Discovery of Potent Multikinase Type-II Inhibitors Targeting CDK5 in the DFG-out Inactive State with Promising Potential against Glioblastoma.

Kinases have proven valuable targets in successful cancer drug discovery projects, but not yet for malignant brain tumors where type-II inhibition of cyclin-dependent kinase 5 (CDK5) stabilizing the DFG-out inactive state has potential for design of selective and clinically efficient drug candidates. In the absence of crystallographic evidence for a CDK5 DFG-out inactive state protein-ligand complex, for the first time, a model was designed using metadynamics/molecular dynamics simulations. Glide docking of the ZINC15 biogenic database identified [pyrimidin-2-yl]amino-furo[3,2-b]-furyl-urea/amide hit chemical scaffolds. For four selected analogues (4, 27, 36, and 42), potent effects on glioblastoma cell viability in U87-MG, T98G, and U251-MG cell lines and patient-derived cultures were generally observed (IC50s ∼ 10-40 µM at 72 h). Selectivity profiling against 11 homologous kinases revealed multikinase inhibition (CDK2, CDK5, CDK9, and GSK-3α/ß), most potent for GSK-3α in the nanomolar range (IC50s ∼ 0.23-0.98 µM). These compounds may therefore have diverse anticancer mechanisms of action and are of considerable interest for lead optimization.

Consent in pregnancy: A qualitative study of the experiences of ethnic minority women.

OBJECTIVE: Consent in ante-natal and birthing contexts is often challenging, controversial and poorly understood. Increasing evidence indicates that ethnic minority women's overall experiences of ante-natal care are unsatisfactory, but little is known about their involvement in the consent process. This study aims to explore the views and experiences of ethnic minority women when making decisions requiring their consent. DESIGN: Qualitative interview study SETTING: A national study conducted in the UK SAMPLE: Seventeen self-selecting ethnic minority women who had given birth in a UK hospital in the previous 12 months. METHODS: In-depth telephone interviews with seventeen women. A thematic analysis was conducted with a focus on women's experiences of the consent process. RESULTS: Three themes were identified. 1. Compromised choice: women experienced limited choice; some women were not asked for their consent at all, or consent was presumed. 2. Pressured consent and silencing: women reported feeling undermined and 'othered' based on their ethnicity. 3. Impersonal consent: discussions were impersonal and not tailored to women as individuals; some women suggested that healthcare professionals ignored cultural concerns which were important to them. PRACTICE IMPLICATIONS: There is an urgent need for healthcare professionals to be supported in actively facilitating consent consultations which enable women from ethnic minority backgrounds to freely voice their concerns and priorities without censure. CONCLUSIONS: This exploratory study is a first step towards understanding how consent is experienced by ethnic minority women. Many women's experiences reflected failure of healthcare professionals to support genuine choice-making which was perceived to be further undermined by negativity related to women's ethnicity and cultural identity. There is a need for further research focusing on the consent experiences of specific ethnic minority groups.

Therapeutic Effects of Mesenchymal Stromal Cells Require Mitochondrial Transfer and Quality Control.

Due to their beneficial effects in an array of diseases, Mesenchymal Stromal Cells (MSCs) have been the focus of intense preclinical research and clinical implementation for decades. MSCs have multilineage differentiation capacity, support hematopoiesis, secrete pro-regenerative factors and exert immunoregulatory functions promoting homeostasis and the resolution of injury/inflammation. The main effects of MSCs include modulation of immune cells (macrophages, neutrophils, and lymphocytes), secretion of antimicrobial peptides, and transfer of mitochondria (Mt) to injured cells. These actions can be enhanced by priming (i.e., licensing) MSCs prior to exposure to deleterious microenvironments. Preclinical evidence suggests that MSCs can exert therapeutic effects in a variety of pathological states, including cardiac, respiratory, hepatic, renal, and neurological diseases. One of the key emerging beneficial actions of MSCs is the improvement of mitochondrial functions in the injured tissues by enhancing mitochondrial quality control (MQC). Recent advances in the understanding of cellular MQC, including mitochondrial biogenesis, mitophagy, fission, and fusion, helped uncover how MSCs enhance these processes. Specifically, MSCs have been suggested to regulate peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC1α)-dependent biogenesis, Parkin-dependent mitophagy, and Mitofusins (Mfn1/2) or Dynamin Related Protein-1 (Drp1)-mediated fission/fusion. In addition, previous studies also verified mitochondrial transfer from MSCs through tunneling nanotubes and via microvesicular transport. Combined, these effects improve mitochondrial functions, thereby contributing to the resolution of injury and inflammation. Thus, uncovering how MSCs affect MQC opens new therapeutic avenues for organ injury, and the transplantation of MSC-derived mitochondria to injured tissues might represent an attractive new therapeutic approach.

