Transcriptomic and proteomic elucidation of Z chromosome dosage compensation in Helicoverpa armigera.

Transcriptomic data have been used to study sex chromosome dosage compensation (SCDC) in approximately 10 Lepidoptera ZW species, yielding a consensus compensation pattern of Z ≈ ZZ < AA . $$ \approx \mathrm{ZZ}<\mathrm{AA}. $$ It remains unclear whether this compensation pattern holds when examining more Lepidoptera ZW species and/or using proteomic data to analyse SCDC. Here we combined transcriptomic and proteomic data as well as transcriptional level of six individual Z genes to reveal the SCDC pattern in Helicoverpa armigera, a polyphagous lepidopteran pest of economic importance. Transcriptomic analysis showed that the Z chromosome expression of H. armigera was balanced between male and female but substantially reduced relative to autosome expression, exhibiting an SCDC pattern of Z ≈ ZZ < AA $$ \approx \mathrm{ZZ}<\mathrm{AA} $$ . When using H. amigera midgut proteomic data, the SCDC pattern of this species changed from Z ≈ ZZ < AA $$ \approx \mathrm{ZZ}<\mathrm{AA} $$ at transcriptomic level to Z = ZZ = AA at the proteomic level. RT-qPCR analysis of transcript abundance of six Z genes found that compensation for each Z gene could vary from no compensation to overcompensation, depending on the individual genes and tissues tested. These results demonstrate for the first time the existence of a translational compensation mechanism, which is operating in addition to a translational mechanism, such as has been reported in other lepidopteran species. And the transcriptional compensation mechanism functions to accomplish Z chromosome dosage balance between the sexes (M = F on the Z chromosome), whereas the translation compensation mechanism operates to achieve dosage compensation between Z chromosome and autosome (Z = AA).

Quantitative analysis of solid dosage forms of Atenolol by Raman spectroscopy.

ObjectiveTo develop a Raman spectroscopy-based analytical model for quantification of solid dosage forms of active pharmaceutical ingredient (API) of Atenolol.Significance:For the quantitative analysis of pharmaceutical drugs, Raman Spectroscopy is a reliable and fast detection method. As part of this study, Raman Spectroscopy is explored for the quantitative analysis of different concentrations of Atenolol.MethodsVarious solid-dosage forms of Atenolol were prepared by mixing API with excipients to form different solid-dosage formulations of Atenolol. Multivariate data analysis techniques such as Principal Component Analysis (PCA) and Partial least square regression (PLSR) were used for the qualitative and quantitative analysis, respectively.ResultsAs the concentration of the drug increased in formulation, the peak intensities of the distinctive Raman spectral characteristics associated with the API (Atenolol) gradually increased. Raman spectral data sets were classified using PCA due to their distinctive spectral characteristics. Additionally, a prediction model was built using PLSR analysis to assess the quantitative relationship between various API (Atenolol) concentrations and spectral features. With a goodness of fit value of 0.99, the root mean square errors of calibration (RMSEC) and prediction (RMSEP) were determined to be 1.0036 mg and 2.83 mg, respectively. The API content in the blind/unknown Atenolol formulation was determined as well using the PLSR model.ConclusionBased on these results, Raman spectroscopy may be used to quickly and accurately analyze pharmaceutical samples and for their quantitative determination.

3D printed dosage forms, where are we headed?

INTRODUCTION: 3D Printing (3DP) is an innovative fabrication technology that has gained enormous popularity through its paradigm shifts in manufacturing in several disciplines, including healthcare. In this past decade, we have witnessed the impact of 3DP in drug product development. Almost eight years after the first USFDA approval of the 3D printed tablet Levetiracetam (Spritam), the interest in 3DP for drug products is high. However, regulatory agencies have often questioned its large-scale industrial practicability, and 3DP drug approval/guidelines are yet to be streamlined. AREAS COVERED: In this review, major technologies involved with the fabrication of drug products are introduced along with the prospects of upcoming technologies, including AI (Artificial Intelligence). We have touched upon regulatory updates and discussed the burning limitations, which require immediate focus, illuminating status, and future perspectives on the near future of 3DP in the pharmaceutical field. EXPERT OPINION: 3DP offers significant advantages in rapid prototyping for drug products, which could be beneficial for personalizing patient-based pharmaceutical dispensing. It seems inevitable that the coming decades will be marked by exponential growth in personalization, and 3DP could be a paradigm-shifting asset for pharmaceutical professionals.

