Osimertinib with or without Chemotherapy in EGFR-Mutated Advanced NSCLC.

BACKGROUND: Osimertinib is a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) that is selective for EGFR-TKI-sensitizing and EGFR T790M resistance mutations. Evidence suggests that the addition of chemotherapy may extend the benefits of EGFR-TKI therapy. METHODS: In this phase 3, international, open-label trial, we randomly assigned in a 1:1 ratio patients with EGFR-mutated (exon 19 deletion or L858R mutation) advanced non-small-cell lung cancer (NSCLC) who had not previously received treatment for advanced disease to receive osimertinib (80 mg once daily) with chemotherapy (pemetrexed [500 mg per square meter of body-surface area] plus either cisplatin [75 mg per square meter] or carboplatin [pharmacologically guided dose]) or to receive osimertinib monotherapy (80 mg once daily). The primary end point was investigator-assessed progression-free survival. Response and safety were also assessed. RESULTS: A total of 557 patients underwent randomization. Investigator-assessed progression-free survival was significantly longer in the osimertinib-chemotherapy group than in the osimertinib group (hazard ratio for disease progression or death, 0.62; 95% confidence interval [CI], 0.49 to 0.79; P<0.001). At 24 months, 57% (95% CI, 50 to 63) of the patients in the osimertinib-chemotherapy group and 41% (95% CI, 35 to 47) of those in the osimertinib group were alive and progression-free. Progression-free survival as assessed according to blinded independent central review was consistent with the primary analysis (hazard ratio, 0.62; 95% CI, 0.48 to 0.80). An objective (complete or partial) response was observed in 83% of the patients in the osimertinib-chemotherapy group and in 76% of those in the osimertinib group; the median response duration was 24.0 months (95% CI, 20.9 to 27.8) and 15.3 months (95% CI, 12.7 to 19.4), respectively. The incidence of grade 3 or higher adverse events from any cause was higher with the combination than with monotherapy - a finding driven by known chemotherapy-related adverse events. The safety profile of osimertinib plus pemetrexed and a platinum-based agent was consistent with the established profiles of the individual agents. CONCLUSIONS: First-line treatment with osimertinib-chemotherapy led to significantly longer progression-free survival than osimertinib monotherapy among patients with EGFR-mutated advanced NSCLC. (Funded by AstraZeneca; FLAURA2 ClinicalTrials.gov number, NCT04035486.).

Discordance between GCIG CA-125 progression and RECIST progression in the CALYPSO trial of patients with platinum-sensitive recurrent ovarian cancer.

BACKGROUND: CA-125 alone is widely used to diagnose progressive disease (PD) in platinum-sensitive recurrent ovarian cancer (PSROC) on chemotherapy. However, there are increasing concerns regarding its accuracy. We assessed concordance between progression defined by CA-125 and RECIST using data from the CALYPSO trial. METHODS: We computed concordance rates for PD by CA-125 and RECIST to determine the positive (PPV) and negative predictive values (NPV). RESULTS: Of 769 (79%) evaluable participants, 387 had CA-125 PD, where only 276 had concordant RECIST PD (PPV 71%, 95% CI 67-76%). For 382 without CA-125 PD, 255 had RECIST PD but 127 did not (NPV 33%, 95% CI 29-38). There were significant differences in NPV according to baseline CA-125 (≤100 vs >100: 42% vs 25%, P < 0.001); non-measurable vs measurable disease (51% vs 26%, P < 0.001); and platinum-free-interval (>12 vs 6-12 months: 41% vs 14%, P < 0.001). We observed falling CA-125 levels in 78% of patients with RECIST PD and CA-125 non-PD. CONCLUSION: Approximately 2 in 3 women with PSROC have RECIST PD but not CA-125 PD by GCIG criteria. Monitoring CA-125 levels alone is not reliable for detecting PD. Further research is required to investigate the survival impact of local therapy in radiological detected early asymptomatic PD.

CRISPR-Cas13b-mediated suppression of hepatitis B virus replication and protein expression.