A systematic review of the effectiveness and implementation readiness of psychosocial interventions for psychosis in South Asia.

BACKGROUND: Little is known about the effectiveness and implementation of psychosocial interventions for psychosis in low- and middle-income countries (LMICs). In South Asia, specialist psychiatric resources are scarce. Support for psychosis often falls on the family or caregiver which can increase feelings of burden, impact caregivers' wellbeing, and increase mental health stigma. Psychosocial interventions are increasingly used for psychosis in South Asia and could reduce relapse and symptoms, reduce caregiver burden, conserve cost and resources. The aim of this review was to appraise the effectiveness and implementation readiness of psychosocial interventions for people with psychosis in South Asia. METHOD: A systematic search was conducted on MEDLINE, PsycINFO, Global Health, and Web of Science. The review was prospectively registered on PROSPERO (CRD42022329254). Studies were rated on two scales assessing quality and implementation readiness. RESULTS: Twenty-six papers were included, nine intervention-types including community-based interventions/assertive outreach; CaCBTp; FAP; psychoeducation; cognitive retraining/rehabilitation; social cognition/skills; family/ caregiver intervention; telehealth intervention; yoga-based intervention in six South Asian countries. Findings suggest a multicomponent community-based intervention (MCBI) was the most implementation ready due to its standardisation, good clinical outcomes for patients and caregivers, and training and cost evaluations. CONCLUSION: Of the included studies, MCBI and community-based outreach interventions utilising lay health workers appear to be the most implementation ready and are suggested to best address the treatment gap in South Asia.

Exploring the prevalence of Human Papillomavirus (HPV) genotypes in PAP smear samples of women in northern region of United Arab Emirates (UAE): HPV Direct Flow CHIP system-based pilot study.

OBJECTIVE: The aim of this study was to explore the prevalence of low and high-risk HPV genotypes in PAP smear samples of women in northern region of the UAE using HPV direct flow CHIP method. METHODS: A cross-sectional retrospective study was conducted between September 2021 to April 2022. A total of 104 liquid-based cervical cytology samples were obtained from women aged 20-59 years attending the Gynaecology out-patient department of Thumbay University Hospital and other hospitals of Northern Emirates of UAE, processed for the routine cytological examination to identify and differentiate morphological changes of the PAP smear samples. HPV genotyping was performed using HPV direct flow CHIP method. RESULTS: In total, 112 HPV genotypes were detected in 63 women (60.57%) included 18 abnormal cytological and 45 normal epithelial samples. 63 LR and 49 HR HPV genotypes were identified in all the 63 positive samples. Highest rate of infection with multiple LR and HR HPV genotypes were detected in women aged 40-49 years (25.9%) and 20-29 years (23.5%). Infection by HPV6 (13.46%), HPV11 (9.61%), HPV16 (9.61%), HPV62/81 (7.69%) and HPV45 (7.69%) were the most common genotypes. A moderate increase than expected incidence of HPV45 and 62/81 (7.69%) were detected. Co-infection with multiple low and high-risk genotypes is present in 20.2% cases; in that, HPV6 (15.9%) was the most common followed by HPV62/81 (12.7%) and HPV16 (11.11%). The prevalence of HPV18 was found to be 1.6%. CONCLUSION: The genotypes 6, 45, 16, 11, 67, 62/81 were the most common HPV infections in the women between the age group of 21 and 59-years-old. A moderate increase of HPV45, 62/81 and much less prevalence of HPV18 were detected in the study population. 43.27% of the normal epithelia were positive to different low and high-risk HPV genotypes. This finding highlights the importance of molecular genotyping of HPV to emphasize the cervical screening triage.

