Modeling local coronavirus outbreaks.

This article presents an overview of methods developed for the modeling and control of local coronavirus outbreaks. The article reviews early transmission dynamics featuring exponential growth in infections, and links this to a renewal epidemic model where the current incidence of infection depends upon the expected value of incidence randomly lagged into the past. This leads directly to simple formulas for the fraction of the population infected in an unmitigated outbreak, and reveals herd immunity as the solution to an optimization problem. The model also leads to direct and easy-to-understand formulas for aligning observable epidemic indicators such as cases, hospitalizations and deaths with the unobservable incidence of infection, and as a byproduct leads to a simple first-order approach for estimating the effective reproduction number R t . The model also leads naturally to direct assessments of the effectiveness of isolation in preventing the spread of infection. This is illustrated with application to repeat asymptomatic screening programs of the sort utilized by universities, sports teams and businesses to prevent the spread of infection.

Scaling SARS-CoV-2 wastewater concentrations to population estimates of infection.

Monitoring the progression of SARS-CoV-2 outbreaks requires accurate estimation of the unobservable fraction of the population infected over time in addition to the observed numbers of COVID-19 cases, as the latter present a distorted view of the pandemic due to changes in test frequency and coverage over time. The objective of this report is to describe and illustrate an approach that produces representative estimates of the unobservable cumulative incidence of infection by scaling the daily concentrations of SARS-CoV-2 RNA in wastewater from the consistent population contribution of fecal material to the sewage collection system.

[The mortality in Amsterdam from 1554 to 2021]. / De sterfte in Amsterdam van 1554 tot 2021.

Between 1554 and 2021, the number of and mortality from epidemics in Amsterdam decreased sharply. The decrease in epidemic outbreaks, such as those of plague, smallpox and cholera, paralleled the decrease in chronic mortality from endemic ailments and diseases, such as tuberculosis, malaria and dysentery. There are several theories about the reason for these declines, which are not necessarily mutually exclusive: better nutrition, greater prosperity, increasing altruism, and a growing understanding of cause and effect with targeted medical and public health measures. In the powder keg of chronic poverty and poor public health, a social crisis, such as war, migration, and natural disaster, usually was the spark that led to epidemic outbreaks. The nature and extent of poverty and ill health have changed and improved over the centuries, but the threat of man-made crises is unfortunately unabated.

Predicting daily COVID-19 case rates from SARS-CoV-2 RNA concentrations across a diversity of wastewater catchments.

We assessed the relationship between municipality COVID-19 case rates and SARS-CoV-2 concentrations in the primary sludge of corresponding wastewater treatment facilities. Over 1700 daily primary sludge samples were collected from six wastewater treatment facilities with catchments serving 18 cities and towns in the State of Connecticut, USA. Samples were analyzed for SARS-CoV-2 RNA concentrations during a 10 month time period that overlapped with October 2020 and winter/spring 2021 COVID-19 outbreaks in each municipality. We fit lagged regression models to estimate reported case rates in the six municipalities from SARS-CoV-2 RNA concentrations collected daily from corresponding wastewater treatment facilities. Results demonstrate the ability of SARS-CoV-2 RNA concentrations in primary sludge to estimate COVID-19 reported case rates across treatment facilities and wastewater catchments, with coverage probabilities ranging from 0.94 to 0.96. Lags of 0 to 1 days resulted in the greatest predictive power for the model. Leave-one-out cross validation suggests that the model can be broadly applied to wastewater catchments that range in more than one order of magnitude in population served. The close relationship between case rates and SARS-CoV-2 concentrations demonstrates the utility of using primary sludge samples for monitoring COVID-19 outbreak dynamics. Estimating case rates from wastewater data can be useful in locations with limited testing availability, testing disparities, or delays in individual COVID-19 testing programs.

Aligning SARS-CoV-2 indicators via an epidemic model: application to hospital admissions and RNA detection in sewage sludge.

