) and the exercise intensity that elicits MFO (Fatmax), and total energy expenditure (EE). RESULTS: A significant interaction was shown for REE (p < 0.01) and RFO (p < 0.01). Area under the curve analysis showed an increased REE for the 140 mg compared to the 100 mg formula (p = 0.02) and placebo (p < 0.01) and an increased REE for the 100 mg formula compared to placebo (p = 0.02). RFO significantly decreased for caffeinated formulas at 30 min post ingestion compared to placebo and baseline (p < 0.01) and significantly increased for the 140 mg formula at 60 min post-ingestion (p = 0.03). A main effect was shown for serum glycerol concentrations over time (p < 0.01). No significant differences were shown for V̇O2max (p = 0.12), Fatmax (p = 0.22), and MFO (p = 0.05), and EE (p = 0.08) across drinks. CONCLUSIONS: Our results suggest that TFD formulas containing 100 and 140 mg of caffeine are effective in increasing REE and that a 40 mg of caffeine difference between the tested formulas may impact REE and RFO in healthy individuals within 60 min of ingestion.

Minimal Effects of Moderate Normobaric Hypoxia on the Upper Body Work-Time Relationship in Recreationally Active Women.

Background: Sex-based differences in metabolism and morphological characteristics may result in unique exercise responses during periods of limited oxygen availability. Purpose: To evaluate the effects of moderate normobaric hypoxia on the parameters of the work-time relationship during upper body exercise in women. Materials and Methods: Thirteen recreationally active women (age: 22.7 ± 2.6 years; height: 167 ± 8.6 cm; weight: 66.4 ± 9.7 kg; body fat: 27.6% ± 5% body fat) completed a maximal graded exercise test in both normobaric hypoxia (H; fraction of inspired oxygen (FiO2) = 0.14) and normoxia (N; FiO2 = 0.20) on an arm ergometer to determine peak oxygen uptake (VO2peak) and peak power output (PPO). Each participant completed four constant, work rate, arm-cranking time-to-exhaustion tests at 90%-120% PPO in both environmental conditions. Linear regression was used to estimate critical power (CP) and anaerobic capacity (W') through the work-time relationship during the constant work rate tests. Paired sample t-tests compared mean differences between VO2peak, PPO, CP, and W' between conditions (normoxia vs. hypoxia). Two-way (condition × intensity) repeated measures analysis of variance (ANOVA) was used to compare total work (TW) and time to exhaustion. Results: Hypoxia significantly reduced VO2peak (N: 1.73 ± 0.31 L·minute-1 vs. H: 1.62 ± 0.27 L·minute-1, p = 0.008), but had no effects on PPO (N: 78.08 ± 14.51 W vs. H: 75.38 ± 13.46 W, p = 0.09), CP (N: 57.44 ± 18.89 W vs. H: 56.01 ± 12.36 W, p = 0.55), and W' (N: 4.81 ± 1.01 kJ vs. H: 4.56 ± 0.91 kJ, p = 0.51). No significant condition × intensity interactions were noted for TW or time to exhaustion (p > 0.05). Conclusions: Moderate normobaric hypoxia significantly reduced VO2peak, but had minimal effects on CP and W' using the work-time model in women.

Alterations in energy system contribution following upper body sprint interval training.

PURPOSE: The primary purpose of this study was to examine the influence of different work-to-rest ratios on relative energy system utilization during short-term upper-body sprint interval training (SIT) protocols. METHODS: Forty-two recreationally trained men were randomized into one of three training groups [10 s work bouts with 2 min of rest (10:2, n = 11) or 4 min of rest (10:4, n = 11), or 30 s work bouts with 4 min of rest (30:4, n = 10)] or a control group (CON, n = 10). Participants underwent six training sessions over 2 weeks with 4-6 'all-out' sprints. Participants completed an upper body Wingate test (30 s 'all-out' using 0.05 kg kg-1 of the participant's body mass) pre- and post-intervention from which oxygen consumption and blood lactate were used to estimate oxidative, glycolytic, and adenosine triphosphate-phosphocreatine (ATP-PCr) energy system provisions. An analysis of covariance was performed on all testing measurements collected at post with the associated pre-values used as covariates. RESULTS: Relative energy contribution (p = 0.026) and energy expenditure (p = 0.019) of the ATP-PCr energy system were greater in 10:4 (49.9%; 62.1 kJ) compared to CON (43.1%; 47.2 kJ) post training. No significant differences were found between groups in glycolytic or oxidative energy contribution over a 30 s upper body Wingate test. CONCLUSION: SIT protocols with smaller work-to-rest ratios may enhance ATP-PCr utilization in a 30 s upper body Wingate over a 2-week intervention.

Early Dark Energy can Resolve the Hubble Tension.