BACKGROUND & AIMS: New antiviral approaches are urgently required that target multiple aspects of the hepatitis B virus (HBV) replication cycle to improve rates of functional cure. HBV RNA represents a novel therapeutic target. Here, we programmed Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas13b endonuclease, to specifically target the HBV pregenomic RNA (pgRNA) and viral mRNAs in a novel approach to reduce HBV replication and protein expression. METHODS: Cas13b CRISPR RNAs (crRNAs) were designed to target multiple regions of HBV pgRNA. Mammalian cells with replication competent wildtype HBV DNA of different genotypes, a HBV stable cell line, a HBV infection model and a hepatitis B surface antigen (HBsAg)-expressing stable cell line were transfected with PspCas13b-blue fluorescent protein (BFP) and crRNAs plasmids and the impact on HBV replication and protein expression was measured. WT HBV DNA, PspCas13b-BFP and crRNA plasmids were simultaneously hydrodynamically injected into mice, and sera HBsAg was measured. PspCas13b mRNA and crRNA were also delivered by lipid nanoparticles (LNP) in a HBsAg-expressing stable cell line and the impact on secreted HBsAg determined. RESULTS: Our HBV targeting crRNAs strongly suppressed HBV replication and protein expression in mammalian cells by up to 96% (p<0.0001). HBV protein expression was also reduced in an HBV stable cell line and in the HBV infection model. CRISPR-Cas13b crRNAs reduced HBsAg expression by 50% (p<0.0001) in vivo. LNP-encapsulated PspCas13b mRNA reduced secreted HBsAg by 87% (p=0.0168) in a HBsAg-expressing stable cell line. CONCLUSIONS: Together, these results show that CRISPR-Cas13b can be programmed to specifically target and degrade HBV RNAs to reduce HBV replication and protein expression, demonstrating its potential as a novel therapeutic option for chronic HBV infection. IMPACT AND IMPLICATIONS: There is an urgent need for new treatments that target multiple aspects of the HBV replication cycle. Here, we present CRISPR-Cas13b as a novel strategy to target HBV replication and protein expression paving the way for its development as a potential new treatment option for patients living with chronic hepatitis B.

ASPiRATION: Australian observational cohort study of comprehensive genomic profiling in metastatic lung cancer tissue.

ASPiRATION is a national prospective observational cohort study assessing the feasibility, clinical and economic value of up-front tissue-based comprehensive genomic profiling (CGP) to identify actionable genomic alterations in participants with newly diagnosed metastatic non-squamous non-small-cell lung cancer in Australia. This study will enrol 1000 participants with tumor available for CGP and standard of care molecular testing (EGFR/ALK/ROS1). Participants with actionable variants may receive novel targeted treatments through ASPiRATION-specific substudies, other trials/programs. Clinical outcome data will be collected for a minimum of 2 years. Study outcomes are descriptive, including the ability of CGP to identify additional actionable variants, leading to personalized treatment recommendations, and will describe the feasibility, efficiency, cost and utility of implementation of CGP nationally.

Lung cancer is the most common cause of cancer death in Australia and worldwide. This disease often happens due to alterations in specific genes that allow cancer cells to develop and spread. Scientists have designed targeted drugs that are better at attacking cancer cells that have specific 'actionable' gene alterations and have less effect on other cells in the body. The result is often more benefit from treatment and fewer side effects than other standard treatments (chemotherapy or immunotherapy). The targeted drugs are well established as the best initial treatments for some gene alterations, but more research is needed to know if this is true for some of the less common or recently identified gene alterations, and where the targeted drugs are very new. Comprehensive genomic profiling is a new way of testing lung cancer cells for all the gene alterations (the well-known ones as well as the rare ones) in a single test. It is expected that this test will find many more of these gene alterations, which will allow more people to have safer and more effective targeted treatments leading to potentially better outcomes, and will allow some people to join clinical trials testing newer targeted treatments. The ASPiRATION study will help work out whether comprehensive genomic profiling is better than the current way of testing for gene alterations in Australia, and if it is feasible to use in all people diagnosed with advanced lung cancer in Australia. Clinical Trial Registration: ACTRN12621000221853 (ANZCTR).

Psychological status of pregnant women during the omicron pandemic outbreak in China.

BACKGROUND: Pregnant women faced great challenges and psychological and physiological changes of varying degrees during the omicron epidemic outbreak. It is important to recognize the potential impact of these challenges on the mental health of pregnant women and to provide appropriate resources and support to mitigate their effects. METHOD: By using the convenience sampling approach, a total of 401 pregnant women from two hospitals of different grades in two cities were included in the survey. The cross-sectional survey was conducted by basic characteristics, Generalized Anxiety Disorder (GAD-7), Patient Health Questionnaire (PHQ-9), Insomnia Severity Index (ISI) and self-made questionnaire. RESULTS: Insomnia affected 207 participants (51.6%), depression affected 160 participants (39.9%) and anxiety affected 151 participants (37.7%). Moreover, pregnant women in provincial capital city were more likely to experience anxiety, depression and insomnia than those in county-level city (P < 0.01). Pregnant women's anxiety, depression and insomnia were positively correlated with the severity of COVID-19 infection (P < 0.05). However, COVID-19 infection had no appreciable impact on maternal demand for termination of pregnancy and cesarean section (P > 0.05). CONCLUSION: Pregnant women frequently suffer from anxiety disorder, depression and insomnia as a result of the omicron pandemic in China. During this period, the community and medical professionals should provide more psychological counseling, conduct health education and offer virtual prenatal care to pregnant women (particularly in the provincial capital city).

