Intra-individual comparison of prostate-specific membrane antigen positron emission tomography/computed tomography versus bone scan in detecting skeletal metastasis at prostate cancer diagnosis.

OBJECTIVES: To compare the diagnostic performance and radiological staging impact of 68 Ga-prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) compared to 99 Tc whole-body bone scan (WBBS) for the detection of skeletal metastasis in the primary staging of prostate cancer (PCa). PATIENTS AND METHODS: A prospective institutional database was retrospectively examined for patients who underwent both PSMA PET and WBBS within a 1 week interval for PCa primary staging. Lesions were categorised as 'negative', 'equivocal', or 'definite' based on nuclear medicine physician interpretation. Metastatic burden was characterised for each imaging modality according to three groups: (i) local disease (no skeletal metastases), (ii) oligometastatic disease (three or fewer skeletal metastases), or (iii) polymetastatic disease (more than three skeletal metastases). RESULTS: There were 667 patients included. The median (interquartile range) prostate-specific antigen level was 9.2 (6.2-16) ng/mL and 60% of patients were high risk according to a modified D'Amico risk classification. The overall distribution of skeletal metastasis detection changed across the two scans overall (P = 0.003), being maintained within high-risk (P = 0.030) and low-risk (P = 0.018) groups. PSMA PET/CT identified more definite skeletal metastases compared to WBBS overall (10.3% vs 7.3%), and according to risk grouping (high: 12% vs 9%, intermediate: 4% vs 1%). Upstaging was more common with PSMA PET/CT than WBBS (P = 0.001). The maximum standardised uptake value (SUVmax ) of the primary tumour was associated with upstaging of skeletal metastases on PSMA PET/CT (P = 0.025), while age was associated with upstaging on WBBS (P = 0.021). The SUVmax of the primary tumour and metastases were both higher according to extent of metastatic disease (P = 0.001 and P < 0.001, respectively). CONCLUSIONS: More skeletal metastases were detected with PSMA PET/CT than WBBS, resulting in a higher upstaging rate mostly in high-risk patients. The SUVmax of the primary tumour and metastases was associated with upstaging.

Unraveling reproductive and maternal health challenges of women living with HIV/AIDS in Vietnam: a qualitative study.

BACKGROUND: Human Immunodeficiency Virus (HIV) remains a significant public health concern worldwide. Women living with HIV/AIDS (WLHA) have the additional and unique need to seek sexual and reproductive health services. WLHA's maternal health journeys can be shaped by the cultural norms and resources that exist in their society. This study sought to understand if and how WLHA's family planning, pregnancy, and motherhood experiences could be influenced by the patriarchal culture, gender roles, and HIV stigma in Vietnam, specifically. METHODS: Between December 2021 and March 2022, 30 WLHA with diverse socioeconomic backgrounds and childbirth experiences were interviewed in Hanoi, Vietnam. These semi-structured interviews covered topics including HIV stigma, gender norms, pregnancy experiences, and child-rearing challenges. Interviews were audio recorded, transcribed, and analysed using ATLAS.ti. RESULTS: Qualitative analyses of participant quotes revealed how limited information on one's health prospects and reproductive options posed a significant challenge to family planning. Societal and familial expectations as well as economic circumstances also influenced reproductive decision-making. WLHA often encountered substandard healthcare during pregnancy, labor, and delivery. Stigma and lack of provider attentiveness resulted in cases where women were denied pain relief and other medical services. Communication breakdowns resulted in failure to administer antiretroviral therapy for newborns. Motherhood for WLHA was shadowed by concerns for not only their own health, but also the wellbeing of their children, as HIV stigma affected their children at school and in society as well. Many WLHA highlighted the constructive or destructive role that family members could play in their childbirth decision-making and care-giving experiences. CONCLUSIONS: Overall, this study underscores the complex ways that cultural expectations, family support, and stigma in healthcare impact WLHA. Efforts to educate and engage families and healthcare providers are warranted to better understand and address the needs of WLHA, ultimately improving their reproductive and maternal health.

HIV-related stigma and discrimination have consequential impacts on health and quality of life for women living with HIV (WLHA). WLHA in Vietnam must navigate the additional challenges of a traditionally patriarchal and hierarchical society. Women typically face less educational and occupational opportunities and are often expected to defer to expectations of family and virtue. Stigma among family members, friends, employers, and healthcare providers poses a significant challenge to WLHA autonomy, especially as it relates to their reproductive health decision-making and maternal health experiences. This study aims to better understand the experiences of WLHA throughout family planning, pregnancy, and motherhood. The findings will hopefully shed light on strategies to empower WLHA and to combat HIV- and gender-based stigma not only in Vietnam, but also globally.

