The impacts of telemedicine on assisted reproduction: a systematic review and meta-analysis.

Telemedicine is being applied in assisted reproduction technology (ART) to provide remote consultations, monitoring and support for patients. This study aimed to evaluate the potential advantages of telemedicine in ART treatment in the form of virtual consultations. Studies in which patients were using telemedicine during ART treatment were identified from four scientific databases (PudMed, EMBASE, Scopus, Web of Science). The success of fertility treatments was compared between telemedicine and in-office care, and patient satisfaction with ART through telemedicine was assessed. Eleven studies, comprising 4697 patients, were identified. Quality assessment (Joanna Briggs Institute Critical Appraisal and revised Cochrane risk-of-bias tools) revealed an acceptable risk of bias for both randomized controlled trials and observational studies. Using a fixed-effects model, telemedicine was comparable to in-person care regarding the pregnancy rate achieved (odds ratio 1.02, 95% confidence intervals 0.83-1.26, P = 0.83). A Q-test suggested that all the included studies were homogeneous. Patients who received telemedicine during fertility treatment reported a high level of satisfaction (91%, 95% confidence intervals 80-96%). Egger's test confirmed that no publication bias was found. Telemedicine could serve as a complementary tool during fertility treatment to facilitate patients' satisfaction and overcome some practical problems without compromising treatment outcomes. Future studies should continue exploring the potential applications of telemedicine in assisted reproduction.

Improving biomedical Named Entity Recognition with additional external contexts.

OBJECTIVE: Biomedical Named Entity Recognition (bio NER) is the task of recognizing named entities in biomedical texts. This paper introduces a new model that addresses bio NER by considering additional external contexts. Different from prior methods that mainly use original input sequences for sequence labeling, the model takes into account additional contexts to enhance the representation of entities in the original sequences, since additional contexts can provide enhanced information for the concept explanation of biomedical entities. METHODS: To exploit an additional context, given an original input sequence, the model first retrieves the relevant sentences from PubMed and then ranks the retrieved sentences to form the contexts. It next combines the context with the original input sequence to form a new enhanced sequence. The original and new enhanced sequences are fed into PubMedBERT for learning feature representation. To obtain more fine-grained features, the model stacks a BiLSTM layer on top of PubMedBERT. The final named entity label prediction is done by using a CRF layer. The model is jointly trained in an end-to-end manner to take advantage of the additional context for NER of the original sequence. RESULTS: Experimental results on six biomedical datasets show that the proposed model achieves promising performance compared to strong baselines and confirms the contribution of additional contexts for bio NER. CONCLUSION: The promising results confirm three important points. First, the additional context from PubMed helps to improve the quality of the recognition of biomedical entities. Second, PubMed is more appropriate than the Google search engine for providing relevant information of bio NER. Finally, more relevant sentences from the context are more beneficial than irrelevant ones to provide enhanced information for the original input sequences. The model is flexible to integrate any additional context types for the NER task.

The effects of bivalent human papillomavirus (HPV) vaccination on high-risk anogenital HPV infection among sexually active female adolescents with and without perinatally acquired HIV.

BACKGROUND: Females with perinatal HIV (PHIV) infection are at elevated risk for anogenital high-risk human papillomavirus (HR-HPV) infection. Limited data are available around the effect of the HPV vaccination after initiation of sexual activity among PHIV youth. This study aims to assess the impact of a bivalent HPV vaccination on the persistence of anogenital HR-HPV among sexually active female PHIV youth and matched HIV-negative controls aged 12-24years in Thailand and Vietnam. METHODS: During a 3-year study, prevalent, incident, and persistent HR-HPV infection were assessed at annual visits. A subset of participants received a bivalent HPV vaccine. Samples were taken for HPV testing from the vagina, cervix, and anus. HR-HPV persistence was defined as the detection of the same genotype(s) at any anogenital compartment over≥two consecutive visits. RESULTS: Of the 93 PHIV and 99 HIV-negative female youth enrolled in this study, 25 (27%) PHIV and 22 (22%) HIV-negative youth received a HPV vaccine. Persistent infection with any HR-HPV type was significantly lower among PHIV youth who received the vaccine compared to those who did not (33%vs 61%, P =0.02); a difference was not observed among HIV-negative youth (35%vs 50%, P =0.82). PHIV infection (adjusted prevalence ratio [aPR] 2.31, 95% CI 1.45-3.67) and not receiving a HPV vaccine (aPR, 1.19, 95%CI 1.06-1.33) were associated with persistent anogenital HR-HPV infection. CONCLUSIONS: Bivalent HPV vaccination after initiation of sexual activity was associated with reduced persistence of anogenital HR-HPV infection in Southeast Asian PHIV female youth, which may be related to vaccine cross-protection. Primary and catch-up HPV vaccinations should be prioritised for children and youth with HIV.

Pembrolizumab in Asian patients with microsatellite-instability-high/mismatch-repair-deficient colorectal cancer.