Neurotrophic neolignans of Pinus koraiensis twigs.

Four undescribed neolignan analogs, together with eight known compounds, were isolated from the twigs of Pinus koraiensis (Korean pine). The chemical structure of the isolated compounds was determined through extensive spectroscopic analysis and chemical method. Their relative and absolute configurations were assigned through a well-established empirical rule and electronic circular dichroism (ECD) analysis, respectively. Four compounds (3 and 9-11) at 20 µM concentration showed significant neurotrophic effect by inducing nerve growth factor (NGF) secretion in C6 cells with the stimulation levels a range of 140.82 ± 4.62% to 160.04 ± 11.04%. Additionally, the result indicated that the glycosylation of neolignan led to an improvement in neurotrophic activity compared to their aglycone form. A compound (7) inhibited nitric oxide production with an IC50 value of 31.74 µM in LPS-activated BV2 cells.

Exploring biomedical and traditional care pathways for people with psychosis in Karachi, Pakistan.

Background: Psychosis is known to have an adverse impact on an individual's quality of life, social and occupational functioning. A lack of treatment options for psychotic disorders such as schizophrenia contributes to adverse outcomes for individuals. A significant proportion of people with psychosis consult both formal and traditional routes of care. This warrants a need to explore perceptions around treatment options provided by diverse care providers, as the identification of avenues for support can improve psychiatric, alternative treatment and social outcomes. Methods: Focus groups discussions (FGDs) and in-depth interviews (IDIs) were used. Interactive Research and Development (IRD) research staff conducted 20 IDIs and 2 FGDs to obtain information about the perspectives, treatment pathways and experiences of individuals with psychosis, their caregivers, and service providers. Questions for clinician care providers and faith healers revolved around perceptions of psychosis, service users' background, subject knowledge and treatment, feedback and referral mechanisms, and promotion of services. A thematic analysis was used to analyze the interviews and coding was conducted on NVivo. Results: The results were categorized into five themes: perception of psychosis, experience of seeking/receiving care, assessment and diagnosis methods, promotion of services, and living with psychosis. Across service providers and patients, there was a wide variety of causes attributed to psychosis, and an overall lack of awareness regarding severe mental health conditions from both formal and informal care-providers. Biomedical treatment received mixed reviews, while some reported it as beneficial, the limited number of institutes and clinicians to cater for patients, stigma within society and care providers, the burden of caregiving, and misinformation from faith healers were all significant barriers to treatment. Conclusion: The results highlight the use of traditional healing practices for psychosis in Pakistan, which, coupled with inadequate referral mechanisms, present an opportunity to bridge the treatment gap between clinical and traditional healing practices through integration of treatment within community structures and systems. Better awareness of psychosis and its treatment methods, alongside interventions that reduce stigma could help facilitate help-seeking behavior and reduce the burden of caregiving.

Targeted health and social care interventions for women and infants who are disproportionately impacted by health inequalities in high-income countries: a systematic review.

BACKGROUND: Disadvantaged populations (such as women from minority ethnic groups and those with social complexity) are at an increased risk of poor outcomes and experiences. Inequalities in health outcomes include preterm birth, maternal and perinatal morbidity and mortality, and poor-quality care. The impact of interventions is unclear for this population, in high-income countries (HIC). The review aimed to identify and evaluate the current evidence related to targeted health and social care service interventions in HICs which can improve health inequalities experienced by childbearing women and infants at disproportionate risk of poor outcomes and experiences. METHODS: Twelve databases searched for studies across all HICs, from any methodological design. The search concluded on 8/11/22. The inclusion criteria included interventions that targeted disadvantaged populations which provided a component of clinical care that differed from standard maternity care. RESULTS: Forty six index studies were included. Countries included Australia, Canada, Chile, Hong Kong, UK and USA. A narrative synthesis was undertaken, and results showed three intervention types: midwifery models of care, interdisciplinary care, and community-centred services. These intervention types have been delivered singularly but also in combination of each other demonstrating overlapping features. Overall, results show interventions had positive associations with primary (maternal, perinatal, and infant mortality) and secondary outcomes (experiences and satisfaction, antenatal care coverage, access to care, quality of care, mode of delivery, analgesia use in labour, preterm birth, low birth weight, breastfeeding, family planning, immunisations) however significance and impact vary. Midwifery models of care took an interpersonal and holistic approach as they focused on continuity of carer, home visiting, culturally and linguistically appropriate care and accessibility. Interdisciplinary care took a structural approach, to coordinate care for women requiring multi-agency health and social services. Community-centred services took a place-based approach with interventions that suited the need of its community and their norms. CONCLUSION: Targeted interventions exist in HICs, but these vary according to the context and infrastructure of standard maternity care. Multi-interventional approaches could enhance a targeted approach for at risk populations, in particular combining midwifery models of care with community-centred approaches, to enhance accessibility, earlier engagement, and increased attendance. TRIAL REGISTRATION: PROSPERO Registration number: CRD42020218357.