Reduced dose helical CT scout imaging on next generation wide volume CT system decreases scan length and overall radiation exposure.

Purpose: Traditional CT acquisition planning is based on scout projection images from planar anterior-posterior and lateral projections where the radiographer estimates organ locations. Alternatively, a new scout method utilizing ultra-low dose helical CT (3D Landmark Scan) offers cross-sectional imaging to identify anatomic structures in conjunction with artificial intelligence based Anatomic Landmark Detection (ALD) for automatic CT acquisition planning. The purpose of this study is to quantify changes in scan length and radiation dose of CT examinations planned using 3D Landmark Scan and ALD and performed on next generation wide volume CT versus examinations planned using traditional scout methods. We additionally aim to quantify changes in radiation dose reduction of scans planned with 3D Landmark Scan and performed on next generation wide volume CT. Methods: Single-center retrospective analysis of consecutive patients with prior CT scan of the same organ who underwent clinical CT using 3D Landmark Scan and automatic scan planning. Acquisition length and dose-length-product (DLP) were collected. Data was analyzed by paired t-tests. Results: 104 total CT examinations (48.1 % chest, 15.4 % abdomen, 36.5 % chest/abdomen/pelvis) on 61 individual consecutive patients at a single center were retrospectively analyzed. 79.8 % of scans using 3D Landmark Scan had reduction in acquisition length compared to the respective prior acquisition. Median acquisition length using 3D Landmark Scan was 26.7 mm shorter than that using traditional scout methods (p < 0.001) with a 23.3 % median total radiation dose reduction (245.6 (IQR 150.0-400.8) mGy cm vs 320.3 (IQR 184.1-547.9) mGy cm). CT dose index similarly was overall decreased for scans planned with 3D Landmark and ALD and performed on next generation CT versus traditional methods (4.85 (IQR 3.8-7) mGy vs. 6.70 (IQR 4.43-9.18) mGy, respectively, p < 0.001). Conclusion: Scout imaging using reduced dose 3D Landmark Scan images and Anatomic Landmark Detection reduces acquisition range in chest, abdomen, and chest/abdomen/pelvis CT scans. This technology, in combination with next generation wide volume CT reduces total radiation dose.

YY1-mediated enhancer-promoter communication in the immunoglobulin µ locus is regulated by MSL/MOF recruitment.

The rearrangement and expression of the immunoglobulin µ heavy chain (Igh) gene require communication of the intragenic Eµ and 3' regulatory region (RR) enhancers with the variable (VH) gene promoter. Eµ binding of the transcription factor YY1 has been implicated in enhancer-promoter communication, but the YY1 protein network remains obscure. By analyzing the comprehensive proteome of the 1-kb Eµ wild-type enhancer and that of Eµ lacking the YY1 binding site, we identified the male-specific lethal (MSL)/MOF complex as a component of the YY1 protein network. We found that MSL2 recruitment depends on YY1 and that gene knockout of Msl2 in primary pre-B cells reduces µ gene expression and chromatin looping of Eµ to the 3' RR enhancer and VH promoter. Moreover, Mof heterozygosity in mice impaired µ expression and early B cell differentiation. Together, these data suggest that the MSL/MOF complex regulates Igh gene expression by augmenting YY1-mediated enhancer-promoter communication.

Cholangiocarcinoma, sequential chemotherapy, and prognostic tests.