The phase 3 KEYNOTE-177 study evaluated pembrolizumab versus chemotherapy with or without bevacizumab or cetuximab in patients with newly diagnosed, microsatellite-instability-high (MSI-H)/mismatch-repair-deficient (dMMR) metastatic colorectal cancer (mCRC). Primary endpoints were progression-free survival (PFS) per RECIST v1.1 by blinded independent central review (BICR) and overall survival (OS). Secondary endpoints were overall response rate (ORR) per RECIST v1.1 by BICR and safety. Here, we report results from the post hoc analysis of patients who were enrolled in Asia from the final analysis (FA) of KEYNOTE-177. A total of 48 patients from Japan, Korea, Singapore, and Taiwan (pembrolizumab, n = 22; chemotherapy, n = 26) were included. At FA, median time from randomization to data cutoff (February 19, 2021) was 45.3 (range 38.1-57.8) months with pembrolizumab and 43.9 (range 36.6-55.1) months with chemotherapy. Median PFS was not reached (NR; 95% confidence interval [CI] 1.9 months-NR) with pembrolizumab versus 10.4 (95% CI 6.3-22.0) months with chemotherapy (hazard ratio [HR] 0.56, 95% CI 0.26-1.20). Median OS was NR (range 13.8 months-NR) versus 30.0 (14.7-NR) months (HR 0.65, 95% CI 0.27-1.55) and ORR was 50% (95% CI 28-72) versus 46% (95% CI 27-67). Grade 3/4 treatment-related adverse events (TRAEs) were reported by two patients (9%) in the pembrolizumab arm and 20 (80%) in the chemotherapy arm. Immune-mediated adverse events or infusion reactions were reported by six patients (27%) and 10 patients (40%), respectively. No deaths due to TRAEs occurred. These data support first-line pembrolizumab as a standard of care for patients from Asia with MSI-H/dMMR mCRC. ClinicalTrials.gov identifier: NCT02563002.

Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer.

BACKGROUND: Programmed death 1 (PD-1) blockade has clinical benefit in microsatellite-instability-high (MSI-H) or mismatch-repair-deficient (dMMR) tumors after previous therapy. The efficacy of PD-1 blockade as compared with chemotherapy as first-line therapy for MSI-H-dMMR advanced or metastatic colorectal cancer is unknown. METHODS: In this phase 3, open-label trial, 307 patients with metastatic MSI-H-dMMR colorectal cancer who had not previously received treatment were randomly assigned, in a 1:1 ratio, to receive pembrolizumab at a dose of 200 mg every 3 weeks or chemotherapy (5-fluorouracil-based therapy with or without bevacizumab or cetuximab) every 2 weeks. Patients receiving chemotherapy could cross over to pembrolizumab therapy after disease progression. The two primary end points were progression-free survival and overall survival. RESULTS: At the second interim analysis, after a median follow-up (from randomization to data cutoff) of 32.4 months (range, 24.0 to 48.3), pembrolizumab was superior to chemotherapy with respect to progression-free survival (median, 16.5 vs. 8.2 months; hazard ratio, 0.60; 95% confidence interval [CI], 0.45 to 0.80; P = 0.0002). The estimated restricted mean survival after 24 months of follow-up was 13.7 months (range, 12.0 to 15.4) as compared with 10.8 months (range, 9.4 to 12.2). As of the data cutoff date, 56 patients in the pembrolizumab group and 69 in the chemotherapy group had died. Data on overall survival were still evolving (66% of required events had occurred) and remain blinded until the final analysis. An overall response (complete or partial response), as evaluated with Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, was observed in 43.8% of the patients in the pembrolizumab group and 33.1% in the chemotherapy group. Among patients with an overall response, 83% in the pembrolizumab group, as compared with 35% of patients in the chemotherapy group, had ongoing responses at 24 months. Treatment-related adverse events of grade 3 or higher occurred in 22% of the patients in the pembrolizumab group, as compared with 66% (including one patient who died) in the chemotherapy group. CONCLUSIONS: Pembrolizumab led to significantly longer progression-free survival than chemotherapy when received as first-line therapy for MSI-H-dMMR metastatic colorectal cancer, with fewer treatment-related adverse events. (Funded by Merck Sharp and Dohme and by Stand Up to Cancer; KEYNOTE-177 ClinicalTrials.gov number, NCT02563002.).

Wealth inequalities in physical and cognitive impairments across Japan and Europe: the role of health expenditure and infrastructure.