Augmented Parkin-dependent mitophagy underlies the hepatoprotective effect of remote ischemic conditioning used prior to hemorrhagic shock.

BACKGROUND AND AIMS: Hemorrhagic shock-resuscitation (HSR) following trauma contributes to organ dysfunction by causing ischemia-reperfusion injury (IRI). We previously showed that 'remote ischemic preconditioning' (RIPC) exerted multi-organ protection from IRI. Maintenance of mitochondrial quality by clearance of dysfunctional mitochondria via mitophagy is vital in restoring organ integrity. We hypothesized that parkin-dependent mitophagy played a role in RIPC-induced hepatoprotection following HSR. METHODS: The hepatoprotective effect of RIPC in a murine model of HSR-IRI was investigated in wild type and parkin-/- animals. Mice were subjected to HSR ± RIPC and blood and organs were collected, followed by cytokine ELISAs, histology, qPCR, Western blots, and transmission electron microscopy. RESULTS: HSR increased hepatocellular injury, as measured by plasma ALT and liver necrosis, while antecedent RIPC prevented this injury; in parkin-/- mice, RIPC failed to exert hepatoprotection. The ability of RIPC to lessen HSR-induced rises in plasma IL-6 and TNFα, was lost in parkin-/- mice. While RIPC alone did not induce mitophagy, the application of RIPC prior to HSR caused a synergistic increase in mitophagy, this increase was not observed in parkin-/- mice. RIPC induced shifts in mitochondrial morphology favoring mitophagy in WT but not in parkin-/- animals. CONCLUSIONS: RIPC was hepatoprotective in WT mice following HSR but not in parkin-/- mice. Loss of protection in parkin-/- mice corresponded with the failure of RIPC plus HSR to upregulate the mitophagic process. Improving mitochondrial quality by modulating mitophagy, may prove to be an attractive therapeutic target in disease processes caused by IRI.

Genomic, transcriptomic, and metabolomic analysis of Oldenlandia corymbosa reveals the biosynthesis and mode of action of anti-cancer metabolites.

Plants accumulate a vast array of secondary metabolites, which constitute a natural resource for pharmaceuticals. Oldenlandia corymbosa belongs to the Rubiaceae family, and has been used in traditional medicine to treat different diseases, including cancer. However, the active metabolites of the plant, their biosynthetic pathway and mode of action in cancer are unknown. To fill these gaps, we exposed this plant to eight different stress conditions and combined different omics data capturing gene expression, metabolic profiles, and anti-cancer activity. Our results show that O. corymbosa extracts are active against breast cancer cell lines and that ursolic acid is responsible for this activity. Moreover, we assembled a high-quality genome and uncovered two genes involved in the biosynthesis of ursolic acid. Finally, we also revealed that ursolic acid causes mitotic catastrophe in cancer cells and identified three high-confidence protein binding targets by Cellular Thermal Shift Assay (CETSA) and reverse docking. Altogether, these results constitute a valuable resource to further characterize the biosynthesis of active metabolites in the Oldenlandia group, while the mode of action of ursolic acid will allow us to further develop this valuable compound.

Hericerin derivatives activates a pan-neurotrophic pathway in central hippocampal neurons converging to ERK1/2 signaling enhancing spatial memory.