Introduction: Routine blood tests are prognostic tests for patients with cholangiocarcinoma. New drug regimens may produce a median overall survival of 2 years or more. Methods: This single practice, IRB-approved, phase II trial examines prognostic tests, Kaplan-Meier survival, and univariate Cox regression analyses. Eligibility requires: intent-to-treat; signed consent; advanced measurable intrahepatic cholangiocarcinoma, with or without resistance to the test drugs; any adult age; performance status 0-2; and expected survival of ≥ 6 weeks. Biweekly treatment, with 1/3 of standard dosages in mg/M2, includes: Gemcitabine 500; 5-Fluorouracil 1200 over 24 hours; Leucovorin 180; Irinotecan 80; and on day 2, Oxaliplatin 40. On progression, drugs are added on day 2: first, Docetaxel 25 precedes Oxaliplatin, with or without Mitomycin C 6 after Oxaliplatin. The next sequential additions are day 1, Cetuximab 400 total mg, then 200 mg weekly, and then Bevacizumab 10 mg/kg is substituted for Cetuximab (FDA IND# 119005). Results: For 35 patients, 19 with 1-2 lines of prior therapy, resistant tumors, and 16 no prior therapy, survival at 24-months is ≥ 72 and ≥ 58%, respectively. For 14 patients aged ≥ 70 years, ≥ 63% survive 24 months, P = 0.28. Validated tests that predict ≤ 6-month survivals find median survival times of 17-months through > 2-years when compared to patients with favorable tests: Neutrophils lymphocyte ratio > 3.0, HR = 6.54, P < 6.4x10-3; absolute neutrophil count > 8000/µl, HR = 4.95, P < 6.5x10-3; serum albumin < 3.5 g/dl, HR = 4.10, P < 0.03; and lymphocyte monocyte ratio< 2.1, HR = 1.6, P = 0.50. Overall, the 76 (60-90)% of patients with 0-2 out of 4 high risk tests survive ≥ 24 months, (P = 7.1x10-3). Treatments produce neither hospitalization, neutropenic fever, severe enteritis, nor severe neuropathies. Conclusion: Two-year survival is replicable and predictable. Findings warrant phase III validation tests of sequential regimens, re-challenge with recombination, low dosages, and blood tests that are associated with lethal mechanisms that impair response and survival.

Effects of Sex Differences and Combined Use of Clozapine on Initial Dosage Optimization of Valproic Acid in Patients with Bipolar Disorder.

BACKGROUND: Due to the narrow therapeutic window and large pharmacokinetic variation of valproic acid (VPA), it is difficult to make an optimal dosage regimen. The present study aims to optimize the initial dosage of VPA in patients with bipolar disorder. METHODS: A total of 126 patients with bipolar disorder treated by VPA were included to construct the VPA population pharmacokinetic model retrospectively. Sex differences and combined use of clozapine were found to significantly affect VPA clearance in patients with bipolar disorder. The initial dosage of VPA was further optimized in male patients without the combined use of clozapine, female patients without the combined use of clozapine, male patients with the combined use of clozapine, and female patients with the combined use of clozapine, respectively. RESULTS: The CL/F and V/F of VPA in patients with bipolar disorder were 11.3 L/h and 36.4 L, respectively. It was found that sex differences and combined use of clozapine significantly affected VPA clearance in patients with bipolar disorder. At the same weight, the VPA clearance rates were 1.134, 1, 1.276884, and 1.126 in male patients without the combined use of clozapine, female patients without the combined use of clozapine, male patients with the combined use of clozapine, and female patients with the combined use of clozapine, respectively. This study further optimized the initial dosage of VPA in male patients without the combined use of clozapine, female patients without the combined use of clozapine, male patients with the combined use of clozapine, and female patients with the combined use of clozapine, respectively. CONCLUSION: This study is the first to investigate the initial dosage optimization of VPA in patients with bipolar disorder based on sex differences and the combined use of clozapine. Male patients had higher clearance, and the recommended initial dose decreased with increasing weight, providing a reference for the precision drug use of VPA in clinical patients with bipolar disorder.

Update on cannabis in human sexuality.

RATIONALE: Sexuality is a central aspect of being human that encompasses many facets. Cannabis, a widely used psychoactive substance, has been associated with various effects on sexuality. The relationship between cannabis and sexuality is complex and multifaceted, involving physiological, psychological, and social factors. OBJECTIVES: This review aims to provide an overview of the current literature on the effects of cannabis on several sexual functions, including sexual desire, arousal, orgasm, and sexual satisfaction. It also discusses the potential mechanisms underlying these effects, as well as the impact of dose and frequency of use. RESULTS: This review has revealed a complex relationship between cannabis dosage and its influence on sexuality. It appears that the frequency of cannabis use in humans has been associated with the frequency of sexual activities. Individuals who use cannabis more frequently tend to report higher levels of sexual activity. Moreover, there is a notable gender difference in how cannabis affects sexuality. In addition, we found lower doses of cannabis to be linked to heightened sexual desire and enjoyment, whereas higher doses may lead to a decrease in sexual desire and performance. CONCLUSIONS: Overall, the association between cannabis and sexuality is complex and warrants further research to better understand the psychological and neurological mechanisms that underlie the effect of cannabis on these sexuality functions and its implications for sexual health. To advance in this endeavor, a crucial step is establishing a precise measurement of dosage in human studies.

