Building Capacity for Cervical Cancer Prevention in U.S.-Affiliated Pacific Islands: The Pacific Against Cervical Cancer Project.

The U.S.-affiliated Pacific Islands (USAPI) have higher cervical cancer incidence and mortality rates and lower screening coverage compared with the United States. This is likely because of economic, geographical, health care delivery, and cultural barriers for women living in these resource-constrained, isolated regions. The most recent U.S. and World Health Organization cervical cancer screening guidelines recommended primary human papillomavirus (HPV) testing as one screening option or the preferred screening modality. Primary HPV screening-based strategies offer several advantages over current screening methods in the USAPI. However, adoption of this newer screening modality has been slow in the United States and not yet incorporated into USAPI screening programs. The U.S. Centers for Disease Control and Prevention and partners initiated the Pacific Against Cervical Cancer (PACe) project in 2019 to evaluate the feasibility, acceptability, and cost-effectiveness of primary HPV testing-based strategies in Guam and in Yap, Federated States of Micronesia. This report provides an overview of the PACe project and outlines the approaches we took in implementing primary HPV testing as a new cervical cancer screening strategy (including the option of self-sampling in Yap), encompassing four core components: (1) community engagement and education, (2) medical and laboratory capacity building, (3) health information and system improvement, and (4) modeling and cost-effectiveness analysis. The PACe project provides examples of systematic implementation and resource appropriate technologies to the USAPI, with broader implications for never screened and under-screened populations in the United States and Pacific as they face similar barriers to accessing cervical cancer screening services.

Lifestyle practices and associated factors among adults with hypertension: Conquering Hypertension in Vietnam-solutions at the grassroots level study.

BACKGROUND: Vietnam is experiencing an increasing prevalence of hypertension in its adult population. In addition to medical therapy, modifying adverse lifestyle practices is important for effective blood pressure control. There are limited data on unhealthy lifestyle practices in patients with chronic diseases, however, particularly among hypertensive patients living in rural Vietnam. Our study objectives were to examine the prevalence of unhealthy lifestyle practices and associated factors among rural Vietnamese adults with uncontrolled hypertension. METHODS: Data from the baseline survey of a cluster randomized trial among hypertensive Vietnamese adults (2017-2022) were utilized. Information on unhealthy lifestyle practices including smoking, excessive alcohol consumption, physical inactivity, and inadequate fruit and vegetable intake was collected from study participants. The primary study outcome was having ≥2 unhealthy lifestyle practices. A multivariable logistic regression model was used to examine factors associated with the primary study outcome. RESULTS: The mean age of the 671 patients was 67 years and 45.0% were men. Nearly three out of every four participants had one or fewer unhealthy practices, 24.0% had two, and 3.3% had three or all four unhealthy lifestyle practices. Men, individuals who did unpaid work or were unemployed, and individuals with hypertension level III were more likely to have ≥2 unhealthy lifestyle practices, whereas individuals with higher education were less likely to have ≥2 unhealthy lifestyle practices compared with respective comparison groups. CONCLUSIONS: We observed a high prevalence of unhealthy lifestyle practices among rural Vietnamese patients with uncontrolled hypertension. Several demographic factors were associated with a greater number of unhealthy lifestyle practices. Newer interventions and educational programs encouraging lifestyle modification practices are needed to control hypertension among adults living in rural settings of Vietnam.

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.

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.

Benefits and harms of cervical screening, triage and treatment strategies in women living with HIV.

