Fine mapping and analysis of a candidate gene controlling Phytophthora blight resistance in cucumber.

Cucumber blight is a destructive disease. The best way to control this disease is resistance breeding. This study focuses on disease resistance gene mapping and molecular marker development. We used the resistant cucumber, JSH, and susceptible cucumber, B80, as parents to construct F2 populations. Bulked segregant analysis (BSA) combined with specific length amplified fragment sequencing (SLAF-seq) were used, from which we developed cleaved amplified polymorphic sequence (CAPs) markers to map the resistance gene. Resistance in F2 individuals showed a segregation ratio of resistance:susceptibility close to 3:1. The gene in JSH resistant cucumber was mapped to an interval of 9.25 kb, and sequencing results for the three genes in the mapped region revealed three mutations at base sites 225, 302, and 591 in the coding region of Csa5G139130 between JSH and B80, but no mutations in coding regions of Csa5G139140 and Csa5G139150. The mutations caused changes in amino acids 75 and 101 of the protein encoded by Csa5G139130, suggesting that Csa5G139130 is the most likely resistance candidate gene. We developed a molecular marker, CAPs-4, as a closely linked marker for the cucumber blight resistance gene. This is the first report on mapping of a cucumber blight resistance gene and will provideg a useful marker for molecular breeding of cucumber resistance to Phytophthora blight.

ESGO-ESMO-ESP consensus conference recommendations on ovarian cancer: pathology and molecular biology and early, advanced and recurrent disease.

The European Society of Gynaecological Oncology, the European Society for Medical Oncology (ESMO) and the European Society of Pathology held a consensus conference (CC) on ovarian cancer on 15-16 June 2022 in Valencia, Spain. The CC panel included 44 experts in the management of ovarian cancer and pathology, an ESMO scientific advisor and a methodologist. The aim was to discuss new or contentious topics and develop recommendations to improve and harmonise the management of patients with ovarian cancer. Eighteen questions were identified for discussion under four main topics: (i) pathology and molecular biology, (ii) early-stage disease and pelvic mass in pregnancy, (iii) advanced stage (including older/frail patients) and (iv) recurrent disease. The panel was divided into four working groups (WGs) to each address questions relating to one of the four topics outlined above, based on their expertise. Relevant scientific literature was reviewed in advance. Recommendations were developed by the WGs and then presented to the entire panel for further discussion and amendment before voting. This manuscript focuses on the recommendation statements that reached a consensus, their voting results and a summary of evidence supporting each recommendation.

Regions Important for Hemagglutination Activity and Serotypes of Avibacterium paragallinarum HMTp210 Protein.

Avibacterium paragallinarum is an important respiratory pathogen of domestic chickens. Avibacterium paragallinarum has been subtyped into three serogroups and nine serovars according to the Page and revised Kume schemes. The major hemagglutinin antigen of A. paragallinarum is HMTp210, which is a large protein of about 2000 amino acids (aa), including a 70-aa signal peptide at its N-terminal end. However, the regions important for the hemagglutination (HA) activity and serotypes of HMTp210 remain unclear. In this study we constructed a series of A. paragallinarum strains expressing HMTp210 in-frame deletion mutants and determined their HA titers to identify the regions important for the HA activity and serotypes of HMTp210. Two distinct types of HA activities were found in HMTp210. The type 1 HA activity resided in the region spanning the full-length HA (aa 71-2084), whereas the type 2 resided in the region spanning aa 1003-2084. The putative ligand binding of the type 1 HA activity was located at aa 176-360, which had a structure similar to YadA of Yersinia enterocolitica. The putative ligand binding site of the type 2 HA activity was located at aa 1003-1125, which had a structure similar to UspA1 from Moraxella catarrhalis. The type 1 HA activity appeared to be Page serogroup specific, whereas type 2 appeared to be Kume serovar specific. Finally, sequence analyses of the regions spanning aa 1-400 and aa 1100-1600 of HMTp210 could be useful for the molecular serotyping (the Page and revised Kume schemes) of A. paragallinarum isolates.