Radiotherapy for Solitary Bony or Extramedullary Plasmacytoma.

Background/Aim: This study aimed to determine the oncological outcomes associated with curative radiotherapy for solitary bony or extramedullary plasmacytomas by drawing on clinical data from a single tertiary center. This study aimed to provide a comprehensive understanding of the efficacy of radiotherapeutic interventions and delineate the patterns of disease recurrence. Patients and Methods: Eleven consecutive patients diagnosed with solitary bony or extramedullary plasmacytomas and treated between May 2007 and November 2023 were retrospectively screened. Different radiotherapy doses and fractionations were employed, and statistical analyses were performed to assess overall survival (OS) and disease-free survival (DFS). Results: Among the 11 patients (9 males and 2 females), primary tumors were located within the bone in seven patients, whereas extramedullary tumors were observed in four patients. The median prescribed radiation dose was 46 Gy. The 5-year OS and DFS were 83.3% and 28.9%, respectively. Progression to multiple myeloma occurred in four patients with primary bony plasmacytoma. Local control rate was 88.9%, and one patient experienced distant metastasis after 32 months. Bony plasmacytoma has a high tendency of leading to multiple myeloma rather than extramedullary plasmacytoma (5-year progression to multiple myeloma-free survival rate, 20.8% vs. 100%, p=0.08). Conclusion: Radiotherapy is effective for solitary plasmacytomas with favorable local control and high objective response rates. A comparison with the existing literature supports the role of radiotherapy in the management of these conditions. The differences in outcomes between bony and extramedullary plasmacytomas emphasize the need for personalized treatment approaches.

Real-time analgesic efficacy and factors determining drug requirements of combined spinal-epidural analgesia for labor: a prospective cohort study.

PURPOSE: Combined spinal-epidural analgesia (CSEA) is effective but not sufficient for labor pain. This study was conducted to assess the real-time analgesic efficacy, side effects of anesthetic drug dosage, and maternal satisfaction in labor to provide reference for the optimization of labor analgesia. METHODS: This was a prospective, cohort, single-center study that included 3020 women who received CSEA for labor analgesia. The visual analogue scale (VAS) for labor pain, real-time anesthetic drug dosage, side effects, adverse labor outcomes, factors influencing average drug dosage, and maternal satisfaction with CSEA were assessed. RESULTS: Overall, the VAS labor pain score was lowest at the first hour after the anesthesia was given. After 4 h for primiparas and 3 h for multiparas, the VAS score was greater than 3 but the anesthetic drug dosage did not reach the maximum allowed dosage at the same time. The average anesthetic drug dosage was positively correlated with fever, urinary retention, uterine atony, prolonged active phase, prolonged second stage, assisted vaginal delivery, and postpartum hemorrhage. The average anesthetic drug dosage was the highest in women ≤ 20 years old, those with a body mass index (BMI) ≥ 24.9 kg/m2, and those with a primary or secondary education level. CONCLUSION: Appropriate age guidance and emphasis on education of labor analgesia, weight management during pregnancy, and real-time anesthetic dosage adjustment during labor based on VAS pain score may have positive effects on the satisfaction of labor analgesia. CLINICAL TRIAL NUMBER AND REGISTRY: Clinicaltrials.gov (ChiCTR2100051809).

In vitro Accuracy of Ultra-Low Dose Cone-Beam Computed Tomography for Detection of Proximal Caries.