Early dark energy (EDE) that behaves like a cosmological constant at early times (redshifts z≳3000) and then dilutes away like radiation or faster at later times can solve the Hubble tension. In these models, the sound horizon at decoupling is reduced resulting in a larger value of the Hubble parameter H_{0} inferred from the cosmic microwave background (CMB). We consider two physical models for this EDE, one involving an oscillating scalar field and another a slowly rolling field. We perform a detailed calculation of the evolution of perturbations in these models. A Markov Chain Monte Carlo search of the parameter space for the EDE parameters, in conjunction with the standard cosmological parameters, identifies regions in which H_{0} inferred from Planck CMB data agrees with the SH0ES local measurement. In these cosmologies, current baryon acoustic oscillation and supernova data are described as successfully as in the cold dark matter model with a cosmological constant, while the fit to Planck data is slightly improved. Future CMB and large-scale-structure surveys will further probe this scenario.

The bicuspid aortic valve: Is it an immunological disease process?

Bicuspid aortic valves (BAVs) are the most common congenital cardiac condition and are characterized by a structural abnormality whereby the aortic valve is composed of two leaflets instead of being trileaflet. It is linked to an increased risk for a variety of complications of the aorta, many with an immunological pathogenesis. The aim of this study is to review and analyze the literature regarding immunological processes involving BAVs, associated common pathologies, and their incidence in the population. This study will also examine current trends in surgical and therapeutic approaches to treatment and discuss the future direction of BAV treatment.

Examining work-to-rest ratios to optimize upper body sprint interval training.

The objective was to compare the metabolic influence of varying work-to-rest ratios during upper body sprint interval training (SIT). Forty-two recreationally-trained men were randomized into a training group [10 s work - 2 min of rest (10:2) or 4 min of rest (10:4), or 30 s work - 4 min of rest (30:4)] or a control group (CON). Participants underwent six training sessions over two weeks. Assessments consisted of a graded exercise test [maximal oxygen consumption (VO2peak) and peak power output (PPO)], four constant-work rate trials [critical power, anaerobic working capacity, and electromyographic fatigue threshold], and an upper body Wingate test (mean/peak power and total work). Post-training absolute and relative VO2peak was greater than pre-training for 30:4 (p = .005 and p = .009, respectively), but lower for CON (p = .001 and p = .006, respectively). Post-training PPO was greater in 30:4 (p < .001). No differences were observed during the constant-work rate trials or Wingate test. Traditional SIT appears to have enhanced VO2peak in the upper body over a short-term two-week intervention.

Effects of normobaric hypoxia on upper body critical power and anaerobic working capacity.

PURPOSE: To evaluate the effects of moderate normobaric hypoxia on the parameters of the work-time relationship in the upper body. METHODS: Twenty-one recreationally active men completed a graded exercise test in both normobaric hypoxia (H) and normoxia (N) to exhaustion on an arm ergometer to determine V̇O2peak and peak power output (PPO). Each participant completed four constant work-rate (CWR) arm-cranking tests at 90-120% PPO in both environmental conditions. Linear regression was used to estimate critical power (CP) and anaerobic working capacity (AWC) via work-time relationship during the CWR tests. RESULTS: H significantly reduced V̇O2peak (N: 2.34 ±â€¯0.34 L vs. H: 2.27 ±â€¯0.34 L, p = 0.041), PPO (N: 125.29 ±â€¯17.98 W vs. H: 121.11 ±â€¯17.98 W, p = 0.001), and CP (N: 90.22 ±â€¯12.88 W vs. H: 85.26 ±â€¯9.64 W, p = 0.042), but had no effect on AWC (N: 9.16 ±â€¯2.81 kJ vs. H: 8.75 ±â€¯3.23 kJ, p = 0.600). DISCUSSION: Moderate normobaric hypoxia appears to reduce CP in the upper body but has a variable effect on AWC.

Near Complete Response in a Patient with Classical Hodgkin Lymphoma Treated with Brentuximab Vedotin Concurrent with Radiation Therapy.

Brentuximab vedotin, an antibody drug conjugate that delivers monomethyl auristatin E into CD-30 expressing cells is FDA approved for the treatment of patients with Hodgkin lymphoma after the failure of autologous stem cell transplantation or at least 2 prior multi-agent chemotherapy regiments. This approval was based on a study that showed an overall response rate of 75% and complete remission in 34%. We present a case of a 24-year-old male with classical nodular sclerosing Hodgkin lymphoma who achieved near complete remission following 5 cycles of brentuximab concurrent with ISRT (involved site radiation therapy) following progression of first-line ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine) and subsequent second-line ICE (ifosfamide, carboplatin, etoposide) chemotherapy. This case not only reiterates the efficacy of brentuximab vedotin in the third-line setting but introduces the role of and need for further clinical trials of combined radiotherapy with brentuximab in Hodgkin lymphoma patients following failure of second-line options.