Multicenter registry of multisystem inflammatory syndrome in children (MIS-C) and Paired comparison with Kawasaki disease.

OBJECTIVES: This study aimed to identify clinical characteristics to differentiate multisystem inflammatory syndrome in children (MIS-C) and Kawasaki disease (KD) in Taiwan, an island with a delayed cluster of MIS-C and a high incidence of KD. Additionally, we studied risk factors for developing severe complications in patients with MIS-C. METHODS: We conducted a retrospective, multicenter, cohort, and observational study that linked data on patients with MIS-C between May and December 2022 and patients with KD between 2019 and 2021 from 12 medical centers. Hemodynamic compromise, defined as the need for inotropic support or fluid challenge, was recorded in patients with MIS-C. We also evaluated maximal coronary Z-scores before treatment and one month after disease onset. RESULTS: A total of 83 patients with MIS-C and 466 patients with KD were recruited. A 1:1 age and gender-matched comparison of 68 MIS-C and KD pairs showed that MIS-C patients had a lower percentage of positive BCG red halos, lower leukocyte/platelet counts, more gastrointestinal symptoms, and a higher risk of hemodynamic compromise. In Taiwan, 38.6% of MIS-C patients experienced hemodynamic compromise, with presence of conjunctivitis and elevated levels of procalcitonin (>1.62 ng/mL) identified as independent risk factors. CONCLUSIONS: We identified two independent risk factors associated with hemodynamic compromise in MIS-C patients. The comparison between matched MIS-C and KD patients highlighted significant differences in clinical presentations, like BCG red halos, which may aid in the differential diagnosis of the two disease entities, especially in regions with a high incidence rate of KD.

Psychological Status of Medical Staff in Obstetrics and Gynecology Hospitals during the Omicron Pandemic Outbreak in China.

Background: Medical staff in China faced great challenges and psychological and physiological changes of varying degrees during the omicron epidemic outbreak. It is important to recognize the potential impact of these challenges on the mental health of medical staff and to provide appropriate resources and support to mitigate their effects. Methods: A total of 354 medical staff in two obstetrics and gynecology hospitals of different grades were included in this survey using convenience sampling. The cross-sectional self-report questionnaires survey was conducted using the Basic Characteristics Questionnaire, Generalized Anxiety Disorder (GAD-7), Patient Health Questionnaire (PHQ-9), and Insomnia Severity Index (ISI). Results: There were 169 (47.7%) participants suffering from anxiety disorder. Working with fever, working in obstetrics, and working with protective clothing were the risk factors for anxiety in medical staff (p < 0.05). One hundred and ninety-six (55.4%) participants were depressed. Working with fever and working in obstetrics were the risk factors for depression in medical staff (p < 0.05). There were 117 (33.1%) participants suffering from insomnia. Working with fever, high educational level, and severe COVID-19 infection status were the risk factors for insomnia in medical staff (p < 0.05). Moreover, medical staff in a provincial hospital were more anxious and depressed than those in a county hospital. At last, there were more participants working with fever in obstetrics (p < 0.05). Conclusion: Anxiety disorder, depression, and insomnia were common among obstetrics and gynecology medical staff during the outbreak of omicron pandemic. During this period, more resources for psychological counselling should be provided to the hospital as well as more reasonable staffing arrangements, and working while having a fever is prohibited, especially in provincial hospital.

Short-term Non-invasive Ventilation for Children with Palliative Care Needs.