Navigating cultural and gender aspects of stigma among women living with HIV in Vietnam.

Women living with HIV often face intersecting challenges of stigma and gender inequality. In Vietnam, this issue is potentially exacerbated by the patriarchal culture. From December 2021 to March 2022, we conducted in-depth interviews with 30 women living with HIV in Hanoi to better understand their experiences and the coping mechanisms to navigate HIV stigma, cultural beliefs and gender norms. The interviews explored various topics including women's social and family roles in Vietnam, HIV-related beliefs, stigma and its impact on one's health and coping strategies. Participants reported stereotypes that assumed that women living with HIV had either engaged in sex work or behaved promiscuously. These stereotypes render them vulnerable to judgement and discrimination owing to widespread expectations of female virtue. As a result, women living with HIV often enacted non-disclosure and self-isolation to avoid stigma. This self-stigmatisation negatively impacted their healthcare-seeking, employment opportunities and ability to fulfil traditional family-caring roles. Conversely, many participants exhibited resilience with the support of family and peers. Overall, the complex interplay between gender, culture and HIV stigma underscores the importance of developing culturally appropriate, multifaceted approaches to engaging family and peers, modifying gender-based discriminatory social practices and enhancing women's self-efficacy and empowerment in Vietnam.

Poly(N-Heterocyclic Carbene)-Capped Alloy and Core-Shell AuAg Bimetallic Nanoparticles.

N-Heterocyclic carbene (NHC)-stabilized metal nanoparticles (NPs) have recently attracted considerable attention. While most efforts in the field have been devoted to the development of NHC-tethered monometallic NPs and enhancing their stabilities under various conditions, their bimetallic counterparts are rare in the literature. Herein, we demonstrate that the covalent immobilization of Au and Ag atoms on polymerized NHCs is a powerful method to access bimetallic AuAg NPs. In addition, we show that while AuAg alloy NPs are often obtained via this method, the use of bimetallic polymeric substrates with lower Ag content, relative to Au, results in the formation of core-shell NPs with Au core and Ag shell. Application of these nanomaterials for oxygen reduction reaction is demonstrated with all materials exhibiting electrocatalytic activity. This work demonstrates for the first time that while bimetallic poly(NHC-metal)s are viable substrates to access NHC-stabilized bimetallic NPs, careful adjustment of metal content in the polymeric substrates can finetune the microstructure of the resulting NPs, i.e. alloy vs. core-shell.

Manipulating Fermentation Pathways in the Hyperthermophilic Archaeon Pyrococcus furiosus for Ethanol Production up to 95°C Driven by Carbon Monoxide Oxidation.

Genetic engineering of hyperthermophilic organisms for the production of fuels and other useful chemicals is an emerging biotechnological opportunity. In particular, for volatile organic compounds such as ethanol, fermentation at high temperatures could allow for straightforward separation by direct distillation. Currently, the upper growth temperature limit for native ethanol producers is 72°C in the bacterium Thermoanaerobacter ethanolicus JW200, and the highest temperature for heterologously-engineered bioethanol production was recently demonstrated at 85°C in the archaeon Pyrococcus furiosus. Here, we describe an engineered strain of P. furiosus that synthesizes ethanol at 95°C, utilizing a homologously-expressed native alcohol dehydrogenase, termed AdhF. Ethanol biosynthesis was compared at 75°C and 95°C with various engineered strains. At lower temperatures, the acetaldehyde substrate for AdhF is most likely produced from acetate by aldehyde ferredoxin oxidoreductase (AOR). At higher temperatures, the effect of AOR on ethanol production is negligible, suggesting that acetaldehyde is produced by pyruvate ferredoxin oxidoreductase (POR) via oxidative decarboxylation of pyruvate, a reaction known to occur only at higher temperatures. Heterologous expression of a carbon monoxide dehydrogenase complex in the AdhF overexpression strain enabled it to use CO as a source of energy, leading to increased ethanol production. A genome reconstruction model for P. furiosus was developed to guide metabolic engineering strategies and understand outcomes. This work opens the door to the potential for 'bioreactive distillation' since fermentation can be performed well above the normal boiling point of ethanol. IMPORTANCE Previously, the highest temperature for biological ethanol production was 85°C. Here, we have engineered ethanol production at 95°C by the hyperthermophilic archaeon Pyrococcus furiosus. Using mutant strains, we showed that ethanol production occurs by different pathways at 75°C and 95°C. In addition, by heterologous expression of a carbon monoxide dehydrogenase complex, ethanol production by this organism was driven by the oxidation of carbon monoxide. A genome reconstruction model for P. furiosus was developed to guide metabolic engineering strategies and understand outcomes.