Regiones importantes para la actividad de hemaglutinación y serotipos de la proteína HMTp210 de Avibacterium paragallinarum. La bacteria Avibacterium paragallinarum es un patógeno respiratorio importante de los pollos domésticos. Avibacterium paragallinarum se subtipificó en tres serogrupos y nueve serovares de acuerdo con los esquemas revisados de Page y Kume. El principal antígeno de la hemaglutinina de A. paragallinarum es la proteína HMTp210, que es una proteína grande de unos 2000 aminoácidos (aa), que incluye un péptido señal de 70 aminoácidos en su extremo N-terminal. Sin embargo, las regiones importantes para la actividad de hemaglutinación (HA) y de los serotipos de la proteína HMTp210 siguen sin estar determinados. En este estudio, se construyó una serie de cepas de A. paragallinarum que expresaban mutantes de deleción en marco de lectura de HMTp210 y se determinaron sus títulos de hemaglutinación para identificar las regiones importantes para la actividad de hemaglutinación y de los serotipos de HMTp210. Se encontraron dos tipos distintos de actividades hemaglutinación en la proteína HMTp210. La actividad de hemaglutinación de tipo 1 residía en la región que abarcaba la longitud completa (aminoácidos 71­2084), mientras que la de tipo 2 residía en la región que abarcaba entre los aminoácidos 1003­2084. El sitio supuesto de unión al ligando de la actividad de hemaglutinación tipo 1 se ubicó entre los aminoácidos 176­360, que tenía una estructura similar a la proteína YadA de Yersinia enterocolitica. El supuesto sitio de unión del ligando de la actividad de hemaglutinación tipo 2 se ubicó entre los aminoácidos 1003­1125, que tenía una estructura similar a la proteína UspA1 de Moraxella catarrhalis. La actividad de hemaglutinación tipo 1 parecía ser específica del serogrupo Page, mientras que la hemaglutinación tipo 2 parecía ser específica del serovar Kume. Finalmente, los análisis de secuencias de las regiones que abarcan los aminácidos 1­400 y aminoácidos 1100­1600 de HMTp210 podrían ser útiles para la serotipificación molecular (por el esquema revisado de Page y Kume revisado) de aislamientos de A. paragallinarum.

Prediction of toxicity outcomes following radiotherapy using deep learning-based models: A systematic review.

PURPOSE: This study aims to perform a comprehensive systematic review of deep learning (DL) models in predicting RT-induced toxicity. MATERIALS AND METHODS: A literature review was performed following the PRISMA guidelines. Systematic searches were performed in PubMed, Scopus, Cochrane and Embase databases from the earliest record up to September 2022. Related studies on deep learning models for radiotherapy toxicity prediction were selected based on predefined PICOS criteria. RESULTS: Fourteen studies of radiotherapy-treated patients on different types of cancer [prostate (n=2), HNC (n=4), liver (n=2), lung (n=4), cervical (n=1), and oesophagus (n=1)] were eligible for inclusion in the systematic review. Information regarding patient characteristics and model development was summarized. Several approaches, such as ensemble learning, data augmentation, and transfer learning, that were utilized by selected studies were discussed. CONCLUSION: Deep learning techniques are able to produce a consistent performance for toxicity prediction. Future research using large and diverse datasets and standardization of the study methodologies are required to improve the consistency of the research output.

Avelumab or talazoparib in combination with binimetinib in metastatic pancreatic ductal adenocarcinoma: dose-finding results from phase Ib of the JAVELIN PARP MEKi trial.