Objectives: Non-invasive ventilation (NIV), namely continuous positive airway pressure (CPAP) and bi-level positive airway pressure (BiPAP), delivers mechanical ventilation without endotracheal intubation. Short-term NIV (planned for <21 days during initiation) can be used for the management of acute respiratory distress (ARD) among paediatric palliative patients with "Do Not Resuscitate or Intubate" (DNI) as the ceiling of care. This study aimed to describe the usage of short-term NIV among paediatric palliative patients in a woman and child hospital with a paediatric palliative subspecialty. Materials and Methods: A retrospective and observational study was conducted on all paediatric palliative patients who received short-term NIV in Tunku Azizah Hospital Kuala Lumpur, Malaysia, from March 2020 to May 2022. Results: During the study period, short-term NIV was offered on 23 occasions for 20 different children. Indications for short-term NIV include 16 (69.6%) occasions of potentially reversible ARD (NIV Category 1) and 7 (30.4%) occasions of comfort care at the end of life (NIV Category 2). The main cause of ARD was pneumonia (90.3%) due to either aspiration or infection. The modality of NIV used was BiPAP only (14 occasions, 60.9%), CPAP only (three occasions, 13%) and both BiPAP and CPAP (six occasions, 26.1%). The median duration of NIV usage was four days (minimum one day and maximum 15 days). NIV was initiated as an escalation from nasal prong, Ventimask or high-flow mask oxygen on 22 occasions and as weaning down post-extubation on one occasion. For the 22 occasions of escalating therapy, there was significant improvement at six hours compared to pre-NIV in the median heart rate (136 to 121, P=0.002), respiratory rate (40 to 31, P=0.002) and oxygen saturation (96% to 99%, P=0.025). All 17 documented parental impressions of the child's condition post six hours of NIV were that the child had improved. Adverse events during short-term NIV include five episodes (21.7%) of stomach distension, four episodes (17.4%) of skin sores on the face and one episode (4.3%) of excessive drooling. Three patients passed away while on NIV in the hospital. For the other 20 (87%) occasions, patients were able to wean off NIV. Post-weaning off NIV, three patients passed away during the same admission. On 17 occasions, patients were discharged home after weaning off NIV. Conclusion: Usage of short-term NIV in paediatric palliative care, where children have an advanced directive in place indicating DNI, as seen in our study, can be a valuable modality of management for distressing symptoms, in addition to the pharmacological management of breathlessness. This is shown through our study to be of benefit in potentially reversible ARD as well as comfort care at the end of life. Further rigorous studies will need to be conducted for a clearer understanding of short-term NIV that would enable the formulation of guidelines to improve the quality of life and death in children.

Limited clinical activity of palbociclib and ribociclib monotherapy in advanced cancers with cyclin D-CDK4/6 pathway alterations in the Dutch DRUP and Australian MoST trials.

The Dutch Drug Rediscovery Protocol (DRUP) and the Australian Cancer Molecular Screening and Therapeutic (MoST) Program are similar nonrandomized, multidrug, pan-cancer trial platforms that aim to identify signals of clinical activity of molecularly matched targeted therapies or immunotherapies outside their approved indications. Here, we report results for advanced or metastatic cancer patients with tumors harboring cyclin D-CDK4/6 pathway alterations treated with CDK4/6 inhibitors palbociclib or ribociclib. We included adult patients that had therapy-refractory solid malignancies with the following alterations: amplifications of CDK4, CDK6, CCND1, CCND2 or CCND3, or complete loss of CDKN2A or SMARCA4. Within MoST, all patients were treated with palbociclib, whereas in DRUP, palbociclib and ribociclib were assigned to different cohorts (defined by tumor type and alteration). The primary endpoint for this combined analysis was clinical benefit, defined as confirmed objective response or stable disease ≥16 weeks. We treated 139 patients with a broad variety of tumor types; 116 with palbociclib and 23 with ribociclib. In 112 evaluable patients, the objective response rate was 0% and clinical benefit rate at 16 weeks was 15%. Median progression-free survival was 4 months (95% CI: 3-5 months), and median overall survival 5 months (95% CI: 4-6 months). In conclusion, only limited clinical activity of palbociclib and ribociclib monotherapy in patients with pretreated cancers harboring cyclin D-CDK4/6 pathway alterations was observed. Our findings indicate that monotherapy use of palbociclib or ribociclib is not recommended and that merging data of two similar precision oncology trials is feasible.

A signal-seeking Phase 2 study of olaparib and durvalumab in advanced solid cancers with homologous recombination repair gene alterations.