Reliability of Self-Report Data on Age of Onset in Essential Tremor: Data from a Prospective, Longitudinal Cohort.

BACKGROUND: Essential tremor (ET) is a highly prevalent neurological disease. Age of onset can occur anytime between childhood and advanced age. Tremor generally starts insidiously. Age of onset is a particularly important data item in clinical and epidemiological research. In general, these data are self-reported by ET cases. A fundamental question is whether ET cases reliably report their age of onset. METHODS: In this prospective, epidemiological study of 125 ET cases, self-reported age of onset data were collected at regular 18 months intervals over four time points. RESULTS: The correlation between self-reported age of onset was high - intra-class correlation coefficient = 0.972 (95% confidence interval = 0.962-0.980, p < 0.001). However, agreement was not perfect. Approximately 20-25% of participant's reports at different time intervals differed by as much as 10 years, and approximately 10% of participant's reports differed by as much as 20 years. CONCLUSIONS: There was a robust correlation between self-reports of age of onset. Yet in a not-insignificant number of cases, there were considerable differences, some of which were substantial. These findings have broad implications for development of diagnostic algorithms, data stratification schemes, and analyses that assess correlations between biomarker data and clinical features (e.g., disease duration).

Monomeric and Polymeric Mesoionic N-Heterocyclic Carbene-Tethered Silver Nanoparticles: Synthesis, Stability, and Catalytic Activity.

In recent years, N-heterocyclic carbenes (NHCs) have garnered significant attention as promising alternatives to thiols to stabilize metallic nanoparticles and planar surfaces. While most studies thus far have focused on NHC-functionalized gold nanoparticles (AuNPs), as an ideal platform to investigate the role of NHCs in stabilizing such nanoparticles, their ability to protect more unstable coinage metal nanoparticles, such as silver nanoparticles (AgNPs), has been largely overlooked. This is despite the fact that AgNPs possess a much more sensitive optical response that, upon their enhanced stability, can broaden their scope of application in various fields, including nanomedicine and catalysis. In this study, the synthesis and use of monomeric and polymeric mesoionic NHC-Ag(I) complexes as precursors to mono- and multidentate NHC-tethered AgNPs are reported. The polymeric analog was obtained by first synthesizing a polymer, containing 1,2,3-triazole repeat units, employing the copper-catalyzed alkyne-azide cycloaddition click polymerization of monomers containing diazide- and dialkyne functional groups. Subsequent quaternization of the triazole moieties and Ag insertion yielded the target NHC-Ag-containing polymer. Using this polymer as well as its monomeric analog as substrates, AgNPs with either catenated networks of NHCs or monomeric NHCs were fabricated by their reduction using borane-tert-butylamine complex. Our stability studies demonstrate that while monomeric NHCs impart some degree of stability to AgNPs, particularly at elevated temperatures in aqueous as well as organic medium, their polymeric analogs further enhance their stability in acidic environment (pH = 2) and against glutathione (3 mM), as an example of a biologically relevant thiol, in aqueous media. To highlight the application of these NHC-functionalized AgNPs in catalysis, we explore the aqueous phase reduction of methyl orange and 4-nitrophenol.

Networking community health workers for service integration: role of social media.

Community health workers (CHW) can play an active role in providing integrated HIV and harm reduction services. We used social media to create a virtual network among Vietnamese CHW. This paper reports CHW's social media engagement and the relationships with other work-related indicators. Sixty CHW participated in an intervention for integrated HIV/drug use service delivery. Following two in-person sessions, Facebook groups were established for CHW to share information, seek consultation, and refer patients. CHW's levels of online engagements were tracked for six months and linked to their service provision confidence, interaction with patients and other providers, and job satisfaction. The CHW made 181 posts, which received 557 comments and 1,607 reactions during the six months. Among the 60 CHW, 22 (36.6%) had three or more posts, 19 (31.7%) had one or two posts, and 19 (31.7%) had no post. Comparing the baseline and 6-month follow-up data, we observed that those who posted three or more times showed better service provision confidence (p = 0.0081), more interaction with providers in other settings (p = 0.0071), and higher job satisfaction (p = 0.0268). Our study suggests using social media to engage CHW in virtual communications to improve service provision in communities.