To support a strategy to eliminate cervical cancer as a public health problem, the World Health Organisation (WHO) reviewed its guidelines for screening and treatment of cervical pre-cancerous lesions in 2021. Women living with HIV have 6-times the risk of cervical cancer compared to women in the general population, and we harnessed a model platform ('Policy1-Cervix-HIV') to evaluate the benefits and harms of a range of screening strategies for women living with HIV in Tanzania, a country with endemic HIV. Assuming 70% coverage, we found that 3-yearly primary HPV screening without triage would reduce age-standardised cervical cancer mortality rates by 72%, with a number needed to treat (NNT) of 38.7, to prevent a cervical cancer death. Triaging HPV positive women before treatment resulted in minimal loss of effectiveness and had more favorable NNTs (19.7-33.0). Screening using visual inspection with acetic acid (VIA) or cytology was less effective than primary HPV and, in the case of VIA, generated a far higher NNT of 107.5. These findings support the WHO 2021 recommendation that women living with HIV are screened with primary HPV testing in a screen-triage-and-treat approach starting at 25 years, with regular screening every 3-5 years.

Benefits, harms and cost-effectiveness of cervical screening, triage and treatment strategies for women in the general population.

In 2020, the World Health Organization (WHO) launched a strategy to eliminate cervical cancer as a public health problem. To support the strategy, the WHO published updated cervical screening guidelines in 2021. To inform this update, we used an established modeling platform, Policy1-Cervix, to evaluate the impact of seven primary screening scenarios across 78 low- and lower-middle-income countries (LMICs) for the general population of women. Assuming 70% coverage, we found that primary human papillomavirus (HPV) screening approaches were the most effective and cost-effective, reducing cervical cancer age-standardized mortality rates by 63-67% when offered every 5 years. Strategies involving triaging women before treatment (with 16/18 genotyping, cytology, visual inspection with acetic acid (VIA) or colposcopy) had close-to-similar effectiveness to HPV screening without triage and fewer pre-cancer treatments. Screening with VIA or cytology every 3 years was less effective and less cost-effective than HPV screening every 5 years. Furthermore, VIA generated more than double the number of pre-cancer treatments compared to HPV. In conclusion, primary HPV screening is the most effective, cost-effective and efficient cervical screening option in LMICs. These findings have directly informed WHO's updated cervical screening guidelines for the general population of women, which recommend primary HPV screening in a screen-and-treat or screen-triage-and-treat approach, starting from age 30 years with screening every 5 years or 10 years.

Clonal Hematopoiesis as a Molecular Risk Factor for Doxorubicin-Induced Cardiotoxicity: A Proof-of-Concept Study.

PURPOSE: The main dose-limiting toxicity of anthracyclines is cardiotoxicity. Clonal hematopoiesis (CH), somatic mutations in hematopoietic stem or progenitor cells in patients without hematologic malignancy, is also associated with risk for adverse cardiovascular events and worse outcomes overall. We hypothesize that CH increases risk for doxorubicin-induced cardiotoxicity (DIC). METHODS: We conducted a retrospective cohort study in patients treated with doxorubicin for cancer (N = 100). Patients (n = 25) had incident symptomatic heart failure, decline in left ventricular ejection fraction, or arrhythmia. CH was identified using paired peripheral blood and tumor DNA. RESULTS: After adjusting for age at doxorubicin initiation, diabetes, dyslipidemia, and chest radiation, high cumulative dose of doxorubicin (>240 mg/m2; odds ratio [OR], 7.00; 95% CI, 1.77 to 27.74; P = .0056), CH (OR, 8.58; 95% CI, 2.05 to 35.99; P = .0033), and history of smoking (OR, 3.15; 95% CI, 1.00 to 9.93; P = .0495) were associated with DIC. CONCLUSION: This study provides preliminary evidence for CH as a predictive risk factor for DIC, which, with further investigation, could serve as an important precision medicine biomarker for the large number of patients with cancer who have CH.

Small molecule allosteric modulation of the adenosine A1 receptor.