BACKGROUND: Combinations of avelumab [anti-programmed death-ligand 1 (anti-PD-L1)] or talazoparib [poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor] with binimetinib (MEK inhibitor) were expected to result in additive or synergistic antitumor activity relative to each drug administered alone. Here, we report phase Ib results from JAVELIN PARP MEKi, which investigated avelumab or talazoparib combined with binimetinib in metastatic pancreatic ductal adenocarcinoma (mPDAC). PATIENTS AND METHODS: Patients with mPDAC that had progressed with prior treatment received avelumab 800 mg every 2 weeks plus binimetinib 45 mg or 30 mg two times daily (continuous), or talazoparib 0.75 mg daily plus binimetinib 45 mg or 30 mg two times daily (7 days on/7 days off). The primary endpoint was dose-limiting toxicity (DLT). RESULTS: A total of 22 patients received avelumab plus binimetinib 45 mg (n = 12) or 30 mg (n = 10). Among DLT-evaluable patients, DLT occurred in five of 11 patients (45.5%) at the 45-mg dose, necessitating de-escalation to 30 mg; DLT occurred in three of 10 patients (30.0%) at the 30-mg dose. Among patients treated at the 45-mg dose, one (8.3%) had a best overall response of partial response. Thirteen patients received talazoparib plus binimetinib 45 mg (n = 6) or 30 mg (n = 7). Among DLT-evaluable patients, DLT occurred in two of five patients (40.0%) at the 45-mg dose, necessitating de-escalation to 30 mg; DLT occurred in two of six patients (33.3%) at the 30-mg dose. No objective responses were observed. CONCLUSIONS: Combinations of avelumab or talazoparib plus binimetinib resulted in higher-than-expected DLT rates. However, most DLTs were single occurrences, and the overall safety profiles were generally consistent with those reported for the single agents. CLINICAL TRIAL REGISTRATION: ClinicalTrials.govNCT03637491; https://clinicaltrials.gov/ct2/show/NCT03637491.

Recommendations for the use of next-generation sequencing in patients with metastatic cancer in the Asia-Pacific region: a report from the APODDC working group.

INTRODUCTION: Next-generation sequencing (NGS) diagnostics have shown clinical utility in predicting survival benefits in patients with certain cancer types who are undergoing targeted drug therapies. Currently, there are no guidelines or recommendations for the use of NGS in patients with metastatic cancer from an Asian perspective. In this article, we present the Asia-Pacific Oncology Drug Development Consortium (APODDC) recommendations for the clinical use of NGS in metastatic cancers. METHODS: The APODDC set up a group of experts in the field of clinical cancer genomics to (i) understand the current NGS landscape for metastatic cancers in the Asia-Pacific (APAC) region; (ii) discuss key challenges in the adoption of NGS testing in clinical practice; and (iii) adapt/modify the European Society for Medical Oncology guidelines for local use. Nine cancer types [breast cancer (BC), gastric cancer (GC), nasopharyngeal cancer (NPC), ovarian cancer (OC), prostate cancer, lung cancer, and colorectal cancer (CRC) as well as cholangiocarcinoma and hepatocellular carcinoma (HCC)] were identified, and the applicability of NGS was evaluated in daily practice and/or clinical research. Asian ethnicity, accessibility of NGS testing, reimbursement, and socioeconomic and local practice characteristics were taken into consideration. RESULTS: The APODDC recommends NGS testing in metastatic non-small-cell lung cancer (NSCLC). Routine NGS testing is not recommended in metastatic BC, GC, and NPC as well as cholangiocarcinoma and HCC. The group suggested that patients with epithelial OC may be offered germline and/or somatic genetic testing for BReast CAncer gene 1 (BRCA1), BRCA2, and other OC susceptibility genes. Access to poly (ADP-ribose) polymerase inhibitors is required for NGS to be of clinical utility in prostate cancer. Allele-specific PCR or a small-panel multiplex-gene NGS was suggested to identify key alterations in CRC. CONCLUSION: This document offers practical guidance on the clinical utility of NGS in specific cancer indications from an Asian perspective.

[Clinical and genetic characteristics of 9 rare cases with coexistence of dual genetic diagnoses].