PURPOSE: To determine the safety and efficacy of PARP plus PD-L1 inhibition (olaparib + durvalumab, O + D) in patients with advanced solid, predominantly rare cancers harbouring homologous recombination repair (HRR) defects. PATIENTS AND METHODS: In total, 48 patients were treated with O + D, 16 with BRCA1/2 alterations (group 1) and 32 with other select HRR alterations (group 2). Overall, 32 (66%) patients had rare or less common cancers. The primary objective of this single-arm Phase II trial was a progression-free survival rate at 6 months (PFS6). Post hoc exploratory analyses were conducted on archival tumour tissue and serial bloods. RESULTS: The PFS6 rate was 35% and 38% with durable objective tumour responses (OTR) in 3(19%) and 3(9%) in groups 1 and 2, respectively. Rare cancers achieving an OTR included cholangiocarcinoma, perivascular epithelioid cell (PEComa), neuroendocrine, gallbladder and endometrial cancer. O + D was safe, with five serious adverse events related to the study drug(s) in 3 (6%) patients. A higher proportion of CD38 high B cells in the blood and higher CD40 expression in tumour was prognostic of survival. CONCLUSIONS: O + D demonstrated no new toxicity concerns and yielded a clinically meaningful PFS6 rate and durable OTRs across several cancers with HRR defects, including rare cancers.

Multicenter Validation of Abbreviated MRI for Detecting Early-Stage Hepatocellular Carcinoma.

Background Abbreviated MRI is a proposed paradigm shift for hepatocellular carcinoma (HCC) surveillance, but data on its performance are lacking for histopathologically confirmed early-stage HCC. Purpose To evaluate the sensitivity and specificity of dynamic contrast-enhanced abbreviated MRI for early-stage HCC detection, using surgical pathologic findings as the reference standard. Materials and Methods This retrospective study was conducted at three U.S. liver transplant centers in patients with cirrhosis who underwent liver resection or transplant between January 2009 and December 2019 and standard "full" liver MRI with and without contrast enhancement within 3 months before surgery. Patients who had HCC-directed treatment before surgery were excluded. Dynamic abbreviated MRI examinations were simulated from the presurgical full MRI by selecting the coronal T2-weighted and axial three-dimensional fat-suppressed T1-weighted dynamic contrast-enhanced sequences at precontrast, late arterial, portal venous, and delayed phases. Two abdominal radiologists at each center independently interpreted the simulated abbreviated examinations with use of the Liver Imaging Reporting and Data System version 2018. Patients with any high-risk liver observations (>LR-3) were classified as positive; otherwise, they were classified as negative. With liver pathologic findings as the reference standard for the presence versus absence of early-stage HCC, the sensitivity, specificity, and their 95% CIs were calculated. Logistic regression was used to identify factors associated with correct classification. Results A total of 161 patients with early-stage HCC (median age, 62 years [IQR, 58-67 years]; 123 men) and 138 patients without HCC (median age, 55 years [IQR, 47-63 years]; 85 men) were confirmed with surgical pathologic findings. The sensitivity and specificity of abbreviated MRI were 88.2% (142 of 161 patients) (95% CI: 83.5, 92.5) and 89.1% (123 of 138 patients) (95% CI: 84.4, 93.8), respectively. Sensitivity was lower for Child-Pugh class B or C versus Child-Pugh class A cirrhosis (64.1% vs 94.2%; P < .001). Conclusion With surgical pathologic findings as the reference standard, dynamic abbreviated MRI had high sensitivity and specificity for early-stage hepatocellular carcinoma detection in patients with compensated cirrhosis but lower sensitivity in those with decompensated cirrhosis. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Kim in this issue.

A Pilot Study of Biliary Atresia Newborn Screening Using Dried Blood Spot Matrix Metalloproteinase-7.

OBJECTIVES: Timely diagnosis is a critical challenge and is associated with improved survival of biliary atresia (BA) patients. We aimed to measure matrix metalloproteinase-7 (MMP-7) levels in BA patients within 3 days of birth using the dried blood spot (DBS) method and evaluate its potential as a screening tool. METHODS: The study enrolled 132 patients, including 25 patients diagnosed with BA and 107 non-BA patients with other congenital or perinatal conditions from the National Taiwan University Children Hospital. The stored DBS samples collected from 48 to 72 hours of life were retrieved from newborn screening centers. MMP-7 on the DBS was quantified using a sensitive sandwich enzyme-linked immunosorbent assay (ELISA). RESULTS: The MMP-7 levels of BA patients on the DBS were significantly higher than those of non-BA patients (19.2 ± 10.4 vs 5.6 ± 2.7 ng/mL, P value < 0.0001). MMP-7 levels in non-BA patients, including 5 patients with hepatobiliary structural anomaly, 9 patients with intrahepatic cholestasis, and 93 patients with other perinatal diseases, were 11.6 ± 4.2 ng/mL, 6.9 ± 3.0 ng/mL, and 5.2 ± 2.1 ng/mL, respectively. The DBS MMP-7 level showed good accuracy for identifying BA, with an area under the curve of 93.7% [95% confidence interval (CI): 87.7%-99.7%]. The MMP-7 cutoff at 8.0 ng/mL showed a sensitivity of 92.0% (95% CI: 75.0%-98.6%) and specificity of 92.5% (95% CI: 85.9%-96.1%) for detecting BA from other congenital or perinatal diseases. CONCLUSIONS: MMP-7 DBS analysis can be used to distinguish BA from other conditions as early as 3 days of age.