The traditional medicinal mushroom Hericium erinaceus is known for enhancing peripheral nerve regeneration through targeting nerve growth factor (NGF) neurotrophic activity. Here, we purified and identified biologically new active compounds from H. erinaceus, based on their ability to promote neurite outgrowth in hippocampal neurons. N-de phenylethyl isohericerin (NDPIH), an isoindoline compound from this mushroom, together with its hydrophobic derivative hericene A, were highly potent in promoting extensive axon outgrowth and neurite branching in cultured hippocampal neurons even in the absence of serum, demonstrating potent neurotrophic activity. Pharmacological inhibition of tropomyosin receptor kinase B (TrkB) by ANA-12 only partly prevented the NDPIH-induced neurotrophic activity, suggesting a potential link with BDNF signaling. However, we found that NDPIH activated ERK1/2 signaling in the absence of TrkB in HEK-293T cells, an effect that was not sensitive to ANA-12 in the presence of TrkB. Our results demonstrate that NDPIH acts via a complementary neurotrophic pathway independent of TrkB with converging downstream ERK1/2 activation. Mice fed with H. erinaceus crude extract and hericene A also exhibited increased neurotrophin expression and downstream signaling, resulting in significantly enhanced hippocampal memory. Hericene A therefore acts through a novel pan-neurotrophic signaling pathway, leading to improved cognitive performance.

Diagnostic Significance Of Bone Marrow Examination Amongst The Patients With Abnormal Haematological Parameters.

BACKGROUND: Bone Marrow examination is considered to be the most indispensable diagnostic tool for the evaluation of many neoplastic and non-neoplastic haematological disorders. After an initial assessment of suspicious cases on abnormal laboratory parameters along with the clinical presentation of the patient marrow examination is finally required for diagnosis as well as management of many haematological malignancies as it offers a clear cytological as well as histological picture of Bone Marrow aspirate and biopsy respectively. The Objective was to evaluate the significance of Bone Marrow examination in patients with abnormal haematological parameters. METHODS: A retrospective study conducted at the Pathology Department of Pak Emirates Military Hospital from (Jan-June 2022) On data from150 patients who were advised to undergo bone marrow examination due to abnormal lab parameters and peripheral smear findings after informed consent and approval from the ethics review committee, to find out the correlation of abnormal haematological parameters and aspirate findings which have led to a definitive diagnosis. Data comprising basic demographic variables (age, gender etc.), Abnormal Haematological Parameters (CBC), peripheral smear findings and Aspirate findings were analyzed using SPSS version 23.0. RESULTS: Out of 150 studied participants with abnormal haematological parameters 24 (16%) were diagnosed on bone marrow examination as acute leukaemia / Hodgkin's and Non-Hodgkin's lymphoma respectively, 13 (9%) cases of aplastic anaemia and Autoimmune HaemolyticAnaemia, 33 (22%)cases of hypersplenism, CML and multiple myeloma. While 22 (15%) cases were diagnosed with BME as CKD and reactive changes. Moreover, 22(15%) cases were found to have Iron Deficiency anaemia respectively. CONCLUSIONS: The study revealed that patients with abnormal haematological parameters should undergo bone marrow examination to ascertain the diagnosis for malignant as well as non-malignant conditions that could cause abnormal lab parameters.

Risk Analysis and Assessment of Lipid Abnormalities as the Earliest Complication in Newly Diagnosed Diabetic and Non-Diabetic Individuals of a Local Population.

Lipid variations have been frequently observed in global populations that can affect health status. Mainly studies have been conducted on the type 2 diabetic population, but limited data is available on newly diagnosed ones to unravel complications and risk predictors independent of disease progression. This study comprising 244 individuals was carried out to assess the lipid abnormalities in newly diagnosed diabetics and non-diabetics. The clinical and socio-demographic data were collected and analyzed using independent samples t-test and linear regression. Serum lipid variations were observed individually and in combination. The individuals in group I (diabetics with dyslipidemia) revealed elevated levels of low-density lipoprotein and serum triglycerides higher than in group II (non-diabetics with dyslipidemia). The frequency of deranged total cholesterol in group I was observed to be higher than in group II. Independent samples t-test showed a significant mean difference in variables between the two groups. Linear regression analysis showed a significant variable outcome for predictors between high-density lipoprotein (HDL) and physical activity (B= -0.043, 95% CI: -0.80, -0.006) and total cholesterol (TC) with family history (B= -0.062, 95% CI: -0.123, -0.001). The findings conclude that lipid levels deranged independently regardless of type 2 diabetes mellitus and present as an early onset in type 2 diabetes instead of later stage complication. These derangements of lipid levels are an independent risk factor for future cardiovascular pathology.