Although prior research has provided insights into the association between country-level factors and health inequalities, key research gaps remain. First, most previous studies examine subjective rather than objective health measures. Second, the wealth dimension in health inequalities is understudied. Third, a handful of studies explicitly focus on older adults. To bridge these research gaps, this study measures wealth-related inequalities in physical and cognitive impairments and examines the extent to which welfare states moderate wealth inequalities in physical and cognitive impairments among older people across Japan and Europe. We utilized harmonized data on non-institutionalized individuals aged 50-75 from the Japanese Study of Aging and Retirement (JSTAR) and the Survey of Health, Ageing and Retirement in Europe (SHARE) (N = 31,969 for physical impairments and 31,348 for cognitive impairments). Our multilevel linear regression analyses examined whether national public health spending and healthcare access resources explained cross-country differences in wealth inequalities in physical and cognitive impairments. We applied a concentration index to quantify the degree of wealth inequalities in impairments. The findings indicate that inequalities in both impairment outcomes favored wealthier individuals in all countries, but the magnitude of inequality varied by country. Furthermore, a higher share of public health spending, lower out-of-pocket expenditure, and higher investment in healthcare resources were associated with lower wealth inequalities, especially for physical impairments. Our findings suggest that different health interventions and policies may be needed to mitigate specific impairment inequalities.

Incidence of fish-borne trematode infections and associated factors: results from a cohort study in highly endemic communities in northern Vietnam.

Fish-borne trematodes (FiBT) are an important group of zoonotic parasites negatively affecting human health, mainly in Asia. Most studies on FiBT have applied a cross-sectional design, which provides weaker evidence on potential risk factors for transmission than a cohort study. This cohort study aimed to estimate the incidence and identify associated risk factors for FiBT infection in Vietnam. Between April 2018 and May 2019, two communes in Yen Bai province, a highly endemic area for FiBT, were visited for sampling. Participants with a negative stool result for FiBT at baseline, were invited for follow-up and data collection, at months 4, 9, and 13. Stools were examined using Kato-Katz and formalin-ethyl acetate concentration techniques to detect FiBT eggs, whereas a questionnaire was used for interviewing participants to determine the risk factors for FiBT infection during each follow-up period. The incidence risk and the incidence rate were calculated, and univariate and multivariable models were run to identify the risk factors for FiBT. A total of 194 people, negative for FiBT eggs at the baseline survey, were invited to participate in the study, and 111 people agreed to enroll in the follow-up. The incidence risk at months 4, 9, and 13 was 9.0%, 6.4%, and 5.1%, respectively. We finally used data from 95 participants for the risk factor analysis, excluding 16 people lost for the follow-up. Overall, 20 people became infected with FiBT (IR = 21.1%). The incidence rate of FiBT infection was 21.4/100 person-year. In the univariate analysis, consumption of raw fish was the main risk factor (RR = 4.59, 95%CI = 1.95-10.82), followed by being male (RR = 3.41, 95%CI = 1.56-7.45) and drinking alcohol (RR = 3.25, 95%CI = 1.49-7.11). In the multivariable analysis, only consumption of raw-fish dishes was significantly associated with FiBT infection. The people who consumed raw fish were 3.44 (95%CI = 1.11-10.70) times more at risk of infection with FiBT as compared to individuals who did not consume raw fish. It can be concluded that the FiBT incidence is high in the study area. More awareness campaigns are needed to stop eating raw fish in these areas to reduce FBT infection.

The role of capital structure management in maintaining the financial stability of hotel firms during the pandemic-A global investigation.

Due to the detrimental effects of the Covid-19 pandemic on the hotel sector, pandemic crisis management research has received lots of academic attention, from studies in sales-marketing to human resource management. However, financial management has been largely overlooked in the agenda of pandemic crisis management and hotel resilience. Therefore, this paper aims to address the research gap by exploring the role of capital structure management in maintaining financial stability and resilience capacities of hotel firms during this evolving and unpredictable Covid-19 pandemic. Using a database of 1882 firm-quarter observations of 196 hotel firms in 30 countries from Quarter 3 2018 to Quarter 2 2021, it is found that low debt capital structure mitigates the adverse impact of the pandemic on hotel firms' financial stability during this turbulent time; particularly the negative impacts caused by government restrictions on both domestic and international travel. The benefit of low debt levels is more pronounced for more vulnerable hotels such as small, less diversified, and slow growing hotel firms. Also, hotel firms that have less long-term debt are more financial stable and resilient during pandemic period. Research outcomes suggest that financial management, in particular capital structure policies should be a critical part of hotel resilience building and crisis management strategy for hotel firms.

Switchable Organocatalysis from N-heterocyclic Carbene-Carbodiimide Adducts with Tunable Release Temperature.

N-Heterocyclic carbenes (NHCs) are powerful organocatalysts, but practical applications often require in situ generation from stable precursors that "mask" the NHC reactivity via reversible binding. Previously established "masks" are often simple small molecules, such that the NHC structure is used to control both catalytic activity and activation temperature, leading to undesirable tradeoffs. Herein, we show that NHC-carbodiimide (CDI) adducts can be masked precursors for switchable organocatalysis and that the CDI substituents can control the reaction profile without changing the NHC structure. Large electronic variations on the CDI (e.g., alkyl versus aryl) drastically change the catalytically active temperature, whereas smaller perturbations (e.g., different para-substituted phenyls) tune the catalyst release within a narrower window. This control was demonstrated for three classic NHC-catalyzed reactions, each influencing the NHC-CDI equilibrium in different ways. Our results introduce a new paradigm for controlling NHC organocatalysis as well as present practical considerations for designing appropriate masks for various reactions.

Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): final analysis of a randomised, open-label, phase 3 study.

BACKGROUND: Pembrolizumab has shown improved progression-free survival versus chemotherapy in patients with newly diagnosed microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. However, the treatment's effect on overall survival in this cohort of patients was unknown. Here, we present the final overall survival analysis of the KEYNOTE-177 study. METHODS: This randomised, open-label, phase 3 study was done in 193 academic medical centres and hospitals in 23 countries. We recruited patients aged at least 18 years, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and who had previously untreated microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. Patients were randomly assigned (1:1) in blocks of four using an interactive voice response system or integrated web response system to intravenous pembrolizumab 200 mg every 3 weeks or to the investigator's choice of intravenous mFOLFOX6 (oxaliplatin 85 mg/m2 on day 1, leucovorin 400 mg/m2 on day 1, and fluorouracil 400 mg/m2 bolus on day 1 followed by a continuous infusion of 1200 mg/m2 per day for 2 days on days 1-2) or intravenous FOLFIRI (irinotecan 180 mg/m2 on day 1, leucovorin 400 mg/m2 on day 1, and fluorouracil 400 mg/m2 bolus on day 1 followed by a continuous infusion of 1200 mg/m2 per day for 2 days on days 1-2), every 2 weeks with or without intravenous bevacizumab 5 mg/kg every 2 weeks or intravenous weekly cetuximab (first dose 400 mg/m2, then 250 mg/m2 for every subsequent dose). Patients receiving chemotherapy could cross over to pembrolizumab for up to 35 treatment cycles after progression. The co-primary endpoints were overall survival and progression-free survival in the intention-to-treat population. KEYNOTE-177 is registered at ClinicalTrials.gov, NCT02563002, and is no longer enrolling patients. FINDINGS: Between Feb 11, 2016, and Feb 19, 2018, 852 patients were screened, of whom 307 (36%) were randomly assigned to pembrolizumab (n=153) or chemotherapy (n=154). 93 (60%) patients crossed over from chemotherapy to anti-PD-1 or anti-PD-L1 therapy (56 patients to on-study pembrolizumab and 37 patients to off-study therapy). At final analysis (median follow-up of 44·5 months [IQR 39·7-49·8]), median overall survival was not reached (NR; 95% CI 49·2-NR) with pembrolizumab vs 36·7 months (27·6-NR) with chemotherapy (hazard ratio [HR] 0·74; 95% CI 0·53-1·03; p=0·036). Superiority of pembrolizumab versus chemotherapy for overall survival was not demonstrated because the prespecified α of 0·025 needed for statistical significance was not achieved. At this updated analysis, median progression-free survival was 16·5 months (95% CI 5·4-38·1) with pembrolizumab versus 8·2 months (6·1-10·2) with chemotherapy (HR 0·59, 95% CI 0·45-0·79). Treatment-related adverse events of grade 3 or worse occurred in 33 (22%) of 153 patients in the pembrolizumab group versus 95 (66%) of 143 patients in the chemotherapy group. Common adverse events of grade 3 or worse that were attributed to pembrolizumab were increased alanine aminotransferase, colitis, diarrhoea, and fatigue in three (2%) patients each, and those attributed to chemotherapy were decreased neutrophil count (in 24 [17%] patients), neutropenia (22 [15%]), diarrhoea (14 [10%]), and fatigue (13 [9%]). Serious adverse events attributed to study treatment occurred in 25 (16%) patients in the pembrolizumab group and in 41 (29%) patients in the chemotherapy group. No deaths attributed to pembrolizumab occurred; one death due to intestinal perforation was attributed to chemotherapy. INTERPRETATION: In this updated analysis, although pembrolizumab continued to show durable antitumour activity and fewer treatment-related adverse events compared with chemotherapy, there was no significant difference in overall survival between the two treatment groups. These findings support pembrolizumab as an efficacious first-line therapy in patients with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. FUNDING: MSD.

DNA fingerprinting reveals varietal composition of Vietnamese cassava germplasm (Manihot esculenta Crantz) from farmers' field and genebank collections.