Kawasaki disease in children with Bacillus Calmette-Guérin scar reactivity: Focus on coronary outcomes.

BACKGROUND: /Purpose: Reactivity at the Bacillus Calmette-Guérin (BCG) scar is a pathognomonic feature of Kawasaki disease (KD). However, its value in predicting KD outcomes has not been emphasized. This study explored the clinical significance of BCG scar redness with respect to coronary artery outcomes. METHODS: This retrospective study collected data on children with KD from 13 hospitals in Taiwan during 2019-2021. Children with KD were categorized into four groups based on the KD type and BCG scar reactivity. Risk factors of coronary artery abnormalities (CAA) were analyzed in all groups. RESULTS: BCG scar redness occurred in 49% of 388 children with KD. BCG scar redness was associated with younger age, early intravenous immunoglobulin (IVIG) treatment, hypoalbuminemia, and CAA at the first echocardiogram (p < 0.01). BCG scar redness (RR 0.56) and pyuria (RR 2.61) were independent predictors of any CAA within 1 month (p < 0.05). Moreover, pyuria (RR 5.85, p < 0.05) in children with complete KD plus BCG scar redness was associated with CAA at 2-3 months; first IVIG resistance (RR 15.2) and neutrophil levels ≥80% (RR 8.37) in children with complete KD plus BCG scar non-redness were associated with CAA at 2-3 months (p < 0.05). We failed to detect any significant risk factors of CAA at 2-3 months in children with incomplete KD. CONCLUSION: BCG scar reactivity contributes to diverse clinical features in KD. It can be effectively applied to determine the risk factors of any CAA within 1 month and CAA at 2-3 months.

Transcription and imprinting dynamics in developing postnatal male germline stem cells.

Postnatal spermatogonial stem cells (SSCs) progress through proliferative and developmental stages to populate the testicular niche prior to productive spermatogenesis. To better understand, we conducted extensive genomic profiling at multiple postnatal stages on subpopulations enriched for particular markers (THY1, KIT, OCT4, ID4, or GFRa1). Overall, our profiles suggest three broad populations of spermatogonia in juveniles: (1) epithelial-like spermatogonia (THY1(+); high OCT4, ID4, and GFRa1), (2) more abundant mesenchymal-like spermatogonia (THY1(+); moderate OCT4 and ID4; high mesenchymal markers), and (3) (in older juveniles) abundant spermatogonia committing to gametogenesis (high KIT(+)). Epithelial-like spermatogonia displayed the expected imprinting patterns, but, surprisingly, mesenchymal-like spermatogonia lacked imprinting specifically at paternally imprinted loci but fully restored imprinting prior to puberty. Furthermore, mesenchymal-like spermatogonia also displayed developmentally linked DNA demethylation at meiotic genes and also at certain monoallelic neural genes (e.g., protocadherins and olfactory receptors). We also reveal novel candidate receptor-ligand networks involving SSCs and the developing niche. Taken together, neonates/juveniles contain heterogeneous epithelial-like or mesenchymal-like spermatogonial populations, with the latter displaying extensive DNA methylation/chromatin dynamics. We speculate that this plasticity helps SSCs proliferate and migrate within the developing seminiferous tubule, with proper niche interaction and membrane attachment reverting mesenchymal-like spermatogonial subtype cells back to an epithelial-like state with normal imprinting profiles.

Thymol-Loaded Polymeric Nanoparticles Improve the Postharvest Microbiological Safety of Blueberries.

