Mathematical Modeling for Removing Border Entry and Quarantine Requirements for COVID-19, Vanuatu.

The Pacific Island country of Vanuatu is considering strategies to remove border restrictions implemented during 2020 to prevent imported coronavirus disease. We performed mathematical modeling to estimate the number of infectious travelers who had different entry scenarios and testing strategies. Travel bubbles and testing on entry have the greatest importation risk reduction.

Comparison of strategies for daily surveillance of international travellers quarantined in Vanuatu, October-December 2020.

Objective: To prevent importation of coronavirus disease 2019 (COVID-19) to Vanuatu, since March 2020, all travellers to the country have been required to complete a 14-day quarantine in a government-designated facility. A short message service (SMS, or "text message") system was developed to collect information on symptoms of COVID-19 among travellers in quarantine. A trial within a cohort study was conducted among travellers arriving to Vanuatu by air from 27 October to 7 December 2020 to assess SMS acceptability, efficiency and utility and whether SMS-based health monitoring was as effective as in-person monitoring in identifying people with COVID-19 symptoms. Methods: Control group participants received standard monitoring (daily in-person visits) and participants in the intervention group received a daily SMS text requesting a response coded for symptom development. Differences between the two groups were determined using χ2 tests. Results: Of the 495 eligible travellers, 423 participated; 170 were allocated to the control group and 253 to the intervention group. At least one return SMS text was received from 50% (107/212) of participants who were confirmed to have received an SMS text. Less than 2% (4/253) of the intervention group and 0% of the control group reported symptoms. Discussion: The SMS intervention had a high level of acceptability. SMS is a useful tool to monitor symptom development among people in quarantine and for broader public health programmes that require follow up.

Opposing roles of ZEB1 in the cytoplasm and nucleus control cytoskeletal assembly and YAP1 activity.

Epithelial-mesenchymal transition (EMT) facilitates cancer invasion and is initiated by mesenchyme-driving transcription factors and actin cytoskeletal assembly. We show a cytoplasmic-to-nuclear transport gradient of the EMT transcription factor Zeb1 toward sites of invasion in lung adenocarcinoma (LUAD), driven by the EMT inducer Tgfb, which is expressed in M2 polarized macrophages. We show that Zeb1 binds free actin monomers and RhoA in the cytoplasm to inhibit actin polymerization, blocking cell migration and Yap1 nuclear transport. Tgfb causes turnover of the scaffold protein Rassf1a, which targets RhoA. Release of this RhoA inhibition in response to Tgfb overcomes Zeb1's block of cytoskeleton assembly and frees it for nuclear transport. A ZEB1 nuclear transport signature highlights EMT progression, identifies dedifferentiated invasive/metastatic human LUADs, and predicts survival. Blocking Zeb1 nuclear transport with a small molecule identified in this study inhibits cytoskeleton assembly, cell migration, Yap1 nuclear transport, EMT, and precancerous-to-malignant transition.

Challenges to implementation and strengthening of initial COVID-19 surveillance in Vanuatu: January-April 2020.

The Pacific island nation of Vanuatu is vulnerable to emerging infectious diseases, including epidemics and pandemics; chronic food and water insecurity; and natural hazards, including cyclones, earthquakes, tsunamis, landslides and flooding. In March 2020, the World Health Organization characterized the outbreak of novel coronavirus disease 2019 (COVID-19) as a global pandemic. By the end of April 2020, Vanuatu had reported no confirmed cases of COVID-19. Data from several sources are collected in Vanuatu's COVID-19 surveillance system to provide an overview of the situation, including data from case investigations and management, syndromic surveillance for influenza-like illness, hospital surveillance and laboratory surveillance. Review of data collected from January to the end of April 2020 suggests that there was no sustained increase in influenza-like illness in the community and no confirmed cases were identified. Lessons learnt from the early implementation of surveillance activities, the changing landscape of laboratory testing and pharmaceutical interventions, as well as the global experience, particularly in other Pacific island countries, will inform the refinement of COVID-19 surveillance activities in Vanuatu.

Lessons from COVID-19-free Vanuatu: intensive health operations for Phase 1 of repatriation and quarantine, May-July 2020.

International borders to Vanuatu closed on 23 March 2020 due to the global COVID-19 pandemic. In May-July 2020, the Government of Vanuatu focused on the safe and timely return of citizens and residents while ensuring Vanuatu remained COVID-19 free. Under Phase 1 of repatriation, between 27 May and 23 June 2020, 1522 people arrived in the capital, Port Vila, and were placed in compulsory government-mandated 14-day quarantine in 15 hotels. Pre-arrival health operations included collection of repatriate information, quarantine facility assessments, training for personnel supporting the process, and tabletop and functional exercises with live scenario simulations. During quarantine, health monitoring, mental health assessments and psychosocial support were provided. All repatriates completed 14 days of quarantine. One person developed symptoms consistent with COVID-19 during quarantine but tested negative. Overall health operations were considered a success despite logistical and resource challenges. Lessons learnt were documented during a health sector after-action review held on 22 July 2020. Key recommendations for improvement were to obtain timely receipt of repatriate information before travel, limit the number of repatriates received and avoid the mixing of "travel cohorts," ensure sufficient human resources are available to support operations while maintaining other essential services, establish a command and control structure for health operations, develop training packages and deliver them to all personnel supporting operations, and coordinate better with other sectors to ensure health aspects are considered. These recommendations were applied to further improve health operations for subsequent repatriation and quarantine, with Phase 2 commencing on 1 August 2020.

A phase I trial and pharmacokinetic study of tipifarnib, a farnesyltransferase inhibitor, and tamoxifen in metastatic breast cancer.