An Uncommon Presentation of a Metachronous Testicular Primary Nonseminoma and Seminoma Separated by Two Decades and a Testicular Cancer Literature Review.

INTRODUCTION: Testicular cancer is the most common malignancy in men aged 15-40 years [Bols et al.: Philadelphia, Wolters Kluwer, Lippincott Williams & Wilkins, 2011]. Its incidence comprises 0.8% of all male cancers worldwide, with a mortality rate of 0.1%. The incidence has nearly doubled from 1975 to 2007 leading to the concern of environmental causes [Thomas: Am J Epidemiol 2013; 178: 1240-1245]. Testicular cancer presents as a painless testicular mass without transillumination. Testicular cancer is subcategorized under germ cell testicular cancer or sex cord-stromal tumors. Of the germ cell tumors, approximately 90% originate in the testis, with the other 10% being extragonadal [Bols et al.: Philadelphia, Wolters Kluwer, Lippincott Williams & Wilkins, 2011]. Typically, if a patient presents with a testicular mass and is 50 years old or older, the diagnosis of a primary lymphoma is considered until proven otherwise [Bols et al.: Philadelphia, Wolters Kluwer, Lippincott Williams & Wilkins, 2011]. Germ cell testicular cancer is further divided into the subtypes of seminomatous and nonseminomatous; each presents with a unique histology and differing treatment implications. DISCUSSION: Given the uniqueness of our patient's metachronous second testicular primary, we sought to compare our case findings to available historic publications. We sought to address the issues of the incidence of a second primary testicular malignancy with regard to varying histology, age of incidence, and timing of a second primary testicular cancer, the presence of bowel involvement, and finally a brief discussion of testosterone replacement therapy. CONCLUSION: A review of our case presents several unique factors. The above varying literature has shown our patient to have met the odds of a contralateral testicular primary development in that he had a nonseminomatous primary, followed by a second testicular primary seminoma. Our patient exceeded the 15-year cumulative risk of contralateral metachronous testicular cancer of 1.9% versus the seemingly contradictory 5.2% cumulative risk 25 years after the first testicular germ cell tumor. With his second primary (seminoma), he presented with the common retroperitoneal landing zone site, though with an uncommon involvement of the gastrointestinal tract (<1%) and rare incidence of involving the duodenum.

Thermal stability, storage and release of proteins with tailored fit in silica.

Biological substances based on proteins, including vaccines, antibodies, and enzymes, typically degrade at room temperature over time due to denaturation, as proteins unfold with loss of secondary and tertiary structure. Their storage and distribution therefore relies on a "cold chain" of continuous refrigeration; this is costly and not always effective, as any break in the chain leads to rapid loss of effectiveness and potency. Efforts have been made to make vaccines thermally stable using treatments including freeze-drying (lyophilisation), biomineralisation, and encapsulation in sugar glass and organic polymers. Here for the first time we show that proteins can be enclosed in a deposited silica "cage", rendering them stable against denaturing thermal treatment and long-term ambient-temperature storage, and subsequently released into solution with their structure and function intact. This "ensilication" method produces a storable solid protein-loaded material without the need for desiccation or freeze-drying. Ensilication offers the prospect of a solution to the "cold chain" problem for biological materials, in particular for vaccines.

Aspiration-related lung diseases.

Aspiration is a common but underrecognized clinicopathologic entity, with varied radiographic manifestations. Aspiration represents a spectrum of diseases, including diffuse aspiration bronchiolitis, aspiration pneumonitis, airway obstruction by foreign body, exogenous lipoid pneumonia, interstitial fibrosis, and aspiration pneumonia with or without lung abscess formation. Many patients who aspirate do not present with disease, suggesting that pathophysiology is related to a variety of factors, including decreased levels of consciousness, dysphagia, impaired mucociliary clearance, composition of aspirate, and impaired host defenses. In this pictorial essay, we will review the different types of aspiration lung diseases, focusing on their imaging features and differential diagnosis.

New cosmic microwave background constraint to primordial gravitational waves.

Primordial gravitational waves (GWs) with frequencies > or approximately equal to 10(-15) Hz contribute to the radiation density of the Universe at the time of decoupling of the cosmic microwave background (CMB). This affects the CMB and matter power spectra in a manner identical to massless neutrinos, unless the initial density perturbation for the GWs is nonadiabatic, as may occur if such GWs are produced during inflation or some post-inflation phase transition. In either case, current observations provide a constraint to the GW amplitude that competes with that from big-bang nucleosynthesis (BBN), although it extends to much lower frequencies (approximately 10(-15) Hz rather than the approximately 10(-10) Hz from BBN): at 95% confidence level, omega(gw)h(2)