Depth of mediastinal extension can predict sternotomy need for substernal thyroid goiters.

BACKGROUND: Surgical excision of substernal thyroid goiters is usually achieved through a conventional transcervical approach, and transthoracic excision is rarely necessary. Currently, there are no clear guidelines for substernal thyroid goiters that may require a transthoracic approach. This study examined what preoperative factors were significantly associated with transthoracic surgical excision for substernal thyroid goiters. METHODS: A retrospective review of prospectively collected data of 109 patients with substernal thyroid goiters from a single institution was performed. The patients were stratified by transcervical and transthoracic approaches for substernal thyroid goiters. The factors possibly predictive of a transthoracic approach, including substernal extension beyond the thoracic inlet, patient-reported symptoms, tracheal deviation, and malignancy, were analyzed. Demographics including age, sex, and race, among others, were also studied. RESULTS: Of 1,080 patients who underwent surgical resection for multinodular goiter, there were 109 (10%) patients with substernal thyroid goiters. Of the substernal thyroid goiter group, 11 (10%) patients underwent partial sternotomy, whereas 6 (5.5%) underwent total sternotomy. On logistic regression, only substernal component of the thyroid goiter extending beyond the sternal notch into the mediastinum was statistically significant in predicting sternotomy (odds ratio 3.43, confidence interval 1.65-6.41, P < .001). Substernal thyroid goiters with mediastinal extension of ≥5 cm beyond the sternal notch showed a sensitivity of 94% and specificity of 86.5% to predict need of sternotomy. CONCLUSION: Patients with substernal thyroid goiters who exhibit progressive enlargement and/or compressive symptoms should undergo surgical excision. Although most are removed through the conventional transcervical approach, substernal thyroid goiters with a depth of mediastinal extension ≥5 cm have a high likelihood of requiring sternotomy.

A ferrocene-containing nucleoside analogue targets DNA replication in pancreatic cancer cells.

Pancreatic ductal adenocarcinoma (PDAC) is a disease that remains refractory to existing treatments including the nucleoside analogue gemcitabine. In the current study we demonstrate that an organometallic nucleoside analogue, the ferronucleoside 1-(S,Rp), is cytotoxic in a panel of PDAC cell lines including gemcitabine-resistant MIAPaCa2, with IC50 values comparable to cisplatin. Biochemical studies show that the mechanism of action is inhibition of DNA replication, S-phase cell cycle arrest and stalling of DNA-replication forks, which were directly observed at single molecule resolution by DNA-fibre fluorography. In agreement with this, transcriptional changes following treatment with 1-(S,Rp) include activation of three of the four genes (HUS1, RAD1, RAD17) of the 9-1-1 check point complex clamp and two of the three genes (MRE11, NBN) that form the MRN complex as well as activation of multiple downstream targets. Furthermore, there was evidence of phosphorylation of checkpoint kinases 1 and 2 as well as RPA1 and gamma H2AX, all of which are considered biochemical markers of replication stress. Studies in p53-deficient cell lines showed activation of CDKN1A (p21) and GADD45A by 1-(S,Rp) was at least partially independent of p53. In conclusion, because of its potency and activity in gemcitabine-resistant cells, 1-(S,Rp) is a promising candidate molecule for development of new treatments for PDAC.

Terpenoids from Glechoma hederacea var. longituba and their biological activities.