Community Capacity Building for HIV and Addiction Service Integration: An Intervention Trial in Vietnam.

Scientific findings and policy guidelines recommend integrating HIV and drug addiction prevention and care into community-based settings. Systematic capacity-building efforts are warranted to provide technical support for community health workers and improve their confidence in the integrated service provision. An intervention trial was conducted between 2018 and 2019 with 120 community health workers (CHW) from 60 communes in Vietnam's four provinces. The 60 intervention CHW received in-person training to enhance their HIV/addiction-related service knowledge and skills. Online support groups were established between trained CHW and local HIV and addiction specialists. The intervention outcomes were assessed using mixed-effects regression models with the data collected at baseline and every 3 months for 1 year. Adjusted analyses showed that intervention CHW reported a significant increase in the interaction with other treatment providers than the control group at 6 months and remained at the 12-month follow-up. The difference in the improvement of confidence in HIV/addiction-related service delivery between the intervention and control groups was significant at 6-month but became insignificant at the 12-month. Male CHW were more confident in providing services than female CHW at baseline, and gender differences in the changing patterns were observed over time. This capacity-building intervention demonstrated promising outcomes on CHW inter-agency collaborations and confidence in service delivery. Gender divides in healthcare professionals should be attended to in future studies.

RESUMEN: Los hallazgos científicos y los protocolos recomiendan integrar la prevención del VIH y la adicción a las drogas en entornos comunitarios. Se implementan esfuerzos sistemáticos de creación de capacidad para brindar apoyo técnico a los trabajadores de salud comunitarios y mejorar su confianza en la prestación de servicios integrados. Se realizó una prueba de intervención entre 2018 y 2019 con 120 trabajadores de salud comunitarios (TSC) de 60 comunas en las cuatro provincias de Vietnam. Los 60 TSC de intervención recibieron capacitación en persona para mejorar sus conocimientos y habilidades de servicios relacionados con VIH / adicción. Se establecieron grupos de apoyo en línea entre TSC capacitados y especialistas locales en VIH y adicciones. Los resultados de la intervención se evaluaron mediante modelos de regresión de efectos mixtos con los datos recopilados al inicio del estudio y cada tres meses durante un año. Los análisis ajustados mostraron que la intervención CHW informó un aumento significativo en la interacción con proveedores de tratamiento diferentes al grupo de control a los seis meses que se mantuvo en el seguimiento a los 12 meses. La diferencia en el aumento de la confianza en la prestación de servicios relacionados con VIH / adicción entre los grupos de intervención y control fue significativa a los 6 meses, pero se volvió insignificante a los 12 meses. Los TSC masculinos tenían más confianza en la prestación de servicios que las femeninas al inicio del estudio, y se observaron diferencias de género en el cambio de patrones a lo largo del tiempo. Esta intervención de creación de capacidad demostró resultados prometedores en las colaboraciones interinstitucionales de los TSC y la confianza en la prestación de servicios. Las brechas de género en los profesionales de la salud deben ser atendidas en estudios futuros.

Gaps of Knowledge about HIV and Sexually Transmitted Infections Among Industrial Workers in Northern Vietnam.

Industrial workers are a vulnerable population for HIV and sexually transmitted infections (STIs). This cross-sectional study assessed the general knowledge about sexually transmitted infections (STIs) and HIV transmission risk among 289 industrial workers in Northern Vietnam. Results indicated that most workers could identify common routes of HIV transmissions and were aware of common STIs. However, insufficient knowledge about HIV transmission via anal sex practices, as well as common signs and symptoms of STIs were observed. Gender, marital status, education, locality status and health information sources were associated with the knowledge. This study reveals a gap of knowledge about HIV and other STIs, and suggested further tailored education interventions to improve the knowledge and promote sexual health-seeking behaviors in industrial workers.

The Capture of a Disabled Proteasome Identifies Erg25 as a Substrate for Endoplasmic Reticulum Associated Degradation.