Research background: The presence of Yersinia enterocolitica on raw food products raises the concern of yersiniosis as most of the berries are consumed raw. This is a challenging issue from the food safety aspect since it could increase the occurrence of foodborne diseases among humans. Thus, it is crucial to implement an effective sanitation before the packaging. Experimental approach: This study aims to synthesize and characterize thymol-loaded polyvinyl alcohol (Thy/PVA) nanoparticles as a sanitizer for postharvest treatment of blueberries. Thy/PVA nanoparticles were characterized by spectroscopic and microscopic approaches, prior to the analyses of antimicrobial properties. Results and conclusions: The diameter size of the nanoparticles was on average 84.7 nm, with a surface charge of -11.73 mV. Based on Fourier transform infrared (FTIR) measurement, the Thy/PVA nanoparticles notably shifted to the frequency of 3275.70, 2869.66, 1651.02 and 1090.52 cm-1. A rapid burst was observed in the first hour of release study, and 74.9 % thymol was released from the PVA nanoparticles. The largest inhibition zone was displayed by methicillin-resistant Staphylococcus aureus (MRSA), followed by Y. enterocolitica and Salmonella typhi. However, amongst these bacteria, the inhibition and killing of Y. enterocolitica required a lower concentration of Thy/PVA nanoparticles. The treatment successfully reduced the bacterial load of Y. enterocolitica on blueberries by 100 %. Novelty and scientific contribution: Thymol is a plant-based chemical without reported adverse effects to humans. In this study, by using the nanotechnology method of encapsulation with PVA, we improved the stability and physicochemical properties of thymol. This nanoparticle-based sanitizer could potentially promote the postharvest microbiological safety of raw berries, which may become an alternative practice of food safety.

Parents of children with cancer require health literacy support to meet their information needs.

BACKGROUND: Timely and relevant information helps parents to cope when a child is diagnosed with cancer. However, obtaining and understanding information is not a straightforward process for parents. OBJECTIVES: This article aims to explain paediatric cancer parents' information behaviour related to the care of their child. METHODS: Qualitative in-depth interviews were conducted with fourteen Malaysian paediatric cancer parents and eight healthcare professionals who worked with paediatric cancer patients. Reflexivity and inductive approaches were used to interpret the data to identify meaningful themes and subthemes. RESULTS: Three themes about how paediatric cancer parents interact with information emerged: Acquiring information, internalising information, and using information. Information may be actively sought or passively acquired. Cognitive and affective aspects influence how information is internalised into meaningful knowledge. Knowledge then leads to further action including further information gathering. CONCLUSION: Paediatric cancer parents need health literacy support to meet their information needs. They require guidance in identifying and appraising suitable information resources. Development of suitable supporting materials is needed to facilitate parents' ability to comprehend information related to their child's cancer. Understanding parents' information behaviour could assist healthcare professionals in providing information support in the context of paediatric cancer.

The effectiveness of a hydrocolloid crusting method versus standard care in the treatment of incontinence-associated dermatitis among adult patients in an acute care setting: A randomised controlled trial.

INTRODUCTION: Incontinence-associated dermatitis (IAD) is a type of irritant contact dermatitis due to prolonged exposure of the skin to moisture induced by urine or/and faeces. The main principles when treating IAD involves protecting the skin from further exposure to irritants, establishing a healing environment, and eradicating skin infections. This study aimed to evaluate the effectiveness of the hydrocolloid crusting method (HCM) versus the standard care method (SCM) in treating IAD. METHOD: A randomised controlled trial was conducted in an acute tertiary hospital in Singapore between August 2019 to September 2021. Using computer-generated numbers, patients were randomised into either HCM or SCM treatment groups. HCM treatment involved cleansing the affected area with a pH-neutral non-rinse moisturising cleanser, and the application of alternate layers of hydrocolloid powder, and non-sting film barrier spray (repeated three times during each use). Patients in the SCM treatment group received the same cleanser followed by a 30% zinc oxide barrier cream. IAD was assessed daily for up to seven days by the wound care nurses using the IAD severity tool. The primary outcome of the study was the mean difference in IAD score per day between both methods. RESULTS: Forty-four patients were eligible and recruited (22 in HCM; 22 in SCM). Patients in both groups were comparable in age and gender. IAD Category 2 was more predominant in both methods. The most common location of IAD was at the perianal skin and diarrhea related to gastroenteritis was the most prevalent cause of IAD. More patients in the SCM group (n = 12; 54.5%) had their IAD healed within seven days compared to HCM, (n = 7; 31.8%) group. However, the average decrease in IAD scores per day for both methods were found to be similar. CONCLUSION: HCM can be considered as a treatment of IAD along with the use of SCM. A skin care regimen should include effective cleansing, skin protection, and moisturization in IAD management.

Pre- and on-treatment lactate dehydrogenase as a prognostic and predictive biomarker in advanced non-small cell lung cancer.