OBJECTIVES: This study aimed to assess the accuracy of ultra-low dose (ULD) cone-beam computed tomography (CBCT) for detection of proximal caries. METHODS: This in vitro study evaluated 104 molar and premolar teeth. The teeth were mounted in dry skulls and underwent CBCT with four protocols of high-resolution (HR), normal (NORM), ULD-HR, and ULD-NORM; 78 CBCT images were scored by three observers for presence and penetration depth of caries twice with a 2-week interval using a 5-point Likert scale. The teeth were then sectioned and observed under a stereomicroscope (gold standard). The four protocols were compared with each other and with the gold standard. The receiver operating characteristic (ROC) curve was drawn, and the area under the curve (AUC) was calculated and compared by the Chi-square test (alpha = 0.05). RESULTS: The interobserver agreement ranged from 0.5233 to 0.6034 for ULD-NORM, 0.5380 to 0.6279 for NORM, 0.5856 to 0.6300 for ULD-HR, and 0.6614 to 0.7707 for HR images. The intra-observer agreement ranged from 0.6027 to 0.8812 for ULD-HR, 0.7083 to 0.7556 for HR, 0.6076 to 0.9452 for ULD-NORM, and 0.7012 to 0.9221 for NORM images. Comparison of AUC revealed no significant difference between NORM and ULD-NORM (P > 0.05), or HR and ULD-HR (P > 0.05). The highest AUC belonged to HR (0.8529) and the lowest to NORM (0.7774). CONCLUSIONS: Considering the significant reduction in radiation dose in ULD CBCT and its acceptable diagnostic accuracy for detection of proximal caries, this protocol may be used for detection of proximal carious lesions and assessment of their depth.

Effects of antenatal corticosteroids on fetal hemodynamics: a longitudinal study.

Objective: To study the effect of antenatal corticosteroid administration on fetal hemodynamics using longitudinal analysis of Doppler waveforms in the umbilical artery (UA) and middle cerebral artery (MCA). Materials and Methods: This was a retrospective study that included 30 fetuses at risk for preterm birth. Twenty-eight pregnant women were treated with betamethasone for fetal lung maturation. Doppler examinations of the UA and MCA were performed once before and three or eight times after corticosteroid administration. We used a Bayesian hierarchical linear model. Reference ranges were constructed, and associations between variables (gestational age and pre-eclampsia) were tested. Results: The mean maternal age, gestational age at betamethasone administration, and gestational age at delivery were 32.6 ± 5.89 years, 30.2 ± 2.59 weeks, and 32.9 ± 3.42 weeks, respectively. On UA Doppler, there was a significant decrease in the pulsatility index (PI) after corticosteroid administration, with a mean of 0.1147 (credibility interval: 0.03687-0.191) in three observations and a median of 0.1437 (credibility interval: 0.02509-0.2627) in eight observations. However, there was no significant change in the Doppler MCA PI, regardless of gestational age and the presence or absence of pre-eclampsia. Conclusion: Although antenatal corticosteroid administration induced a significant decrease in the Doppler UA PI, we observed no change in the cerebral vasculature.

Objetivo: Estudar o efeito da administração antenatal de corticosteroides na hemodinâmica fetal mediante análise longitudinal do Doppler na artéria umbilical (AU) e artéria cerebral média (ACM). Materiais e Métodos: Este foi um estudo retrospectivo que incluiu 30 fetos com risco de nascimento pré-termo. Vinte e oito gestantes foram tratadas com betametasona para maturação pulmonar fetal. Os exames de Doppler da AU e da ACM foram realizados uma vez antes e depois da administração de corticosteroides, num total de três ou oito observações. Utilizamos o modelo linear hierárquico com abordagem Bayesiana. Foram construídos os intervalos de referência e testadas associações entre variáveis (idade gestacional e pré-eclâmpsia). Resultados: A média ± desvio-padrão da idade materna, idade gestacional na administração de betametasona e idade gestacional no parto foram 32,6 ± 5,89 anos, 30,2 ± 2,59 semanas e 32,9 ± 3,42 semanas, respectivamente. No Doppler da AU, verificou-se diminuição significativa do índice de pulsatilidade (IP) com a terapêutica com corticosteroides (média: 0,1147 [0,03687-0,191]; em três observações) (mediana: 0,1437 [0,02509-0,2627]; em oito observações). No entanto, não foi observada alteração significativa no IP do Doppler da ACM, independentemente da idade gestacional e do diagnóstico de pré-eclâmpsia. Conclusão: Os corticosteroides pré-natais induziram diminuição significativa no IP do Doppler da AU, mas não houve alteração na vasculatura cerebral.

F@#$ pain! A mini-review of the hypoalgesic effects of swearing.