Studies in the yeast Saccharomyces cerevisiae have helped define mechanisms underlying the activity of the ubiquitin-proteasome system (UPS), uncover the proteasome assembly pathway, and link the UPS to the maintenance of cellular homeostasis. However, the spectrum of UPS substrates is incompletely defined, even though multiple techniques-including MS-have been used. Therefore, we developed a substrate trapping proteomics workflow to identify previously unknown UPS substrates. We first generated a yeast strain with an epitope tagged proteasome subunit to which a proteasome inhibitor could be applied. Parallel experiments utilized inhibitor insensitive strains or strains lacking the tagged subunit. After affinity isolation, enriched proteins were resolved, in-gel digested, and analyzed by high resolution liquid chromatography-tandem MS. A total of 149 proteasome partners were identified, including all 33 proteasome subunits. When we next compared data between inhibitor sensitive and resistant cells, 27 proteasome partners were significantly enriched. Among these proteins were known UPS substrates and proteins that escort ubiquitinated substrates to the proteasome. We also detected Erg25 as a high-confidence partner. Erg25 is a methyl oxidase that converts dimethylzymosterol to zymosterol, a precursor of the plasma membrane sterol, ergosterol. Because Erg25 is a resident of the endoplasmic reticulum (ER) and had not previously been directly characterized as a UPS substrate, we asked whether Erg25 is a target of the ER associated degradation (ERAD) pathway, which most commonly mediates proteasome-dependent destruction of aberrant proteins. As anticipated, Erg25 was ubiquitinated and associated with stalled proteasomes. Further, Erg25 degradation depended on ERAD-associated ubiquitin ligases and was regulated by sterol synthesis. These data expand the cohort of lipid biosynthetic enzymes targeted for ERAD, highlight the role of the UPS in maintaining ER function, and provide a novel tool to uncover other UPS substrates via manipulations of our engineered strain.

Antimicrobial resistance tendency and collateral sensitivity of Staphylococcus aureus adapted to antibiotics or extracts of medicinal plants grown in Viet Nam.

Antimicrobial resistance has silently turned into one of the biggest threats to global health, marking the fall of the Golden age of antibiotics. In the search for antibiotic replacement or enhancement, plant-derived natural compounds have attracted lots of interest. Even though firmly believed, the low-resistance tendency of pathogenic bacteria against plant extracts has been scarcely demonstrated. In this study, we investigated the antibacterial activities of diethyl ether extracts from six medicinal plants grown in Viet Nam against Staphylococcus aureus and its variants, which were in vitro adapted to the same extracts. After 30 passages of S. aureus growing under sub-lethal concentrations of plant extracts or antibiotics, the bacteria slowly adapted to the extracts while rapidly resisting the antibiotics. Most of the resulting strains obtained from the adaptation to plant extracts were collaterally sensitive to antibiotics. In contrast, antibiotic-adapted strains showed cross-resistance to both antibiotics and extracts. The findings provided evidence of the low-resistance tendency of S. aureus to antimicrobial plant extracts. It is the first time a collateral antibiotic sensitivity of S. aureus adapted to natural compounds has been observed, suggesting an alternative approach to fight antibiotic resistance.

Analog-Domain Suppression of Strong Interference Using Hybrid Antenna Array.

The proliferation of wireless applications, the ever-increasing spectrum crowdedness, as well as cell densification makes the issue of interference increasingly severe in many emerging wireless applications. Most interference management/mitigation methods in the literature are problem-specific and require some cooperation/coordination between different radio frequency systems. Aiming to seek a more versatile solution to counteracting strong interference, we resort to the hybrid array of analog subarrays and suppress interference in the analog domain so as to greatly reduce the required quantization bits of the analog-to-digital converters and their power consumption. To this end, we design a real-time algorithm to steer nulls towards the interference directions and maintain flat in non-interference directions, solely using constant-modulus phase shifters. To ensure sufficient null depth for interference suppression, we also develop a two-stage method for accurately estimating interference directions. The proposed solution can be applicable to most (if not all) wireless systems as neither training/reference signal nor cooperation/coordination is required. Extensive simulations show that more than 65 dB of suppression can be achieved for 3 spatially resolvable interference signals yet with random directions.

Masked analysis for small-scale cluster randomized controlled trials.

Researchers conducting small-scale cluster randomized controlled trials (RCTs) during the pilot testing of an intervention often look for evidence of promise to justify an efficacy trial. We developed a method to test for intervention effects that is adaptive (i.e., responsive to data exploration), requires few assumptions, and is statistically valid (i.e., controls the type I error rate), by adapting masked visual analysis techniques to cluster RCTs. We illustrate the creation of masked graphs and their analysis using data from a pilot study in which 15 high school programs were randomly assigned to either business as usual or an intervention developed to promote psychological and academic well-being in 9th grade students in accelerated coursework. We conclude that in small-scale cluster RCTs there can be benefits of testing for effects without a priori specification of a statistical model or test statistic.