BACKGROUND: The survival outcomes of patients with advanced non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs) are variable. This study investigated whether pre- and on-treatment lactate dehydrogenase (LDH) could better prognosticate and select patients for ICI therapy. METHODS: Using data from the POPLAR and OAK trials of atezolizumab versus docetaxel in previously treated advanced NSCLC, the authors assessed the prognostic and predictive value of pretreatment LDH (less than or equal to vs greater than the upper limit of normal). They further examined changes in on-treatment LDH by performing landmark analyses and estimated overall survival (OS) distributions according to the LDH level stratified by the response category (complete response [CR]/partial response [PR] vs stable disease [SD]). They repeated pretreatment analyses in subgroups defined by the programmed death ligand 1 (PD-L1) status. RESULTS: This study included 1327 patients with available pretreatment LDH. Elevated pretreatment LDH was associated with an adverse prognosis regardless of treatment (hazard ratio [HR] for atezolizumab OS, 1.49; P = .0001; HR for docetaxel OS, 1.30; P = .004; P for treatment by LDH interaction = .28). Findings for elevated pretreatment LDH were similar for patients with positive PD-L1 expression treated with atezolizumab. Persistently elevated on-treatment LDH was associated with a 1.3- to 2.8-fold increased risk of death at weeks 6, 12, 18, and 24 regardless of treatment. Elevated LDH at 6 weeks was associated with significantly shorter OS regardless of radiological response (HR for CR/PR, 2.10; P = .04; HR for SD, 1.50; P < .01), with similar findings observed at 12 weeks. CONCLUSIONS: In previously treated advanced NSCLC, elevated pretreatment LDH is an independent adverse prognostic marker. There is no evidence that pretreatment LDH predicts ICI benefit. Persistently elevated on-treatment LDH is associated with worse OS despite radiologic response.

The validity of progression-free survival 2 as a surrogate trial end point for overall survival.

BACKGROUND: Overall survival (OS) is the gold-standard end point for oncology trials. However, the availability of multiple therapeutic options after progression and crossover to receive investigational agents confound and delay OS data maturation. Progression-free survival 2 (PFS-2), defined as the time from randomization to progression on first subsequent therapy, has been proposed as a surrogate for OS. Using a meta-analytic approach, the authors aimed to assess the association between OS and PFS-2 and compare this with progression-free survival 1 (PFS-1) and the objective response rate (ORR). METHODS: An electronic literature search was performed to identify randomized trials of systemic therapies in advanced solid tumors that reported PFS-2 as a prespecified end point. Correlations between OS and PFS-2, OS and PFS-1, and OS and ORR as hazard ratios (HRs) or odds ratios (ORs) were assessed via linear regression weighted by trial size. RESULTS: Thirty-eight trials were included, and they comprised 19,031 patients across 8 tumor types. PFS-2 displayed a moderate correlation with OS (r = 0.67; 95% confidence interval [CI], 0.08-0.69). Conversely, correlations of ORR (r = 0.12; 95% CI, 0.00-0.13) and PFS-1 (r = 0.21; 95% CI, 0.00-0.33) were poor. The findings for PFS-2 were consistent for subgroup analyses by treatment type (immunotherapy vs nonimmunotherapy: r = 0.67 vs 0.67), survival post progression (<12 vs ≥12 months: r = 0.86 vs 0.79), and percentage not receiving subsequent treatment (<50% vs ≥50%: r = 0.70 vs 0.63). CONCLUSIONS: Across diverse tumors and therapies, the treatment effect on PFS-2 correlated moderately with the treatment effect on OS. PFS-2 performed consistently better than PFS-1 and ORR, regardless of postprogression treatment and postprogression survival. PFS-2 should be included as a key trial end point in future randomized trials of solid tumors.

Variational Quantum-Neural Hybrid Eigensolver.

The variational quantum eigensolver (VQE) is one of the most representative quantum algorithms in the noisy intermediate-scale quantum (NISQ) era, and is generally speculated to deliver one of the first quantum advantages for the ground-state simulations of some nontrivial Hamiltonians. However, short quantum coherence time and limited availability of quantum hardware resources in the NISQ hardware strongly restrain the capacity and expressiveness of VQEs. In this Letter, we introduce the variational quantum-neural hybrid eigensolver (VQNHE) in which the shallow-circuit quantum Ansatz can be further enhanced by classical post-processing with neural networks. We show that the VQNHE consistently and significantly outperforms the VQE in simulating ground-state energies of quantum spins and molecules given the same amount of quantum resources. More importantly, we demonstrate that, for arbitrary postprocessing neural functions, the VQNHE only incurs a polynomial overhead of processing time and represents the first scalable method to exponentially accelerate the VQE with nonunitary postprocessing that can be efficiently implemented in the NISQ era.