Objective: To analyze the clinical and genetic characteristics of pediatric patients with dual genetic diagnoses (DGD). Methods: Clinical and genetic data of pediatric patients with DGD from January 2021 to February 2022 in Peking University First Hospital were collected and analyzed retrospectively. Results: Among the 9 children, 6 were boys and 3 were girls. The age of last visit or follow-up was 5.0 (2.7,6.8) years. The main clinical manifestations included motor retardation, mental retardation, multiple malformations, and skeletal deformity. Cases 1-4 were all all boys, showed myopathic gait, poor running and jumping, and significantly increased level of serum creatine kinase. Disease-causing variations in Duchenne muscular dystrophy (DMD) gene were confirmed by genetic testing. The 4 children were diagnosed with DMD or Becker muscular dystrophy combined with a second genetic disease, including hypertrophic osteoarthropathy, spinal muscular atrophy, fragile X syndrome, and cerebral cavernous malformations type 3, respectively. Cases 5-9 were clinically and genetically diagnosed as COL9A1 gene-related multiple epiphyseal dysplasia type 6 combined with NF1 gene-related neurofibromatosis type 1, COL6A3 gene-related Bethlem myopathy with WNT1 gene-related osteogenesis imperfecta type XV, Turner syndrome (45, X0/46, XX chimera) with TH gene-related Segawa syndrome, Chromosome 22q11.2 microduplication syndrome with DYNC1H1 gene-related autosomal dominant lower extremity-predominant spinal muscular atrophy-1, and ANKRD11 gene-related KBG syndrome combined with IRF2BPL gene-related neurodevelopmental disorder with regression, abnormal movement, language loss and epilepsy. DMD was the most common, and there were 6 autosomal dominant diseases caused by de novo heterozygous pathogenic variations. Conclusions: Pediatric patients with coexistence of double genetic diagnoses show complex phenotypes. When the clinical manifestations and progression are not fully consistent with the diagnosed rare genetic disease, a second rare genetic disease should be considered, and autosomal dominant diseases caused by de novo heterozygous pathogenic variation should be paid attention to. Trio-based whole-exome sequencing combining a variety of molecular genetic tests would be helpful for precise diagnosis.

[Analysis of 4 children with DYNC1H1 gene related spinal muscular atrophy with lower extremity predominant 1].

Objective: To investigate the clinical features and gene variation characteristics of children with dynein cytoplasmic 1 heavy chain 1 (DYNC1H1) gene associated spinal muscular atrophy with lower extremity predominant (SMALED) 1. Methods: The clinical data of 4 SMALED1 children admitted to Peking University First Hospital from December 2018 to May 2021, who were found to have pathogenic variation of DYNC1H1 gene through genetic testing, except for other genes known to be related to motor retardation, were retrospectively summarized to analyze the phenotype and genotype characteristics. Results: There were 3 males and 1 female. The age of onset was 1 year, 1 day, 1 day and 4 months, respectively. The age of diagnosis was 4 years and 10 months, 9 months, 5 years and 9 months, and 3 years and 1 month, respectively. The clinical manifestations were muscle weakness and muscular atrophy of lower limbs, 2 cases with foot deformity, 1 case with early non progressive joint contracture, 1 case with hip dislocation and 1 case with mental retardation. De novo heterozygous missense variations in DYNC1H1 gene were found in all 4 children. According to the rating of American College of medical genetics and genomics, they were all possible pathogenic and pathogenic variations, with p.R598C, p.P776L, p.Y1109D variations had been reported, and p.I1086R variation had not been reported. Conclusions: For those with unexplained lower limb muscle weakness, muscle atrophy, joint contracture and foot deformity, upper limb motor ability related retention, with or without mental retardation, as well as the motor ability progresses slowly, it is necessary to consider the possibility of SMALED1 and the detection of DYNC1H1 gene when necessary.

Frontal sinus obliteration with beta-tricalcium phosphate putty: case series with long-term radiological follow up.

OBJECTIVES: Frontal sinus obliteration is often performed using fat, autologous bone or a range of synthetic materials. This paper reports the long-term clinical and radiological outcomes of frontal sinus obliteration using beta-tricalcium phosphate putty. METHODS: A retrospective audit was performed of patients who underwent frontal sinus obliteration with beta-tricalcium phosphate putty. Patient-, disease- and procedure-related data were collected. Pre- and post-operative computed tomography scans were reviewed to assess bone integration. RESULTS: Four patients underwent frontal sinus obliteration using beta-tricalcium phosphate putty for treatment of a cerebrospinal leak, mucocele and recalcitrant frontal sinusitis. All patients had disease resolution, with no intra- or post-operative complications reported in the 16.5-month follow up. Post-operative computed tomography scans confirmed native bone obliteration of the frontonasal ducts in all patients. CONCLUSION: Beta-tricalcium phosphate putty is a safe and effective option for bone obliteration of the frontal sinus in a range of pathologies, including cerebrospinal fluid leak.