G protein-coupled receptors (GPCRs) represent the target for approximately a third of FDA-approved small molecule drugs. The adenosine A1 receptor (A1R), one of four adenosine GPCR subtypes, has important (patho)physiological roles in humans. A1R has well-established roles in the regulation of the cardiovascular and nervous systems, where it has been identified as a potential therapeutic target for a number of conditions, including cardiac ischemia-reperfusion injury, cognition, epilepsy, and neuropathic pain. A1R small molecule drugs, typically orthosteric ligands, have undergone clinical trials. To date, none have progressed into the clinic, predominantly due to dose-limiting unwanted effects. The development of A1R allosteric modulators that target a topographically distinct binding site represent a promising approach to overcome current limitations. Pharmacological parameters of allosteric ligands, including affinity, efficacy and cooperativity, can be optimized to regulate A1R activity with high subtype, spatial and temporal selectivity. This review aims to offer insights into the A1R as a potential therapeutic target and highlight recent advances in the structural understanding of A1R allosteric modulation.

Changes in Perioperative Outcomes after Robotic-Assisted Pulmonary Lobectomy during the COVID-19 Era.

Background: The COVID-19 pandemic presented patients with barriers to receiving healthcare. We sought to determine whether changes in healthcare access and practice during the pandemic affected perioperative outcomes after robotic-assisted pulmonary lobectomy (RAPL). Methods: We retrospectively analyzed 721 consecutive patients who underwent RAPL. With March 1st, 2020, defining the start of the COVID-19 pandemic, we grouped 638 patients as "PreCOVID-19" and 83 patients as "COVID-19-Era" based on surgical date. Demographics, comorbidities, tumor characteristics, intraoperative complications, morbidity, and mortality were analyzed. Variables were compared utilizing Student's t-test, Wilcoxon rank-sum test, and Chi-square (or Fisher's exact) test, with significance at p ≤ 0.05 . Multivariable generalized linear regression was used to investigate predictors of postoperative complication. Results: COVID-19-Era patients had significantly higher preoperative FEV1%, lower cumulative smoking history and higher incidences of preoperative atrial fibrillation, peripheral vascular disease (PVD), and bleeding disorders compared to PreCOVID-19 patients. COVID-19-Era patients had lower intraoperative estimated blood loss (EBL), reduced incidence of new-onset postoperative atrial fibrillation (POAF), but higher incidence of effusion or empyema postoperatively. Overall postoperative complication rates between the groups were similar. Older age, increased EBL, lower preoperative FEV1%, and preoperative COPD are all predictive of an increased risk for postoperative complication. Conclusions: COVID-19-Era patients having lower EBL and less new-onset POAF, despite greater incidences of multiple preoperative comorbidities, demonstrates that RAPL is safe during the COVID-19 era. Risk factors for development of postoperative effusion should be determined to minimize risk of empyema in COVID-19-Era patients. Age, preoperative FEV1%, COPD, and EBL should all be considered when planning for complication risk.

Effects of preoperative pulmonary function on perioperative outcomes after robotic-assisted pulmonary lobectomy.

INTRODUCTION: Effects of pulmonary function test (PFT) results on perioperative outcomes were investigated after robotic-assisted video-thoracoscopic (RAVT) pulmonary lobectomy. METHODS: We retrospectively analyzed 706 consecutive patients who underwent RAVT lobectomy by one surgeon over 10.8 years. Preoperative (preop) forced expiratory volume in 1 s as a percent of predicted (FEV1%) was used to group patients as having normal FEV1% (≥80%) versus reduced FEV1% (<80%). Demographics, preop comorbidities, intraoperative (intraop) and postoperative (postop) complications, perioperative outcomes, and median survival time (MST) were compared across patients with normal vs. reduced FEV1% using Chi-Square (X2), Fisher's Exact test, Student's t-test, Kruskal-Wallis test, or Kaplan-Meier analysis respectively, with significance at p ≤ 0.05. Multivariable analysis was performed for perioperative outcomes to investigate the differences across patients in the FEV1% groups. RESULTS: There were 470 patients with normal FEV1% and 236 patients with reduced FEV1%. The two FEV1% groups did not differ in intraop or postop complication rates, except for higher postop other arrhythmia requiring intervention (p = 0.004), prolonged air leak >5 days (p = 0.002), mucous plug formation (p = 0.009), hypoxia (p < 0.001), and pneumonia (p = 0.002), and total postop complications (p < 0.001) in reduced-FEV1% patients. Reduced FEV1% correlated with increased intraop estimated blood loss (p < 0.0001) and skin-to-skin operative time (p < 0.0001). Median overall survival in patients with normal FEV1% was 93.20 months (95% CI: 76.5-126.0) versus 58.9 months (95% CI: 50.4-68.4) in patients with reduced FEV1% (p = 0.0004). CONCLUSION: Patients should have PFTs conducted before surgery to determine at-risk patients. However, RAVT pulmonary lobectomy is feasible and safe even in patients with reduced FEV1%.