The road to cervical cancer elimination in Malaysia: Evaluation of the impact and cost-effectiveness of human papillomavirus screening with self-collection and digital registry support.

The WHO has launched a global strategy to eliminate cervical cancer through the scale-up of human papillomavirus (HPV) vaccination, cervical screening, and cervical cancer treatment. Malaysia has achieved high-coverage HPV vaccination since 2010, but coverage of the existing cytology-based program remains low. Pilot studies found HPV self-sampling was acceptable and effective, with high follow-up rates when a digital registry was used, and recently the Malaysian Government announced plans for a national HPV-based screening program. We therefore evaluated the impact of primary HPV screening with self-collection in Malaysia in the context of Malaysia's existing vaccination program. We used the "Policy1-Cervix" modeling platform to assess health outcomes, cost-effectiveness, resource use and cervical cancer elimination timing (the year when cervical cancer rates reach four cases per 100 000 women) of implementing primary HPV testing with self-collection, assuming 70% routine-screening coverage could be achieved. Based on available data, we assumed that compliance with follow-up was 90% when a digital registry was used, but that compliance with follow-up would be 50-75% without the use of a digital registry. We found that the current vaccination program would prevent 27 000 to 32 200 cervical cancer cases and 11 700 to 14 000 deaths by 2070. HPV testing with a digital registry was cost-effective (CER = $US 6953-7549 < $US 11 373[<1×GDP per capita]) and could prevent an additional 15 900 to 17 800 cases and 9700 to 10 600 deaths by 2070, expediting national elimination by 11 to 20 years, to 2055 to 2059. If HPV screening were implemented without a digital registry, there would be 1800 to 4900 fewer deaths averted by 2070 and the program would be less cost-effective. These results underline the importance of HPV testing as a key elimination pillar in Malaysia.

Impact of HPV vaccination and cervical screening on cervical cancer elimination: a comparative modelling analysis in 78 low-income and lower-middle-income countries.

BACKGROUND: The WHO Director-General has issued a call for action to eliminate cervical cancer as a public health problem. To help inform global efforts, we modelled potential human papillomavirus (HPV) vaccination and cervical screening scenarios in low-income and lower-middle-income countries (LMICs) to examine the feasibility and timing of elimination at different thresholds, and to estimate the number of cervical cancer cases averted on the path to elimination. METHODS: The WHO Cervical Cancer Elimination Modelling Consortium (CCEMC), which consists of three independent transmission-dynamic models identified by WHO according to predefined criteria, projected reductions in cervical cancer incidence over time in 78 LMICs for three standardised base-case scenarios: girls-only vaccination; girls-only vaccination and once-lifetime screening; and girls-only vaccination and twice-lifetime screening. Girls were vaccinated at age 9 years (with a catch-up to age 14 years), assuming 90% coverage and 100% lifetime protection against HPV types 16, 18, 31, 33, 45, 52, and 58. Cervical screening involved HPV testing once or twice per lifetime at ages 35 years and 45 years, with uptake increasing from 45% (2023) to 90% (2045 onwards). The elimination thresholds examined were an average age-standardised cervical cancer incidence of four or fewer cases per 100 000 women-years and ten or fewer cases per 100 000 women-years, and an 85% or greater reduction in incidence. Sensitivity analyses were done, varying vaccination and screening strategies and assumptions. We summarised results using the median (range) of model predictions. FINDINGS: Girls-only HPV vaccination was predicted to reduce the median age-standardised cervical cancer incidence in LMICs from 19·8 (range 19·4-19·8) to 2·1 (2·0-2·6) cases per 100 000 women-years over the next century (89·4% [86·2-90·1] reduction), and to avert 61·0 million (60·5-63·0) cases during this period. Adding twice-lifetime screening reduced the incidence to 0·7 (0·6-1·6) cases per 100 000 women-years (96·7% [91·3-96·7] reduction) and averted an extra 12·1 million (9·5-13·7) cases. Girls-only vaccination was predicted to result in elimination in 60% (58-65) of LMICs based on the threshold of four or fewer cases per 100 000 women-years, in 99% (89-100) of LMICs based on the threshold of ten or fewer cases per 100 000 women-years, and in 87% (37-99) of LMICs based on the 85% or greater reduction threshold. When adding twice-lifetime screening, 100% (71-100) of LMICs reached elimination for all three thresholds. In regions in which all countries can achieve cervical cancer elimination with girls-only vaccination, elimination could occur between 2059 and 2102, depending on the threshold and region. Introducing twice-lifetime screening accelerated elimination by 11-31 years. Long-term vaccine protection was required for elimination. INTERPRETATION: Predictions were consistent across our three models and suggest that high HPV vaccination coverage of girls can lead to cervical cancer elimination in most LMICs by the end of the century. Screening with high uptake will expedite reductions and will be necessary to eliminate cervical cancer in countries with the highest burden. FUNDING: WHO, UNDP, UN Population Fund, UNICEF-WHO-World Bank Special Program of Research, Development and Research Training in Human Reproduction, Canadian Institute of Health Research, Fonds de recherche du Québec-Santé, Compute Canada, National Health and Medical Research Council Australia Centre for Research Excellence in Cervical Cancer Control.