Human social conditions predict the risk of exposure to zoonotic parasites in companion animals in East and Southeast Asia.

BACKGROUND: A recent dramatic surge in pet ownership has been observed across metropolitan areas in Asia. To date, there is a dearth of information on the risk associated with pet ownership for the transmission of parasites on a large scale in Asia, despite this continent giving rise to the largest burden of zoonotic infections worldwide. METHODS: We explored the nature and extent of zoonotic internal (endo-) and external (ecto-) parasites and arthropod-borne pathogens in 2381 client-owned dogs and cats living in metropolitan areas of eight countries in East and Southeast Asia using reliable diagnostic tests and then undertook extensive statistical analyses to define predictors of exposure to zoonotic pathogens. RESULTS: The estimated ORs for overall parasite infections are 1.35 [95% CIs 1.07;1.71] in young animals and 4.10 [1.50;11.2] in the animal group older than 15 years as compared with adult animals, 0.61 [0.48;0.77] in neutered animals as compared to unneutered animals, 0.36 [0.26;0.50] in animals living in urban areas as compared with rural areas, 1.14 [1.08;1.21] for each 1 °C increase of annual mean temperature which varies from 12.0 to 28.0 °C, and 0.86 [0.78;0.95] for each year of life expectancy which varies from 70.9 to 83.3 years. CONCLUSIONS: Here we highlight the influence of human life expectancy and the neutering status of the animals, which reflect increased living standards through access to education and human and veterinary health care, to be both strongly associated with exposure to zoonotic parasites. An integrated approach of local and international authorities to implement and manage educational programs will be crucial for the control of zoonotic infections of companion animals in Asia.

Parasites live on or inside animals or humans and can cause disease. Companion animals (pets) with parasites present a potential risk to the health of their owners, as certain kinds of parasites (known as zoonotic parasites) can affect both animal and human health. Here, we investigated whether human social conditions are associated with zoonotic parasite infections in companion animals in East and Southeast Asia. We found that higher human life expectancy and neutering of the companion animals were associated with fewer zoonotic parasite infections in the animals. These findings highlight the need for an enhanced commitment of local authorities to establish prevention campaigns, including education programs, against zoonotic pathogens. These measures will play a crucial role in alleviating the impact of these diseases in companion animals and humans in Asia.

[Comparison of high-flow nasal cannula oxygen therapy and non-rebreather face mask in the treatment of mild carbon monoxide poisoning].

Objective: To compare the efficacy of high-flow nasal cannula oxygen therapy (HFNC) and non-rebreather face mask (NRFM) in the treatment of mild acute carbon monoxide poisoning (ACOP) in reducing carboxyhemoglobin (COHb) , and to explore the feasibility of HFNC in the treatment of ACOP. Methods: Patients with mild ACOP with COHb >10% who were admitted to the emergency department of Northern Jiangsu People's Hospital from January 2015 to December 2020 were analyzed, and those with altered consciousness, mechanical ventilation and those requiring hyperbaric oxygen therapy were excluded. The patients were divided into HFNC group and NRFM group according to the oxygen therapy used in the emergency department. The COHb decline value and COHb half-life in the two groups were observed. Results: Seventy-one patients were enrolled, including 39 in the NRFM group and 32 in the HFNC group. The baseline COHb in the HFNC group was 24.8%±8.3%, and that in the NRFM group was 22.5%±7.1%, with no significant difference between the two groups (t=1.27, P=0.094) . At 60 min, 90 min and 120 min of treatment, COHb in both groups decreased, but the COHb in HFNC group was lower than that in NRFM group at the same time point (P<0.05) . After 1 h of treatment, the COHb decrease in the HFNC group (16.9%±4.5%) was significantly higher than that in the NRFM group (10.1%±7.8%) (t=4.32, P=0.013) . The mean half-life of COHb in the HFNC group (39.3 min) was significantly lower than that in the NRFM group (61.4 min) (t=4.69, P=0.034) . Conclusion: HFNC treatment of mild ACOP can rapidly reduce blood COHb level, it is a potential oxygen therapy method for clinical treatment of ACOP.