Ascertaining the state of coronavirus outbreaks is crucial for public health decision-making. Absent repeated representative viral test samples in the population, public health officials and researchers alike have relied on lagging indicators of infection to make inferences about the direction of the outbreak and attendant policy decisions. Recently researchers have shown that SARS-CoV-2 RNA can be detected in municipal sewage sludge with measured RNA concentrations rising and falling suggestively in the shape of an epidemic curve while providing an earlier signal of infection than hospital admissions data. The present paper presents a SARS-CoV-2 epidemic model to serve as a basis for estimating the incidence of infection, and shows mathematically how modeled transmission dynamics translate into infection indicators by incorporating probability distributions for indicator-specific time lags from infection. Hospital admissions and SARS-CoV-2 RNA in municipal sewage sludge are simultaneously modeled via maximum likelihood scaling to the underlying transmission model. The results demonstrate that both data series plausibly follow from the transmission model specified and provide a 95% confidence interval estimate of the reproductive number R0 ≈ 2.4 ± 0.2. Sensitivity analysis accounting for alternative lag distributions from infection until hospitalization and sludge RNA concentration respectively suggests that the detection of viral RNA in sewage sludge leads hospital admissions by 3 to 5 days on average. The analysis suggests that stay-at-home restrictions plausibly removed 89% of the population from the risk of infection with the remaining 11% exposed to an unmitigated outbreak that infected 9.3% of the total population.

Repeat SARS-CoV-2 testing models for residential college populations.

Residential colleges are considering re-opening under uncertain futures regarding the COVID-19 pandemic. We consider repeat SARS-CoV-2 testing models for the purpose of containing outbreaks in the residential campus community. The goal of repeat testing is to detect and isolate new infections rapidly to block transmission that would otherwise occur both on and off campus. The models allow for specification of aspects including scheduled on-campus resident screening at a given frequency, test sensitivity that can depend on the time since infection, imported infections from off campus throughout the school term, and a lag from testing until student isolation due to laboratory turnaround and student relocation delay. For early- (late-) transmission of SARS-CoV-2 by age of infection, we find that weekly screening cannot reliably contain outbreaks with reproductive numbers above 1.4 (1.6) if more than one imported exposure per 10,000 students occurs daily. Screening every three days can contain outbreaks providing the reproductive number remains below 1.75 (2.3) if transmission happens earlier (later) with time from infection, but at the cost of increased false positive rates requiring more isolation quarters for students testing positive. Testing frequently while minimizing the delay from testing until isolation for those found positive are the most controllable levers for preventing large residential college outbreaks. A web app that implements model calculations is available to facilitate exploration and consideration of a variety of scenarios.

Snapshot Models of Undocumented Immigration.

Accurately estimating the size of the undocumented immigrant population is a critical component of assessing the health and security risks of undocumented immigration to the United States. To provide one such estimate, we use data from the Mexican Migration Project (MMP), a study that includes samples of undocumented Mexican immigrants to the United States after their return to Mexico. Of particular interest are the departure and return dates of a sampled migrant's most recent sojourn in the United States, and the total number of such journeys undertaken by that migrant household, for these data enable the construction of data-driven undocumented immigration models. However, such data are subject to an extreme physical bias, for to be included in such a sample, a migrant must have returned to Mexico by the time of the survey, excluding those undocumented immigrants still in the United States. In our analysis, we account for this bias by jointly modeling trip timing and duration to produce the likelihood of observing the data in such a "snapshot" sample. Our analysis characterizes undocumented migration flows including single-visit migrants, repeat visitors, and "retirement" from circular migration. Starting with 1987, we apply our models to 30 annual random snapshot surveys of returned undocumented Mexican migrants accounting for undocumented Mexican migration from 1980 to 2016. Scaling to population quantities and supplementing our analysis of southern border crossings with estimates of visa overstays, we produce lower bounds on the total number of undocumented immigrants that are much larger than conventional estimates based on U.S.-based census-linked surveys, and broadly consistent with the more recent estimates reported by Fazel-Zarandi, Feinstein, and Kaplan.

Measurement of SARS-CoV-2 RNA in wastewater tracks community infection dynamics.

We measured severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA concentrations in primary sewage sludge in the New Haven, Connecticut, USA, metropolitan area during the Coronavirus Disease 2019 (COVID-19) outbreak in Spring 2020. SARS-CoV-2 RNA was detected throughout the more than 10-week study and, when adjusted for time lags, tracked the rise and fall of cases seen in SARS-CoV-2 clinical test results and local COVID-19 hospital admissions. Relative to these indicators, SARS-CoV-2 RNA concentrations in sludge were 0-2 d ahead of SARS-CoV-2 positive test results by date of specimen collection, 0-2 d ahead of the percentage of positive tests by date of specimen collection, 1-4 d ahead of local hospital admissions and 6-8 d ahead of SARS-CoV-2 positive test results by reporting date. Our data show the utility of viral RNA monitoring in municipal wastewater for SARS-CoV-2 infection surveillance at a population-wide level. In communities facing a delay between specimen collection and the reporting of test results, immediate wastewater results can provide considerable advance notice of infection dynamics.

Containing 2019-nCoV (Wuhan) coronavirus.