Swearing, or the use of taboo language, has been repeatedly shown to induce hypoalgesia. While reliable hypoalgesic effects have been observed across studies, the mechanisms by which swearing influences pain and the optimal dosage of swearing remain poorly understood. Plausible mechanistic rationale for swearing's impact on pain include sympathetic response, emotion, humor, distraction, aggression, state disinhibition, psychological flow, risky behavior, and self-confidence. It remains unknown how the intensity of the swear word, speech volume, frequency, or timing influences pain modulation. While the majority of evidence demonstrates the efficacy of swearing at attenuating acute pain responses, these studies have utilized healthy populations with controlled experiments in laboratory settings. Comparatively, less is known about how laboratory findings translate practically/clinically to diverse populations, various dosages, and different pain chronicities. A greater understanding of mechanistic underpinnings and practical implications are necessary to feasibly implement swearing as a therapeutic modality to combat pain. The purpose of the following mini-review is to provide an overview of the current evidence on swearing for the reduction of pain, speculate on plausible underlying mechanisms, and discuss the potential for optimization of swearing for real-world translation. Lastly, identifying knowledge gaps to aid in directing future research will be discussed.

Assessing numeracy and medication calculations within undergraduate nursing education: A qualitative study.

AIM: To explore how undergraduate nursing students are assessed on nursing numeracy and medication calculations from the perspective of Australian nurse education leaders. DESIGN: A qualitative study. METHODS: Semi-structured interviews were conducted with 17 nurse education leaders between November 2022 and January 2023. Braun and Clarke's six phases of thematic analysis were used to analyse the data. RESULTS: Five key themes were identified: (i) high expectations to keep the public safe, (ii) diverse assessment formats, (iii) different ways of managing assessment integrity, (iv) assessment conditions incongruent to the clinical setting and (v) supporting struggling students. CONCLUSION: Nurse education leaders set high standards requiring students to achieve 100% in numeracy and medication calculation assessments, thus maintaining the reputation of nursing and patient safety. However, students struggled to meet this expectation. Diverse assessment formats were implemented, with some examination conditions contrary to clinical practice. Currently, there is no benchmark or independent point of registration examination in Australia, hence the problem is each university had a different standard to judge students' competence. Gaining insight into how these assessments are conducted provides an opportunity to work towards an evidence-based model or benchmark for the assessment of numeracy. IMPLICATIONS FOR THE PROFESSION: Dosage errors in clinical practice threaten patient safety and the reputation of the nursing profession. The accuracy rate of calculations by undergraduate and registered nurses is deficient worldwide. This research highlights a major educational issue, that being the wide variation in how numeracy assessments are conducted with no clear pedagogical rationale for a standardised method. Such assessments would establish a national standard, contributing to quality assurance, the development of the nursing profession and improve patient safety.

Development and Preliminary Validation of the Patient Outcome Planning Calculator (POP-C): A Tool for Determining Treatment Dosage in Applied Behavior Analysis.

Board certified behavior analysts (BCBA) are responsible for determining the medically necessary treatment dosage for patients (i.e., the number of hours of therapy a patient should receive per week to optimize progress) during applied behavior analysis (ABA) therapy. However, because there is currently no standard method for making these determinations, BCBAs must rely on their own clinical judgment. Given that clinical judgment may be underdeveloped in some BCBAs, particularly those who are newly certified, more formal strategies are needed to guide decision making as it relates to medical necessity and treatment dosage. In this article we describe the development of the Patient Outcome Planning Calculator (POP-C), a standardized decision-making tool designed to assist novice practitioners in determining the medically necessary ABA treatment intensity and appropriate treatment setting for individuals with autism spectrum disorder (ASD). We present preliminary reliability data as well as construct validity data indicating statistically significant correlations between the POP-C and several norm-referenced and criterion-referenced assessments commonly used to estimate skill level and the corresponding degree of support needed within the ASD population to inform the ABA treatment model and goals. Supplementary Information: The online version contains supplementary material available at 10.1007/s40617-023-00861-6.

Corrigendum: One-carbon pathway metabolites are altered in the plasma of subjects with Down syndrome: relation to chromosomal dosage.

[This corrects the article DOI: 10.3389/fmed.2022.1006891.].