Functional assessment of military aircrew applicants in a hypobaric chamber.

BACKGROUND: Aircrew are exposed to environmental pressure changes. In the Republic of Singapore Air Force (RSAF), applicants assessed to be at intermediate risk of otic barotrauma undergo a hypobaric chamber assessment ["trial of chamber" (TOC)] to functionally evaluate their suitability for military aircrew vocations. AIMS: To identify factors associated with TOC failure among applicants with otorhinolaryngological conditions. METHODS: All applicants to RSAF aircrew vocations who were assessed to be at intermediate risk of otic barotrauma over a 3-yr period were identified using the RSAF Aeromedical Centre's electronic database. Their medical records, as well as the TOC assessment records of the subset of applicants who underwent TOC, were reviewed for demographic data, clinical findings, and TOC outcomes. RESULTS: Of the 483 identified applicants, 374 (77%) had abnormal otoscopic findings, 103 (21%) had rhinitis symptoms, and 6 (1%) had previous ENT surgery. 123 (25%) underwent TOC, of which 20 (16%) failed. Holding other predictor variables constant, the odds of TOC failure increased by 0.79 per unit decrease in BMI (95% CI 0.63-0.99), and the odds of TOC failure increased by 0.93 per kg decrease in body weight (95% CI 0.87-1.00). An abnormal tympanogram was not a statistically significant predictor of TOC failure (OR 1.96, 95% CI 0.59-6.42). Of the 47 applicants who passed TOC and were eventually recruited, none subsequently developed otic barotrauma (mean follow-up, 3.3 yr ± 1.5 yr). CONCLUSIONS: Applicants with lower weight and BMI are more likely to develop otic barotrauma with environmental pressure change. Tympanometry cannot be reliably used to identify applicants who would more likely pass TOC.

THIRD bedside ultrasound protocol for rapid diagnosis of undifferentiated shock: a prospective observational study.

INTRODUCTION: It is clinically challenging to differentiate the pathophysiological types of shock in emergency situations. Here, we evaluated the ability of a novel bedside ultrasound protocol (Tamponade/tension pneumothorax, Heart, Inferior vena cava, Respiratory system, Deep venous thrombosis/aorta dissection [THIRD]) to predict types of shock in the emergency department. METHODS: An emergency physician performed the THIRD protocol on all patients with shock who were admitted to the emergency department. All patients were closely followed to determine their final clinical diagnoses. The kappa index, sensitivity, specificity, positive predictive value, and negative predictive value were calculated for the initial diagnostic impression provided by the THIRD protocol, compared with each patient's final diagnosis. RESULTS: In total, 112 patients were enrolled in this study. The kappa index between initial impression and final diagnosis was 0.81 (95% confidence interval=0.73-0.89; P<0.001). For hypovolaemic, cardiogenic, distributive, and obstructive types of shock, the sensitivities of the THIRD protocol were 100%, 100%, 93%, and 100%, respectively; the sensitivity for a 'mixed' shock aetiology was 86%. The negative predictive value of the THIRD protocol for all five types of shock was ≥96%. CONCLUSION: Initial diagnostic judgements determined using the THIRD protocol showed favourable agreement with the final diagnosis in patients who presented with undifferentiated shock. The THIRD protocol has great potential for use as a bedside approach that can guide the rapid management of undifferentiated shock in emergency settings, particularly for patients with obstructive, hypovolaemic, or cardiogenic shock.

Safety and efficacy of pralsetinib in RET fusion-positive non-small-cell lung cancer including as first-line therapy: update from the ARROW trial.