Comparison between PSMA PET/CT and MRI for Characterizing Hepatocellular carcinoma: A Real-World Study.

Prostate specific membrane antigen (PSMA) is expressed by hepatocellular carcinoma (HCC). PSMA PET/CT has potential as an imaging agent for the detection of HCC including early diagnosis and monitoring for recurrence following surgical resection. This study aims to compare PSMA PET to standard surveillance imaging in the detection of HCC. Patients with suspected or treated HCC were prospectively recruited from a tertiary hospital outpatient clinic. In addition to routine surveillance imaging as recommended by the multidisciplinary team, a PSMA PET/CT was performed. Imaging and clinical characteristics were compared over a follow-up period of up to 12 months. In a cohort of 19 patients with known HCC or suspected recurrent HCC, PSMA PET/CT had similar efficacy to MRI for the detection of HCC, with a sensitivity of 91% and a specificity of 70% and sensitivity of 87% and a specificity of 73% for PSMA PET/CT and MRI, respectively. PSMA PET/CT had a higher negative predictive value of 90%. In this relatively large single centre study, PSMA is shown to have promising equivalence in performance and its role should be further evaluated in multi-centre prospective trials.

Voice Hoarseness with Reflux as a Suspected Etiology: Incidence, Evaluation, Treatment, and Symptom Outcomes.

PURPOSE: To describe the clinical evaluation course, treatments, and outcomes of patients with a primary complaint of hoarseness due to suspected laryngopharyngeal reflux (LPR). METHODS: A retrospective chart review was conducted of patients with a primary complaint of hoarseness with acid reflux as the suspected cause at a single institution between October 2011 and March 2020 who underwent clinical evaluation, treatment, and follow-up. Data collected included diagnostic procedures and treatments received, subjective symptom outcomes, and final diagnosis as determined by the treating physician. RESULTS: A total of 134 patients met the inclusion criteria. Videostroboscopy was the most performed procedure (n = 59, 44%) followed by endoscopy (n = 38, 28%) and pH monitoring (n = 28, 21%). Three patients were removed for statistical analysis of treatment differences and outcomes due to variant treatment plans. Most patients received sole medical management (n = 86, 66%), 7 patients received only voice therapy (5%), and 10 patients underwent surgical management (8%). Several patients received combined medical management and voice therapy (n = 21, 16%). Final diagnoses included gastroesophageal reflux disease (GERD) (25%), followed by multifactorial causes (17%) and dysphonia with unclear etiology (13%). Among all patients, 82 (61%) reported symptom improvement. Twenty-eight patients were diagnosed with LPR or LPR with GERD (21%), and 22 reported symptom improvement (79%). There was a statistically significant relationship between a final diagnosis with a reflux component and symptom improvement (p = .038). There was no statistically significant difference between treatment types and symptom outcomes both within the total patient population (p = .051) and patients diagnosed with a reflux condition (p = .572). CONCLUSION: LPR remains a difficult diagnosis to establish and represents a minority of patients with voice complaints. Despite varying evaluation and treatment modalities, most patients with LPR improved during their treatment and evaluation period without a clear association with any specific type of treatment. Further studies should explore diagnostic criteria for LPR, the necessary and efficient clinical evaluation to establish a diagnosis, and possible beneficial treatments.