PURPOSE: Farnesyltransferase (FTase) inhibitors, which were designed to inhibit oncogenic Ras, act synergistically with tamoxifen in preclinical breast cancer models. We studied the safety and toxicity of tipifarnib in combination with tamoxifen in metastatic breast cancer. The pharmacokinetics and pharmacodynamics of tipifarnib were also assessed. PATIENTS AND METHODS: Patients with metastatic, hormone receptor-positive breast cancer were enrolled. Two cohorts of patients were treated with tipifarnib at either 200 or 300 mg p.o. twice daily for 21 of 28 days. Tamoxifen (20 mg once daily) was started after 1 week of tipifarnib monotherapy to perform pharmacokinetics and FTase inhibition levels in peripheral blood mononuclear cells with tipifarnib alone and with tipifarnib and tamoxifen. RESULTS: A total of 12 heavily pretreated patients with prior progression on hormonal therapy were enrolled. Minimal toxicity was observed at the 200-mg dose level of tipifarnib. At the 300-mg dose, all six patients required dose reduction of tipifarnib due to toxicities that included grade 2 nausea, rash, and fatigue and grade 3 diarrhea and neutropenia. Tipifarnib pharmacokinetic and pharmacodynamic variables were similar in the presence and absence of tamoxifen. Average FTase inhibition was 42% at 200 mg and 54% at 300 mg in peripheral blood mononuclear cells. Of the 12 patients treated, there were two partial responses and one stable disease for >6 months. CONCLUSIONS: Tipifarnib (200 mg twice daily for 21 of 28 days) and tamoxifen (20 mg once daily) can be given safely with minimal toxicity. Tamoxifen does not have a significant effect on tipifarnib pharmacokinetics.

Organisational culture and safety: an interdependent relationship.

Since the early 1990s, a body of evidence regarding the lack of quality in health care has emerged in many countries including Australia, the United Kingdom, New Zealand and the United States of America. It has brought the subject of health care safety to the top of the policy agenda and the forefront of the public debate worldwide. Studies show not only that failure of quality occurs, but also that it inflicts harm and wastes resources on a large scale. Experts in risk management, both within and outside the health care industry, emphasize system failures and system-driven errors over direct human error, and accentuate the crucial role that organisational culture plays in ensuring safety. Examination of the interrelationship between culture and safety in organisations demonstrates that organisational relationships influence both culture and safety and that effective two-way communication is pivotal to the success of the development of a corporate 'safety culture'.

Human resources for health: lessons from the cholera outbreak in Papua New Guinea.

ISSUE: Papua New Guinea is striving to achieve the minimum core requirements under the International Health Regulations in surveillance and outbreak response, and has experienced challenges in the availability and distribution of health professionals. CONTEXT: Since mid-2009, a large cholera outbreak spread across lowland regions of the country and has been associated with more than 15 500 notifications at a case fatality ratio of 3.2%. The outbreak placed significant pressure on clinical and public health services. ACTION: We describe some of the challenges to cholera preparedness and response in this human resource-limited setting, the strategies used to ensure effective cholera management and lessons learnt. OUTCOME: Cholera task forces were useful to establish a clear system of leadership and accountability for cholera outbreak response and ensure efficiencies in each technical area. Cholera outbreak preparedness and response was strongest when human resource and health systems functioned well before the outbreak. Communication relied on coordination of existing networks and methods for empowering local leaders and villagers to modify behaviours of the population. DISCUSSION: In line with the national health emergencies plan, the successes of human resource strategies during the cholera outbreak should be built upon through emergency exercises, especially in non-affected provinces. Population needs for all public health professionals involved in health emergency preparedness and response should be mapped, and planning should be implemented to increase the numbers in relevant areas. Human resource planning should be integrated with health emergency planning. It is essential to maintain and strengthen the human resource capacities and experiences gained during the cholera outbreak to ensure a more effective response to the next health emergency.

Concurrent outbreaks of cholera and peripheral neuropathy associated with high mortality among persons internally displaced by a volcanic eruption.

BACKGROUND: In October 2004, Manam Island volcano in Papua New Guinea erupted, causing over 10 000 villagers to flee to internally displaced person (IDP) camps, including 550 from Dugulaba village. Following violence over land access in March 2010, the IDPs fled the camps, and four months later concurrent outbreaks of acute watery diarrhea and unusual neurological complaints were reported in this population. MATERIALS AND METHODS: A retrospective case-control study was conducted to identify the risk factors for peripheral neuropathy. Rectal swabs were collected from cases of acute watery diarrhea. Hair and serum metals and metalloids were analyzed by Inductively Coupled Plasma-Mass Spectrometry (ICP-MS). RESULTS: There were 17 deaths among the 550 village inhabitants during the outbreak period at a crude mortality rate 21-fold that of a humanitarian crisis. Vibrio cholerae O1 El Tor Ogawa was confirmed among the population. Access to community-level rehydration was crucial to mortality. Peripheral neuropathy was diagnosed among cases with neurological symptoms. A balanced diet was significantly protective against neuropathy. A dose-response relationship was seen between peripheral neuropathy and a decreasing number of micronutrient- rich foods in the diet. Deficiencies in copper, iron, selenium and zinc were identified among the cases of peripheral neuropathy. CONCLUSIONS: Cholera likely caused the mostly preventable excess mortality. Peripheral neuropathy was not caused by cholera, but cholera may worsen existing nutritional deficiencies. The peripheral neuropathy was likely caused by complex micronutrient deficiencies linked to non-diversified diets that potentially increased the vulnerability of this population, however a new zinc-associated neuropathy could not be ruled out. Reoccurrence can be prevented by addressing the root cause of displacement and ensuring access to arable land and timely resettlement.