BACKGROUND: RET fusions are present in 1%-2% of non-small-cell lung cancer (NSCLC). Pralsetinib, a highly potent, oral, central nervous system-penetrant, selective RET inhibitor, previously demonstrated clinical activity in patients with RET fusion-positive NSCLC in the phase I/II ARROW study, including among treatment-naive patients. We report an updated analysis from the ARROW study. PATIENTS AND METHODS: ARROW is a multi-cohort, open-label, phase I/II study. Eligible patients were ≥18 years of age with locally advanced or metastatic solid tumours and an Eastern Cooperative Oncology Group performance status of 0-2 (later 0-1). Patients initiated pralsetinib at the recommended phase II dose of 400 mg once daily until disease progression, intolerance, consent withdrawal, or investigator's decision. The co-primary endpoints (phase II) were overall response rate (ORR) by blinded independent central review and safety. RESULTS: Between 17 March 2017 and 6 November 2020 (data cut-off), 281 patients with RET fusion-positive NSCLC were enrolled. The ORR was 72% [54/75; 95% confidence interval (CI) 60% to 82%] for treatment-naive patients and 59% (80/136; 95% CI 50% to 67%) for patients with prior platinum-based chemotherapy (enrolment cut-off for efficacy analysis: 22 May 2020); median duration of response was not reached for treatment-naive patients and 22.3 months for prior platinum-based chemotherapy patients. Tumour shrinkage was observed in all treatment-naive patients and in 97% of patients with prior platinum-based chemotherapy; median progression-free survival was 13.0 and 16.5 months, respectively. In patients with measurable intracranial metastases, the intracranial response rate was 70% (7/10; 95% CI 35% to 93%); all had received prior systemic treatment. In treatment-naive patients with RET fusion-positive NSCLC who initiated pralsetinib by the data cut-off (n = 116), the most common grade 3-4 treatment-related adverse events (TRAEs) were neutropenia (18%), hypertension (10%), increased blood creatine phosphokinase (9%), and lymphopenia (9%). Overall, 7% (20/281) discontinued due to TRAEs. CONCLUSIONS: Pralsetinib treatment produced robust efficacy and was generally well tolerated in treatment-naive patients with advanced RET fusion-positive NSCLC. Results from the confirmatory phase III AcceleRET Lung study (NCT04222972) of pralsetinib versus standard of care in the first-line setting are pending.

Dispersion compensation of high-speed data using an integrated silicon nitride ring resonator.

Dispersion impairments are a well-known limitation in data center communications, limiting both the usable data rates and reaches. Several companies today adopt silicon photonics as a core technology in their transceiver products. This presents an opportunity for silicon photonics-based dispersion management technologies to be integrated with the transceiver transmitter or receiver. In this manuscript, we present a ring-resonator based, tunable dispersion compensation device, providing dispersion ranging as wide from + 12.9 × 103ps/nm to -12.3 × 103ps/nm. Thermo-optic tuning from 20°C to 70°C is demonstrated to allow continuous wavelength tuning across 200 GHz. High-speed experiments using 25 Gb/s non-return-to-zero data propagating through 20 km of single mode fiber show that a significant improvement in the eye diagram is achieved after compensation with the ring-resonator device. We demonstrate a significant improvement in the BER from 10-3 to 10-11 for data rates of 25 and 25.78125 Gb/s.

Menopausal hormone therapy: why we should no longer be afraid of the breast cancer risk.

The threat that women may develop breast cancer is the major reason why both physicians and women are afraid to use menopausal hormone therapy (MHT). The fear pertains to estrogen-progestin replacement therapy (EPRT) as estrogen-alone replacement therapy has no, or even a reduced, breast cancer risk. We reviewed the way breast cancer risk with EPRT was reported in some major publications since 2002 and tried to put the use-risk association in context. We hope this will make it easier for the physician and the menopausal woman to understand the risk involved and allow more confident and more informed decision-making regarding MHT use. We conclude that there are five interrelated reasons why physicians and women should no longer be afraid of the breast cancer risk with EPRT. We submit that breast cancer related to EPRT use is rare because the risk is very low; the reported increase in breast cancer risk with EPRT is not relevant to current practice; modifiable lifestyle factors, not EPRT, are the real risks for breast cancer; breast cancer-specific mortality is reduced in women who develop breast cancer while on EPRT; and avoiding MHT use when indicated puts a woman in harm's way.