Glechoma hederacea var. longituba (common name: ground ivy) has been used for the treatment of asthma, bronchitis, cholelithiasis, colds, and inflammation. In the present study, three new sesquiterpene glycosides (1-3), two new diterpene glycosides (4 and 5), and four known compounds (6-9) were isolated from its MeOH extract. A structure elucidation was performed for the five new compounds (1-5) using 1D and 2D NMR, HRESIMS, DP4+ and ECD calculations, and chemical methods. All the isolates (1-9) were assessed for their antineuroinflammatory activities on nitric oxide (NO) production in lipopolysaccharide (LPS)-activated BV-2 cells, nerve growth factor (NGF) secretion stimulation activities in C6 glioma cells, and cytotoxic activities against four human cancer cell lines (A549, SK-OV-3, SK-MEL-2, and HCT15). Compounds 2 and 5-7 exhibited inhibitory effects on the NO production with IC50 values of 52.21, 47.90, 61.61, and 25.35 µM, respectively. Compound 5 also exhibited a significant stimulating effect on NGF secretion (122.77 ± 8.10%). Compound 9 showed potent cytotoxic activity against SK-OV-3 (IC50 = 3.76 µM) and SK-MEL-2 (IC50 = 1.48 µM) cell lines, while 7 displayed a strong cytotoxic activity against the SK-MEL-2 (IC50 = 9.81 µM) cell line.

Foliar spray of silicon nanoparticles improved the growth and minimized cadmium (Cd) in wheat under combined Cd and water-limited stress.

The effects of foliar supply of silicon nanoparticles (Si-NPs) on growth, physiology, and cadmium (Cd) uptake by wheat (Triticum aestivum L.) were examined in different soil moisture levels. Seeds were sown in soil containing excess Cd (7.67 mg kg-1) and Si-NPs were applied through foliar dressing with various levels (0, 25, 50, 100 mg L-1) at different time intervals during growth period. Initially, all pots were irrigated with normal moisture level (70% water-holding capacity) and two moisture levels (35%, 70% WHC) were initiated after 6 weeks of plant growth for remaining growth duration and harvesting was done after 124 days of sowing. The results demonstrated the lowest plant growth, yield, and chlorophyll concentrations while the highest oxidative stress and Cd concentrations in plant tissues in water-stressed control (35% WHC) followed by normal control (75% WHC). Si-NPs enhanced the growth, photosynthesis, leaf defense system, and Si concentrations in tissues while minimized the Cd in wheat parts particularly in grains either soil normal or water-stressed conditions. Of the foliar spray, 100 mg L-1 of Si-NPs showed the best results with respect to growth, Cd and Si uptake by plants, and soil post-harvest bioavailable Cd irrespective of soil water levels. In grain, Cd concentration was below threshold limit (0.2 mg kg-1) for cereals in 100-mg kg-1 Si-NPs treatment irrespective of soil water levels. Si-NPs foliar dressing under Cd and water-limited stress might be an effective strategy in increasing growth, yield, and decreasing Cd concentration in wheat grains under experimental conditions. Thus, foliar dressing of Si-NPs minimized the Cd risk in food crops and NPs entry to surroundings, which might be possible after harvesting of crops in soil-applied NPs.

Transient Hypocalcemia After Total Thyroidectomy: The Obesity Paradox at Work?

INTRODUCTION: With increasing rates of obesity worldwide, a correlation between high body mass index (BMI) and postoperative morbidity after thyroid surgery remains unclear. Postoperative transient hypocalcemia is common after total thyroidectomy due to interruption of parathyroid function. This study examines the relationship between BMI and hypocalcemia after total thyroidectomy. MATERIALS AND METHODS: A retrospective review of prospectively collected data for 1135 patients who underwent total thyroidectomy for cancer, multinodular goiter (MNG), or Graves' disease between June 2009 and November 2020 at a single institution was performed. BMI groups followed the World Health Organization classification. Hypocalcemia was defined as serum calcium ≤8 mg/dL. Calcium levels measured on postoperative day 0 and the following morning were compared between the BMI groups. RESULTS: Of 1135 total thyroidectomy patients, 85% were women. The mean age and standard deviation of patients was 49 (± 13) y, with most of Hispanic origin (64%). Overall, 41.5% of patients had cancer, 45% nontoxic MNG, 5.8% toxic MNG, and 12% Graves' disease. Stratified by BMI, 27% of patients were normal, 34% overweight, and 39% obese. Overall, overweight and obese patients experienced less transient hypocalcemia at both time points compared to normal patients postoperatively (P = 0.01 and P = 0.009). Furthermore, overweight and obese patients with Graves' disease experienced less transient hypocalcemia at both time points (P = 0.04 and P = 0.05). There was no statistical difference in other groups. CONCLUSIONS: A protective role of higher BMI or "obesity paradox" for postoperative hypocalcemia may exist in those obese patients after total thyroidectomy.