KEY MESSAGE: A molecular analysis using informative SNP markers in 1570 clones of cassava from Vietnam reveals varietal composition from farmers' field and genebank collections Cassava is the most important smallholder cash crops in Southeast Asia and is especially used in industrial products. Yet, systematic genetic studies on molecular markers from Vietnamese germplasm have not been considered for breeding and conservation programs. We conducted a molecular analysis of 1570 clones of cassava germplasm from farms across six agro-ecological zones using informative SNP markers. We unraveled the genetic diversity and population structure and provided insights into the value of breeding and conservation programs. Duplicated genotypes comprised 98% of the total sample of the Central Highlands region. Ninety-six SNPs were amplified Central Highlands and South East provinces had the highest allelic richness, covering up to 83% of alleles. The average observed heterozygosity (Ho = 0.43) was slightly higher than expected (He = 0.40) across SNP markers, suggesting an excess of heterozygotes plants. Diversity indexes indicated that cassava populations from North West and Eastern Vietnam are genetically diverse (mean He = 0.40). Genetic parentage tests identified 85 unique genetic groups within the varieties KM94, KM419, BRA1305, KM101, KM140, PER262, KM60, KM57 and two unidentified varieties, which accounted for 82% of the frequency distribution. KM94 is the most dominant variety in Vietnamese farms surveyed (38%), reflecting its superior quality and productivity. Discriminant analysis of principal components (DAPC) revealed four main subgroups, which were partially corroborated by neighbor joining (NJ) analyses. After removing duplicates, 31 unique genotypes were distributed across five of the agro-ecological zones. These were well distributed in the subgroups revealed via DAPC and NJ analyses. The genetic groups identified herein could be used to select unique accessions that should ideally conform with ex situ germplasm collections and identify areas where on-farm conservation programs should be targeted. Newly identified genotypes may also contribute as genetic breeding resources that could be used to adapt cassava to future changes and farmers' needs.

Neoadjuvant Stereotactic Body Radiotherapy After Upfront Chemotherapy Improves Pathologic Outcomes Compared With Chemotherapy Alone for Patients With Borderline Resectable or Locally Advanced Pancreatic Adenocarcinoma Without Increasing Perioperative Toxicity.

BACKGROUND: Patients with borderline resectable pancreatic cancer (BRPC) or locally advanced pancreatic cancer (LAPC) are at high risk of margin-positive resection. Neoadjuvant stereotactic body radiation therapy (SBRT) may help sterilize margins, but its additive benefit beyond neoadjuvant chemotherapy (nCT) is unclear. The authors report long-term outcomes for BRPC/LAPC patients explored after treatment with either nCT alone or nCT followed by five-fraction SBRT (nCT-SBRT). METHODS: Patients with BRPC or LAPC from 2011 to 2016 who underwent resection after nCT alone or nCT-SBRT were retrospectively reviewed. Baseline characteristics were compared, and the propensity score with inverse probability weighting (IPW) was used to compare pathologic/survival outcomes. RESULTS: Of 198 patients, 76 received nCT, and 122 received nCT-SBRT. The nCT-SBRT cohort had a higher proportion of LAPC (53% vs 22%; p < 0.001). The duration of nCT was longer for nCT-SBRT (4.6 vs 2.9 months; p = 0.03), but adjuvant chemotherapy was less frequently administered (53% vs 67.1%; p < 0.001). Adjuvant radiation was administered to 30% of the nCT patients. The nCT-SBRT regimen more frequently achieved negative margins (92% vs 70%; p < 0.001), negative nodes (59% vs 42%; p < 0.001), and pathologic complete response (7% vs 0%; p = 0.02). In the multivariate analysis, nCT-SBRT remained associated with R0 resection (p < 0.001). The nCT-SBRT cohort experienced no significant difference in median overall survival (OS) (22.1 vs 24.5 months), local progression-free survival (LPFS) (13.5 vs. 15.4 months), or distant metastasis-free survival (DMFS) (11.7 vs 16.3 months) after surgery. After SBRT, 1-year OS was 77.0% and 2-year OS was 50.4%. Perioperative Claven-Dindo grade 3 or greater morbidity did not differ significantly between the nCT and nCT-SBRT cohorts (p = 0.81). CONCLUSIONS: Despite having more advanced disease, the nCT-SBRT cohort was still more likely to undergo an R0 resection and experienced similar survival outcomes compared with the nCT alone cohort.

Significant Vision Recovery from Filler-Induced Complete Blindness with Combined Intra-Arterial Injection of Hyaluronidase and Thrombolytic Agents.

With the increase of cosmetic injectable hyaluronic acid (HA), there have been more cases with serious complications, including skin necrosis, blindness, and cerebral embolism. Patients who have recovered from HA filler-induced total vision loss are extremely rare. We report a case of a 27-year-old female who developed severe ocular pain on the right side and total vision loss following a 1.0 ml HA filler injection in the nasal dorsum. She arrived at our hospital 4 hours later. Her visual acuity was no light perception (NLP), and she exhibited eyelid ptosis, ophthalmoplegia, and frontal and nasal ecchymosis. She was promptly treated with subcutaneous and retrobulbar hyaluronidase injections, as well as intra-arterial 1500 IU hyaluronidase injections into the right ophthalmic artery with DSA assistance. Her vision improved from NLP to counting fingers at 1.0 meters. Unfortunately, 13 hours later, she felt an intense headache, and her vision again decreased to NLP. We immediately performed an injection of 1500 IU hyaluronidase combined with 8 mg alteplase for intra-arterial thrombolysis (IAT) into the right ophthalmic artery. Her vision improved immediately afterward. After 3 months, her visual acuity had significantly recovered from NLP (admission vision status) to 20/50 (Snellen chart with glasses). Similarly, skin, conjunctival, eye movement, and ptosis symptoms completely recovered. This case demonstrates that reversal of complete blindness due to embolism of the ophthalmic and central retinal arteries could be accomplished through multidisciplinary therapies, especially IAT using fibrinolytic agents combined with hyaluronidase followed by an anticoagulant regimen.Level of evidence VThis journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine Ratings, please refer to Table of Contents or online Instructions to Authors www.springer.com/00266 .