The novel coronavirus 2019-nCoV first appeared in December 2019 in Wuhan, China. While most of the initial cases were linked to the Huanan Seafood Wholesale Market, person-to-person transmission has been verified. Given that a vaccine cannot be developed and deployed for at least a year, preventing further transmission relies upon standard principles of containment, two of which are the isolation of known cases and the quarantine of persons believed at high risk of exposure. This note presents probability models for assessing the effectiveness of case isolation and quarantine within a community during the initial phase of an outbreak with illustrations based on early observations from Wuhan.

Contributions of Persons Living With Dementia to Scientific Research Meetings. Results From the National Research Summit on Care, Services, and Supports for Persons With Dementia and Their Caregivers.

OBJECTIVE: Inclusion of patients in research activities has increased in the United States but no guidelines for inclusion of individuals with cognitive impairment exist. The experiences from the Persons Living with Dementia (PLWD) Stakeholder Group that formed to support the first National Research Summit on Care, Services, and Supports for Persons with Dementia and Their Caregivers provided a test of feasibility of this type of participation for a major research meeting and an opportunity to understand specific contributions of the Group. METHODS: The PLWD Stakeholder Group was formed by Summit co-chairs as one of six stakeholder groups charged with providing input into the Summit agenda and meeting recommendations. Members were recruited through clinician/researchers with personal knowledge of potential members. Following the Summit, Group members convened to review Group contributions to the Summit agenda, list of speakers, and Summit research recommendations. RESULTS: The PLWD Group influenced the content of the Summit agenda and some Group members were invited to contribute through Summit presentations. The Group influenced Summit outcomes: of the 58 research recommendations that emerged, 30 express ideas contributed by the PLWD. CONCLUSIONS: The Stakeholder Group for PLWD proved feasible to implement and impacted the agenda and output of a major national research meeting on dementia.

The Experiences of Persons Living with Dementia Planning for a Dementia Research Meeting. Lessons Learned From the National Research Summit on Care, Services, and Supports for Persons With Dementia and Their Caregivers.

OBJECTIVE: A stakeholder group for persons living with dementia (PLWD) was convened to support the work of a major US dementia research meeting. The objectives of this examination are to present the steps used to implement the Group and guidance for both PLWD and researchers for partnering on research conference planning and participation. METHODS: PLWD met monthly to provide input into the agenda for the 2017 Research Summit on Dementia Care and some Group members also presented at the Summit. Following the Summit, the Group reviewed their contributions and completed an evaluation of the Group process, identifying best practices to support future efforts. RESULTS: Group members were initially unsure about participating due to concerns about ability to contribute and concerns about disease progression. Members reported that participation was a positive experience, however, identifying Group-led governance and attention to Group work process as important contributors. In addition to giving input to the Summit and having the opportunity to interact with researchers, sharing personal experiences with each other was part of the value of the Group to members. Careful Group selection and attention to governance were among the Best Practices members. CONCLUSION: Despite initial uncertainty among members about participating as a Stakeholder Group to inform a national research meeting, members developed a successful process for governance, convening, and providing input to a major national research meeting. Group's self-evaluation yielded specific strategies likely to be useful in formation and implementation of future partnerships between researchers and persons living with dementia.

Intratumoral temozolomide in spontaneous canine gliomas: feasibility of a novel therapy using implanted microcylinders.

Entotherapy an image-guided drug-eluting microcylinder platform, has the potential to bypass the limitations of systemic chemotherapy use in the treatment of canine brain tumours. Gliomas, which are common in dogs and also represent the majority of fatal brain tumours in humans, can be amenable to chemotherapy with temozolomide. Biopolymer microcylinders conjugated with temozolomide and gadolinium were implanted into partially resected tumours of four client-owned dogs with gliomas. All four dogs presented with generalized seizures and had mild to no neurologic deficits at the time of craniotomy. All dogs underwent craniotomy for implantation of the microcylinders into partially resected gliomas (glioblastoma multiforme {n = 1} or oligodendroglioma {n = 3}). All dogs recovered well from the craniotomy and implantation procedure. This novel procedure appears to be feasible and tolerated in tumour-bearing dogs. A future controlled clinical study can now aim to evaluate the microcylinder implantation for long-term efficacy.

The number of undocumented immigrants in the United States: Estimates based on demographic modeling with data from 1990 to 2016.