EVALUATING THE IMPACT OF EARLY NUTRITIONAL ASSESSMENT AND INTERVENTION IN HOSPITALIZED LIVER CIRRHOSIS PATIENTS.

BACKGROUND: Malnutrition is common in liver cirrhosis patients that is correlated with early complications, morbidity and mortality. OBJECTIVE: The purpose of the study was to assess nutritional status, impact of nutritional screening and intervention in liver cirrhosis patients by evaluating their actual energy and protein intake during hospital stay. METHODS: A cross sectional study was conducted wherein all patients' nutritional status was defined by Subjective Global Assessment tool. Adequate energy and protein supply were planned and executed by using individualized nutritional plan for patients with dietitian's collaboration. Anthropometric measurements included height, weight, body mass index, mid upper arm circumference, hand grip strength and triceps skin-fold thickness. Biochemical tests included haemoglobin, mean corpuscular haemoglobin, volume and concentration, albumin and liver function tests. To record the daily food intake, a 24-hour dietary recall was used. RESULTS: Overall 83 patients (mean age 55) were included, among them 46% of patients were moderately malnourished, 12% were normal, while 42% of cirrhotic patients were severely depleted according to Subjective Global Assessment. The mean intake of calories and protein was improved during stay in hospital after nutritional intervention and critical monitoring (P<0.05). Anthropometric measurements at baseline and discharge showed significant differences (P <0.05) in weight, body mass index, triceps skin fold thickness and mid upper arm circumference values, but not in hand grip strength that was associated with malnourishment among patients. CONCLUSION: Providing individualized nutritional intervention and its monitoring by qualified dietitians during hospital stay helps to improve intake in patients that prevent further risk of malnutrition and related complications.

Giving birth in a pandemic: women's birth experiences in England during COVID-19.

BACKGROUND: Expectant parents worldwide have experienced changes in the way they give birth as a result of COVID-19, including restrictions relating to access to birthing units and the presence of birthing partners during the birth, and changes to birth plans. This paper reports the experiences of women in England. METHODS: Data were obtained from both closed- and open-ended responses collected as part of the national COVID in Context of Pregnancy, Infancy and Parenting (CoCoPIP) Study online survey (n = 477 families) between 15th July 2020 - 29th March 2021. Frequency data are presented alongside the results of a sentiment analysis; the open-ended data was analysed thematically. RESULTS: Two-thirds of expectant women reported giving birth via spontaneous vaginal delivery (SVD) (66.1%) and a third via caesarean section (CS) (32.6%) or 'other' (1.3%). Just under half (49.7%) of the CS were reported to have been elective/planned, with 47.7% being emergencies. A third (37.4%) of participants reported having no changes to their birth (as set out in their birthing plan), with a further 25% reporting COVID-related changes, and 37.4% reporting non-COVID related changes (e.g., changes as a result of birthing complications). One quarter of the sample reported COVID-related changes to their birth plan, including limited birthing options and reduced feelings of control; difficulties accessing pain-relief and assistance, and feelings of distress and anxiety. Under half of the respondents reported not knowing whether there could be someone present at the birth (44.8%), with 2.3% of respondents reporting no birthing partner being present due to COVID-related restrictions. Parental experiences of communication and advice provided by the hospital prior to delivery were mixed, with significant stress and anxiety being reported in relation to both the fluctuating guidance and lack of certainty regarding the presence of birthing partners at the birth. The sentiment analysis revealed that participant experiences of giving birth during the pandemic were predominately negative (46.9%) particularly in relation to the first national lockdown, with a smaller proportion of positive (33.2%) and neutral responses (19.9%). CONCLUSION: The proportion of parents reporting birthing interventions (i.e., emergency CS) was higher than previously reported, as were uncertainties related to the birth, and poor communication, leading to increased feelings of anxiety and high levels of negative emotions. The implications of these findings are discussed.