Health-related quality of life in patients with microsatellite instability-high or mismatch repair deficient metastatic colorectal cancer treated with first-line pembrolizumab versus chemotherapy (KEYNOTE-177): an open-label, randomised, phase 3 trial.

BACKGROUND: In the KEYNOTE-177 study, pembrolizumab monotherapy provided statistically significant and clinically meaningful improvements in progression-free survival versus chemotherapy as first-line treatment in patients with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. To further support the efficacy and safety findings of the KEYNOTE-177 study, results of the health-related quality of life (HRQOL) analyses are reported here. METHODS: KEYNOTE-177 is an open-label, randomised, phase 3 trial being done at 192 cancer centres in 23 countries, in patients aged 18 years and older with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and who had not received previous systemic therapy for metastatic disease. Eligible patients were randomly assigned (1:1) centrally by use of interactive voice response or integrated web response technology to receive pembrolizumab 200 mg intravenously every 3 weeks or investigator's choice chemotherapy (mFOLFOX6 [leucovorin, fluorouracil, and oxaliplatin] or FOLFIRI [leucovorin, fluorouracil, and irinotecan] intravenously every 2 weeks with or without intravenous bevacizumab or cetuximab). Patients and investigators were not masked to treatment assignment. The primary endpoints were progression-free survival (previously reported) and overall survival (data to be reported at the time of the final analysis). HRQOL outcomes were evaluated as prespecified exploratory endpoints. The analysis population comprised all randomly assigned patients who received at least one dose of study treatment and completed at least one HRQOL assessment. HRQOL outcomes were mean change from baseline to prespecified week 18 in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and EORTC Quality of Life Questionnaire-Colorectal 29 (EORTC QLQ-CR29) scale and item scores, and in the EuroQoL 5 Dimensions 3 Levels (EQ-5D-3L) visual analogue scale and health utility scores; the proportion of patients with improved, stable, or deteriorated scores from baseline to prespecified week 18 in EORTC QLQ-C30 scales and items; and time to deterioration in EORTC QLQ-C30 global health status/quality of life (GHS/QOL), physical functioning, social functioning, and fatigue scores and EORTC QLQ-CR29 urinary incontinence scores. The threshold for a small and clinically meaningful mean difference in EORTC QLQ-C30 score was 5-8 points. This study is registered with ClinicalTrials.gov, NCT02563002 and is ongoing; recruitment is closed. FINDINGS: Between Feb 11, 2016, and Feb 19, 2018, 307 patients were enrolled and randomly assigned to receive pembrolizumab (n=153) or chemotherapy (n=154). The HRQOL analysis population comprised 294 patients (152 receiving pembrolizumab and 142 receiving chemotherapy). As of Feb 19, 2020, median time from randomisation to data cutoff was 32·4 months (IQR 27·7-37·8). Least squares mean (LSM) change from baseline to prespecified week 18 showed a clinically meaningful improvement in EORTC QLQ-C30 GHS/QOL scores with pembrolizumab versus chemotherapy (between-group LSM difference 8·96 [95% CI 4·24-13·69]; two-sided nominal p=0·0002). Median time to deterioration was longer with pembrolizumab versus chemotherapy for GHS/QOL (hazard ratio 0·61 [95% CI 0·38-0·98]; one-sided nominal p=0·019), physical functioning (0·50 [95% CI 0·32-0·81]; one-sided nominal p=0·0016), social functioning (0·53 [95% CI 0·32-0·87]; one-sided nominal p=0·0050), and fatigue scores (0·48 [95% CI 0·33-0·69]; one-sided nominal p<0·0001). INTERPRETATION: Pembrolizumab monotherapy led to clinically meaningful improvements in HRQOL compared with chemotherapy in patients with previously untreated microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. These data, along with the previously reported clinical benefits, support pembrolizumab as a first-line treatment option for this population. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co, Kenilworth, NJ, USA.

Increased Burden of Concordant and Sequential Anogenital Human Papillomavirus Infections Among Asian Young Adult Women With Perinatally Acquired HIV Compared With HIV-Negative Peers.