We apply standard demographic principles of inflows and outflows to estimate the number of undocumented immigrants in the United States, using the best available data, including some that have only recently become available. Our analysis covers the years 1990 to 2016. We develop an estimate of the number of undocumented immigrants based on parameter values that tend to underestimate undocumented immigrant inflows and overstate outflows; we also show the probability distribution for the number of undocumented immigrants based on simulating our model over parameter value ranges. Our conservative estimate is 16.7 million for 2016, nearly fifty percent higher than the most prominent current estimate of 11.3 million, which is based on survey data and thus different sources and methods. The mean estimate based on our simulation analysis is 22.1 million, essentially double the current widely accepted estimate. Our model predicts a similar trajectory of growth in the number of undocumented immigrants over the years of our analysis, but at a higher level. While our analysis delivers different results, we note that it is based on many assumptions. The most critical of these concern border apprehension rates and voluntary emigration rates of undocumented immigrants in the U.S. These rates are uncertain, especially in the 1990's and early 2000's, which is when-both based on our modeling and the very different survey data approach-the number of undocumented immigrants increases most significantly. Our results, while based on a number of assumptions and uncertainties, could help frame debates about policies whose consequences depend on the number of undocumented immigrants in the United States.

An Adaptive Approach to Locating Mobile HIV Testing Services.

BACKGROUND: Public health agencies suggest targeting "hotspots" to identify individuals with undetected HIV infection. However, definitions of hotspots vary. Little is known about how best to target mobile HIV testing resources. METHODS: We conducted a computer-based tournament to compare the yield of 4 algorithms for mobile HIV testing. Over 180 rounds of play, the algorithms selected 1 of 3 hypothetical zones, each with unknown prevalence of undiagnosed HIV, in which to conduct a fixed number of HIV tests. The algorithms were: 1) Thompson Sampling, an adaptive Bayesian search strategy; 2) Explore-then-Exploit, a strategy that initially draws comparable samples from all zones and then devotes all remaining rounds of play to HIV testing in whichever zone produced the highest observed yield; 3) Retrospection, a strategy using only base prevalence information; and; 4) Clairvoyance, a benchmarking strategy that employs perfect information about HIV prevalence in each zone. RESULTS: Over 250 tournament runs, Thompson Sampling outperformed Explore-then-Exploit 66% of the time, identifying 15% more cases. Thompson Sampling's superiority persisted in a variety of circumstances examined in the sensitivity analysis. Case detection rates using Thompson Sampling were, on average, within 90% of the benchmark established by Clairvoyance. Retrospection was consistently the poorest performer. LIMITATIONS: We did not consider either selection bias (i.e., the correlation between infection status and the decision to obtain an HIV test) or the costs of relocation to another zone from one round of play to the next. CONCLUSIONS: Adaptive methods like Thompson Sampling for mobile HIV testing are practical and effective, and may have advantages over other commonly used strategies.

A Randomized, Open-Label, Safety and Exploratory Efficacy Study of Kanglaite Injection (KLTi) plus Gemcitabine versus Gemcitabine in Patients with Advanced Pancreatic Cancer.

Background: This study was designed to assess the safety and preliminary efficacy of KLTi plus gemcitabine in patients with locally advanced or metastatic pancreatic cancer. Methods: In a randomized, open-label study, patients with locally advanced or metastatic pancreatic cancer were randomized 2:1 to receive KLTi plus gemcitabine or gemcitabine monotherapy. Three sequential cohorts were tested at 30 g/day, 50 g/day, and 30 g/day. Gemcitabine was administered at 1000 mg/m2 on days 1, 8 and 15 of each 28 day cycle. KLTi was administered on days 1-5, 8-12, and 15-19 of each 28 day cycle. Patients received study treatment until disease progression. The primary endpoint was progression-free survival in the ITT population. Safety evaluation was based on patients who received any study treatment. ClinicalTrials.gov identifier NCT00733850. Results: Eighty-five patients were randomized including 41 (28:13) in Cohort 1, 18 (12:6) in Cohort 2, and 26 (17:9) in Cohort 3. Due to a different dose and/or shift in patient populations in Cohort 2 and 3, efficacy data for the 30 gm dose are presented in this manuscript for Cohort 1 alone, and for the combination of Cohort 1+3. The 30 gm KLTi + gemcitabine group had a statistically significant improvement in progression-free survival (PFS) as assessed by blinded independent radiology review in the ITT population, with a median of 112 days, versus 58 days in the gemcitabine group (HR 0.50; 95% CI: 0.27, 0.92), p = 0.0240. The incidence rates of TEAEs, CTCAE Grade 3 or higher TEAEs, and SAEs were similar between the two arms. There were no deaths related to KLTi + gemcitabine treatment. Conclusion: Kanglaite Injection (30 g/day) plus a standard regimen of gemcitabine demonstrated encouraging clinical evidence of anti-neoplastic activity and a well-tolerated safety profile.