Towards the elimination of cervical cancer in low-income and lower-middle-income countries: modelled evaluation of the effectiveness and cost-effectiveness of point-of-care HPV self-collected screening and treatment in Papua New Guinea.

INTRODUCTION: WHO has launched updated cervical screening guidelines, including provisions for primary HPV screen-and-treat. Papua New Guinea (PNG) has a high burden of cervical cancer, but no national cervical screening programme. We recently completed the first field trials of a screen-and-treat algorithm using point-of-care self-collected HPV and same-day treatment (hereafter self-collected HPV S&T) and showed this had superior clinical performance and acceptability to visual inspection of the cervix with acetic acid (VIA). We, therefore, evaluated the effectiveness, cost-effectiveness and resource implications of a national cervical screening programme using self-collected HPV S&T compared with VIA in PNG. METHODS: An extensively validated platform ('Policy1-Cervix') was calibrated to PNG. A total of 38 strategies were selected for investigation, and these incorporated variations in age ranges and screening frequencies and allowed for the identification of the optimal strategy across a wide range of possibilities. A selection of strategies that were identified as being the most effective and cost-effective were then selected for further investigation for longer-term outcomes and budget impact estimation. In the base case, we assumed primary HPV testing has a sensitivity to cervical intraepithelial neoplasia 2 (CIN2+) + of 91.8% and primary VIA of 51.5% based on our earlier field evaluation combined with evidence from the literature. We conservatively assumed HPV sampling and testing would cost US$18. Costs were estimated from a service provider perspective based on data from local field trials and local consultation. RESULTS: Self-collected HPV S&T was more effective and more cost-effective than VIA. Either twice or thrice lifetime self-collected HPV S&T would be cost-effective at 0.5× gross domestic product (GDP) per capita (incremental cost-effectiveness ratio: US$460-US$656/life-years saved; 1GDPper-capita: US$2829 or PGK9446 (year 2019)) and could prevent 33 000-42 000 cases and 23 000-29 000 deaths in PNG over the next 50 years, if scale-up reached 70% coverage from 2023. CONCLUSION: Self-collected HPV S&T was effective and cost-effective in the high-burden, low-resource setting of PNG, and, if scaled-up rapidly, could prevent over 20 000 deaths over the next 50 years. VIA screening was not effective or cost-effective. These findings support, at a country level, WHO updated cervical screening guidelines and indicate that similar approaches could be appropriate for other low-resource settings.

Age-based exclusions in clinical trials: A review and new perspectives.

BACKGROUND: Despite elderly populations having a greater risk of being diagnosed with serious medical conditions, there has been limited clinical testing conducted on geriatric patients. By analyzing cancer, cardiovascular diseases, and type 2 diabetes data from ClinicalTrials.gov, we investigate two factors that may have significant impact on the exclusion of elderly patients from clinical trials. METHODS: We examine age exclusion across phases and funder types and demonstrate the extent of these exclusions over all interventional studies that commenced enrollment on or after January 2010 to Oct 2021. RESULTS: Cancer trials have the lowest percentage of age capped enrollment, with 22.18%, 24.13%, and 32.77% of the studies listing an upper age limit in Phases 1, 2, and 3, respectively. In comparison, cardiovascular disease trials are age capped in 51.32%, 39.9%, and 34.94% of trials, and type 2 diabetes capped in 90.3%, 74.42%, and 36.75% of trials in Phases 1, 2, and 3 respectively. Our result shows no significant changes in the percentage of trials with upper age limits pre- and post- NIH Inclusion Across the Lifespan Policy. CONCLUSION: Our analysis reveals cancer trials were the most age-inclusive. Further, NIH-funded trials have historically set fewer age caps compared to those whose funding has come from non-NIH sources, which provides optimism that inclusivity can be feasible for all trials.