BACKGROUND: Youth with perinatally acquired HIV (YPHIV) are at higher risk for anogenital human papillomavirus (HPV) infection. METHODS: We enrolled a cohort of YPHIV and HIV-negative youth in Thailand and Vietnam, matched by age and lifetime sex partners, and followed them up for 144 weeks (to 2017). Participants had annual pelvic examinations with samples taken for HPV genotyping. Concordant infection was simultaneous HPV detection in multiple anogenital compartments (cervical, vaginal, anal); sequential infection was when the same type was found in successive compartments (cervicovaginal to/from anal). Generalized estimating equations were used to assess factors associated with concordant infection, and Cox regression was used to assess factors associated with sequential infection. RESULTS: A total of 93 YPHIV and 99 HIV-negative women were enrolled, with a median age of 19 years (interquartile range, 18-20 years). High-risk anogenital HPV infection was ever detected in 76 (82%) YPHIV and 66 (67%) HIV-negative youth during follow-up. Concordant anogenital high-risk HPV infection was found in 62 (66%) YPHIV versus 44 (34%) HIV-negative youth. Sequential cervicovaginal to anal high-risk HPV infection occurred in 20 YPHIV versus 5 HIV-negative youth, with an incidence rate of 9.76 (6.30-15.13) versus 2.24 (0.93-5.38) per 100 person-years. Anal to cervicovaginal infection occurred in 4 YPHIV versus 0 HIV-negative women, with an incidence rate of 1.78 (0.67-4.75) per 100 person-years. Perinatally acquired HIV was the one factor independently associated with both concordant and sequential high-risk HPV infection. CONCLUSIONS: Children and adolescents with perinatally acquired HIV should be prioritized for HPV vaccination, and cervical cancer screening should be part of routine HIV care for sexually active YPHIV.

Massively parallel sequencing of human skeletal remains in Vietnam using the precision ID mtDNA control region panel on the Ion S5™ system.

Mitochondrial DNA (mtDNA) analysis using Sanger sequencing has been a routine practice for the identification of human skeletal remains. However, this process is usually challenging since DNA from the remains is highly degraded and at low concentration. Recently, the advent and implementation of massively parallel sequencing (MPS) have been offered the ability to improve mtDNA sequence data for forensic analysis. To assess the utility of the Ion S5™ system - an MPS platform for mtDNA analysis in challenging samples, we sequenced the mitochondrial control region of 52 age-old skeletal remains. Using the Precision ID mtDNA Control Region Panel, 50 full and two partial control region haplotypes at relatively high mean coverage of 2494 × were achieved for variant calling. Further variant analysis at 10% threshold for point heteroplasmy showed high degradation degree in terms of DNA damage in our bone samples. A higher point heteroplasmy threshold of 20% was required to diminish most of background noise caused by the damage. The results from this study indicated the potential application of the Ion S5™ system in sequencing degraded samples in Vietnam and provided valuable data sources for forensic analyses in the future.

Respiratory microbes detected in hospitalized adults with acute respiratory infections: associations between influenza A(H1N1)pdm09 virus and intensive care unit admission or fatal outcome in Vietnam (2015-2017).

BACKGROUND: Acute respiratory tract infection (ARI) is a leading cause of hospitalization, morbidity, and mortality worldwide. Respiratory microbes that were simultaneously detected in the respiratory tracts of hospitalized adult ARI patients were investigated. Associations between influenza A(H1N1)pdm09 virus (H1N1pdm) detection and intensive care unit (ICU) admission or fatal outcome were determined. METHODS: This prospective observational study was conducted between September 2015 and June 2017 at Bach Mai Hospital, Hanoi, Vietnam. Inclusion criteria were hospitalized patients aged ≥15 years; one or more of symptoms including shortness of breath, sore throat, runny nose, headache, and muscle pain/arthralgia in addition to cough and fever > 37.5 °C; and ≤ 10 days from the onset of symptoms. Twenty-two viruses, 11 bacteria, and one fungus in airway specimens were examined using a commercial multiplex real-time PCR assay. Associations between H1N1pdm detection and ICU admission or fatal outcome were investigated by univariate and multivariate logistic regression analyses. RESULTS: The total of 269 patients (57.6% male; median age, 51 years) included 69 ICU patients. One or more microbes were detected in the airways of 214 patients (79.6%). Single and multiple microbes were detected in 41.3 and 38.3% of patients, respectively. Influenza A(H3N2) virus was the most frequently detected (35 cases; 13.0%), followed by H1N1pdm (29 cases; 10.8%). Hematological disease was associated with ICU admission (p < 0.001) and fatal outcomes (p < 0.001) using the corrected significance level (p = 0.0033). Sex, age, duration from onset to sampling, or number of detected microbes were not significantly associated with ICU admission or fatal outcomes. H1N1pdm detection was associated with ICU admission (odds ratio [OR] 3.911; 95% confidence interval [CI] 1.671-9.154) and fatal outcome (OR 5.496; 95% CI 1.814-16.653) after adjusting for the confounding factors of comorbidities, bacteria/Pneumocystis jirovecii co-detection, and age. CONCLUSIONS: H1N1pdm was associated with severe morbidity and death in adult patients hospitalized with respiratory symptoms. The diagnosis of subtype of influenza virus may be epidemiologically important.