Mortality impact of achieving WHO cervical cancer elimination targets: a comparative modelling analysis in 78 low-income and lower-middle-income countries.

BACKGROUND: WHO is developing a global strategy towards eliminating cervical cancer as a public health problem, which proposes an elimination threshold of four cases per 100 000 women and includes 2030 triple-intervention coverage targets for scale-up of human papillomavirus (HPV) vaccination to 90%, twice-lifetime cervical screening to 70%, and treatment of pre-invasive lesions and invasive cancer to 90%. We assessed the impact of achieving the 90-70-90 triple-intervention targets on cervical cancer mortality and deaths averted over the next century. We also assessed the potential for the elimination initiative to support target 3.4 of the UN Sustainable Development Goals (SDGs)-a one-third reduction in premature mortality from non-communicable diseases by 2030. METHODS: The WHO Cervical Cancer Elimination Modelling Consortium (CCEMC) involves three independent, dynamic models of HPV infection, cervical carcinogenesis, screening, and precancer and invasive cancer treatment. Reductions in age-standardised rates of cervical cancer mortality in 78 low-income and lower-middle-income countries (LMICs) were estimated for three core scenarios: girls-only vaccination at age 9 years with catch-up for girls aged 10-14 years; girls-only vaccination plus once-lifetime screening and cancer treatment scale-up; and girls-only vaccination plus twice-lifetime screening and cancer treatment scale-up. Vaccination was assumed to provide 100% lifetime protection against infections with HPV types 16, 18, 31, 33, 45, 52, and 58, and to scale up to 90% coverage in 2020. Cervical screening involved HPV testing at age 35 years, or at ages 35 years and 45 years, with scale-up to 45% coverage by 2023, 70% by 2030, and 90% by 2045, and we assumed that 50% of women with invasive cervical cancer would receive appropriate surgery, radiotherapy, and chemotherapy by 2023, which would increase to 90% by 2030. We summarised results using the median (range) of model predictions. FINDINGS: In 2020, the estimated cervical cancer mortality rate across all 78 LMICs was 13·2 (range 12·9-14·1) per 100 000 women. Compared to the status quo, by 2030, vaccination alone would have minimal impact on cervical cancer mortality, leading to a 0·1% (0·1-0·5) reduction, but additionally scaling up twice-lifetime screening and cancer treatment would reduce mortality by 34·2% (23·3-37·8), averting 300 000 (300 000-400 000) deaths by 2030 (with similar results for once-lifetime screening). By 2070, scaling up vaccination alone would reduce mortality by 61·7% (61·4-66·1), averting 4·8 million (4·1-4·8) deaths. By 2070, additionally scaling up screening and cancer treatment would reduce mortality by 88·9% (84·0-89·3), averting 13·3 million (13·1-13·6) deaths (with once-lifetime screening), or by 92·3% (88·4-93·0), averting 14·6 million (14·1-14·6) deaths (with twice-lifetime screening). By 2120, vaccination alone would reduce mortality by 89·5% (86·6-89·9), averting 45·8 million (44·7-46·4) deaths. By 2120, additionally scaling up screening and cancer treatment would reduce mortality by 97·9% (95·0-98·0), averting 60·8 million (60·2-61·2) deaths (with once-lifetime screening), or by 98·6% (96·5-98·6), averting 62·6 million (62·1-62·8) deaths (with twice-lifetime screening). With the WHO triple-intervention strategy, over the next 10 years, about half (48% [45-55]) of deaths averted would be in sub-Saharan Africa and almost a third (32% [29-34]) would be in South Asia; over the next 100 years, almost 90% of deaths averted would be in these regions. For premature deaths (age 30-69 years), the WHO triple-intervention strategy would result in rate reductions of 33·9% (24·4-37·9) by 2030, 96·2% (94·3-96·8) by 2070, and 98·6% (96·9-98·8) by 2120. INTERPRETATION: These findings emphasise the importance of acting immediately on three fronts to scale up vaccination, screening, and treatment for pre-invasive and invasive cervical cancer. In the next 10 years, a one-third reduction in the rate of premature mortality from cervical cancer in LMICs is possible, contributing to the realisation of the 2030 UN SDGs. Over the next century, successful implementation of the WHO elimination strategy would reduce cervical cancer mortality by almost 99% and save more than 62 million women's lives. FUNDING: WHO, UNDP, UN Population Fund, UNICEF-WHO-World Bank Special Program of Research, Development and Research Training in Human Reproduction, Germany Federal Ministry of Health, National Health and Medical Research Council Australia, Centre for Research Excellence in Cervical Cancer Control, Canadian Institute of Health Research, Compute Canada, and Fonds de recherche du Québec-Santé.