A case of Wilson disease with the ATP7B mutation presenting movement disorders.

BACKGROUND: Wilson disease is an autosomal recessive condition manifested when abnormal copper accumulation in the body particularly involving many organs such as brain, liver, and cornea. Diagnosis is challenging with the completion of tests in blood and urine, a liver biopsy, and clinical evaluation. ATP7B mutations with more than 600 identified variants are the genetic disorders of Wilson disease. CASE DESCRIPTION: We report an adolescent case with no family history presented with extrapyramidal dyskinesia. Other symptoms include liver cirrhosis and Kayser-Fleischer ring. The typical presentation of blood test results and brain MRI images helps us to suspect Wilson disease in this case. We confirmed to have a p.R778L form and a p.S105X form in ATP7B mutations. After combining therapy with trihexyphenidyl and trientine, the patient's medical condition was stable and no side effects were observed. CONCLUSION: Screening for the diagnosis of Wilson disease is essential in helping patients benefit from early treatment and genetic counseling.

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.

68Ga-PSMA PET/CT versus CT and bone scan for investigation of PSA failure post radical prostatectomy.

OBJECTIVE: To evaluate the use of Gallium-68 prostate-specific membrane antigen positron emission tomography/computed tomography (68Ga-PSMA PET/CT), compared with conventional CT abdomen/pelvis (CTAP) and whole body single photon emission CT bone scan (BS), for detection of local or distant metastasis following biochemical failure/recurrence in post-prostatectomy patients. METHODS: We conducted a review of our prospectively maintained, institutional database to identify 384 patients with post-prostatectomy biochemical failure/recurrence who underwent PSMA PET/CT, CTAP and BS from February 2015 to August 2017 in Nepean Hospital, tertiary referral centre. The results of the three imaging modalities were analysed for their ability to detect local recurrence and distant metastases. PSMA PET/CT and CTAP imaging were separately performed on the same day and the BS was performed within several days (mostly in 24 h). Difference in detection rates was determined between the modalities and the Chi square test was used to determine significance. RESULTS: A total of 384 patients were identified with a median prostate-specific antigen (PSA) of 0.465 ng/mL (interquartile range =0.19-2.00 ng/mL). Overall, PSMA PET/CT was positive for 245 (63.8%) patients whereas CTAP and BS were positive in 174 patients (45.3%). A total of 98 patients (25.5%) had local or distant metastasis detected on PSMA only, while 20 patients (5.2%) had recurrences detected on CTAP but not on PSMA PET/CT. CONCLUSION: The use of PSMA PET/CT has a higher detection rate of predicted local or distant metastasis compared to CTAP and BS in the staging of patients with biochemical recurrences after radical prostatectomy.

Environmental health risk assessment of heavy metal exposure among children living in an informal e-waste processing village in Viet Nam.

This study was conducted to compare the exposure levels of five heavy metals via different pathways based on the field samplings and questionnaire surveys of children residing in an informal e-waste processing village and a reference village in Viet Nam. The findings revealed that levels of the total average daily intake (ADI) of the five heavy metals collected from a child at the exposed village were 3.90 times higher (p < 0.01) than that of a child at the reference village. Ingestion of cooked rice was the largest contributor to the total ADI of the children tested at both villages. However, the risks from water drinking and dermal contact of soil were negligible. The total non-carcinogenic risk and carcinogenic risk in an exposed child were significantly higher (p < 0.01) than their respective risks in a reference child. The non-carcinogenic risk to an exposed child was likely to occur, while the risk to a reference child was negligible. The carcinogenic risks found in children from both of the villages, however, were higher than the acceptable values, indicating the potential health risks to the children from both villages. The susceptibility of children to heavy metal contaminations shown in this study suggests that a mitigating measure need to be initiated jointly by a public agency and a private organization to prevent children from the risks of being exposed to the contaminants.

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.