Comparison of the Stanford ECG Left Atrial Criteria With the International ECG Criteria for Sports Screening.

OBJECTIVE: Because the International left atrial enlargement electrocardiographic (ECG) screening criteria (ECG-LAE) for athletes are rarely fulfilled in young athletes, we compared it with evidence-based criteria from a recent clinical outcome study of ECG left atrial abnormality (ECG-LAA). DESIGN: Retrospective analyses. SETTING: Routine preparticipation ECG screening in California. PARTICIPANTS: Four thousand four hundred thirty-eight young individuals (18.5 ± 5.4 years, 40% women). ASSESSMENT OF RISK FACTORS: The International criteria for ECG-LAE were applied: prolonged P wave duration of ≥120 ms in leads I or II AND negative portion of ≥1 mm in depth in lead V1. This was compared with Stanford criteria for ECG-LAA: prolonged P wave duration of ≥140 ms odds ratio (OR) negative portion in V1 and V2 greater than 1 mm. MAIN OUTCOME MEASURES: Differences in the classification of abnormal ECGs between the 2 criteria applied to the same population of young athletes. RESULTS: Only 33 (0.7%) of our subjects fulfilled the International criteria for ECG-LAE while 110 (2.5%) fulfilled the ECG-LAA criteria. Adding our new ECG-LAA criterion and considering it a major criterion raised the abnormal ECG prevalence and athletes referred for further evaluation from 2.9% to 4.4%. CONCLUSIONS: The Stanford evidence-based criterion for ECG-LAA incorporating V2 and replacing "or" for "and" regarding P wave duration increased the yield of abnormal classification for P waves. Future follow-up studies are needed to confirm that this new criterion should be included in future ECG screening consensus documents.

Population, Virulence, and Mycotoxin Profile of Fusarium spp. Associated With Basal Rot of Allium spp. in Vietnam.

Fusarium basal rot (FBR) is particularly problematic to Allium producers worldwide. In Vietnam, information on the profile of FBR is scarce, even though the presence of Fusarium spp. in Allium plants has long been recorded. In this study, a total of 180 isolates of Fusarium spp. were recovered from Allium bulbs/plants showing symptoms of FBR in 34 commercial Allium fields around Da Lat, Lam Dong, Vietnam. These isolates were identified to the species level by sequencing the internal transcribed spacer region and the translation elongation factor 1α gene. F. oxysporum was most prevalent (81%) in samples from all locations and Allium varieties, followed by F. solani (15%) and F. proliferatum (4%), which were only found in onion (Allium cepa L.). Pathogenicity tests on onion seedlings (56 isolates) and mini bulbs (10 isolates) indicated that onion can be infected by all of these species but virulence varied greatly between isolates. Moreover, isolates that were virulent on seedlings were sometimes not virulent on bulbs and vice versa, which points to a specialization of isolates for the host phenology. Mycotoxin analyses showed that the highest amounts of beauvericin were detected in seedlings and bulbs infected by F. oxysporum, whereas F. proliferatum was mainly responsible for the presence of fumonisin B1 in bulbs, suggesting a natural occurrence of beauvericin and fumonisin B1 in onions infected by these pathogens.

The Drought-Mediated Soybean GmNAC085 Functions as a Positive Regulator of Plant Response to Salinity.

Abiotic stress factors, such as drought and salinity, are known to negatively affect plant growth and development. To cope with these adverse conditions, plants have utilized certain defense mechanisms involved in various aspects, including morphological, biochemical and molecular alterations. Particularly, a great deal of evidence for the biological importance of the plant-specific NAM, ATAF1/2, CUC2 (NAC) transcription factors (TFs) in plant adaptation to abiotic stress conditions has been reported. A previous in planta study conducted by our research group demonstrated that soybean (Glycine max) GmNAC085 mediated drought resistance in transgenic Arabidopsis plants. In this study, further characterization of GmNAC085 function in association with salt stress was performed. The findings revealed that under this condition, transgenic soybean plants overexpressing GmNAC085 displayed better germination rates than wild-type plants. In addition, biochemical and transcriptional analyses showed that the transgenic plants acquired a better defense system against salinity-induced oxidative stress, with higher activities of antioxidant enzymes responsible for scavenging hydrogen peroxide or superoxide radicals. Higher transcript levels of several key stress-responsive genes involved in the proline biosynthetic pathway, sodium ion transporter and accumulation of dehydrins were also observed, indicating better osmoprotection and more efficient ion regulation capacity in the transgenic lines. Taken together, these findings and our previous report indicate that GmNAC085 may play a role as a positive regulator in plant adaptation to drought and salinity conditions.