AI in the Intensive Care Unit: Up-to-Date Review.

AI is the latest technologic trend that likely will have a huge impact in medicine. AI's potential lies in its ability to process large volumes of data and perform complex pattern analyses. The ICU is an area of medicine that is particularly conducive to AI applications. Much AI ICU research currently is focused on improving high volumes of data on high-risk patients and making clinical workflow more efficient. Emerging topics of AI medicine in the ICU include AI sensors, sepsis prediction, AI in the NICU or SICU, and the legal role of AI in medicine. This review will cover the current applications of AI medicine in the ICU, potential pitfalls, and other AI medicine-related topics relevant for the ICU.

Identification and Characterization of a B-Raf Kinase α-Helix Critical for the Activity of MEK Kinase in MAPK Signaling.

In the MAPK pathway, an oncogenic V600E mutation in B-Raf kinase causes the enzyme to be constitutively active, leading to aberrantly high phosphorylation levels of its downstream effectors, MEK and ERK kinases. The V600E mutation in B-Raf accounts for more than half of all melanomas and ∼3% of all cancers, and many drugs target the ATP binding site of the enzyme for its inhibition. Because B-Raf can develop resistance against these drugs and such drugs can induce paradoxical activation, drugs that target allosteric sites are needed. To identify other potential drug targets, we generated and kinetically characterized an active form of B-RafV600E expressed using a bacterial expression system. In doing so, we identified an α-helix on B-Raf, found at the B-Raf-MEK interface, that is critical for their interaction and the oncogenic activity of B-RafV600E. We assessed the binding between B-Raf mutants and MEK using pull downs and biolayer interferometry and assessed phosphorylation levels of MEK in vitro and in cells as well as its downstream target ERK to show that mutating certain residues on this α-helix is detrimental to binding and downstream activity. Our results suggest that this B-Raf α-helix binding site on MEK could be a site to target for drug development to treat B-RafV600E-induced melanomas.

The catalytic mechanism of electron-bifurcating electron transfer flavoproteins (ETFs) involves an intermediary complex with NAD.

Electron bifurcation plays a key role in anaerobic energy metabolism, but it is a relatively new discovery, and only limited mechanistic information is available on the diverse enzymes that employ it. Herein, we focused on the bifurcating electron transfer flavoprotein (ETF) from the hyperthermophilic archaeon Pyrobaculum aerophilum The EtfABCX enzyme complex couples NADH oxidation to the endergonic reduction of ferredoxin and exergonic reduction of menaquinone. We developed a model for the enzyme structure by using nondenaturing MS, cross-linking, and homology modeling in which EtfA, -B, and -C each contained FAD, whereas EtfX contained two [4Fe-4S] clusters. On the basis of analyses using transient absorption, EPR, and optical titrations with NADH or inorganic reductants with and without NAD+, we propose a catalytic cycle involving formation of an intermediary NAD+-bound complex. A charge transfer signal revealed an intriguing interplay of flavin semiquinones and a protein conformational change that gated electron transfer between the low- and high-potential pathways. We found that despite a common bifurcating flavin site, the proposed EtfABCX catalytic cycle is distinct from that of the genetically unrelated bifurcating NADH-dependent ferredoxin NADP+ oxidoreductase (NfnI). The two enzymes particularly differed in the role of NAD+, the resting and bifurcating-ready states of the enzymes, how electron flow is gated, and the two two-electron cycles constituting the overall four-electron reaction. We conclude that P. aerophilum EtfABCX provides a model catalytic mechanism that builds on and extends previous studies of related bifurcating ETFs and can be applied to the large bifurcating ETF family.