Impact and cost-effectiveness of the 6-month BPaLM regimen for rifampicin-resistant tuberculosis in Moldova: A mathematical modeling analysis.

BACKGROUND: Emerging evidence suggests that shortened, simplified treatment regimens for rifampicin-resistant tuberculosis (RR-TB) can achieve comparable end-of-treatment (EOT) outcomes to longer regimens. We compared a 6-month regimen containing bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) to a standard of care strategy using a 9- or 18-month regimen depending on whether fluoroquinolone resistance (FQ-R) was detected on drug susceptibility testing (DST). METHODS AND FINDINGS: The primary objective was to determine whether 6 months of BPaLM is a cost-effective treatment strategy for RR-TB. We used genomic and demographic data to parameterize a mathematical model estimating long-term health outcomes measured in quality-adjusted life years (QALYs) and lifetime costs in 2022 USD ($) for each treatment strategy for patients 15 years and older diagnosed with pulmonary RR-TB in Moldova, a country with a high burden of TB drug resistance. For each individual, we simulated the natural history of TB and associated treatment outcomes, as well as the process of acquiring resistance to each of 12 anti-TB drugs. Compared to the standard of care, 6 months of BPaLM was cost-effective. This strategy was estimated to reduce lifetime costs by $3,366 (95% UI: [1,465, 5,742] p < 0.001) per individual, with a nonsignificant change in QALYs (-0.06; 95% UI: [-0.49, 0.03] p = 0.790). For those stopping moxifloxacin under the BPaLM regimen, continuing with BPaL plus clofazimine (BPaLC) provided more QALYs at lower cost than continuing with BPaL alone. Strategies based on 6 months of BPaLM had at least a 93% chance of being cost-effective, so long as BPaLC was continued in the event of stopping moxifloxacin. BPaLM for 6 months also reduced the average time spent with TB resistant to amikacin, bedaquiline, clofazimine, cycloserine, moxifloxacin, and pyrazinamide, while it increased the average time spent with TB resistant to delamanid and pretomanid. Sensitivity analyses showed 6 months of BPaLM to be cost-effective across a broad range of values for the relative effectiveness of BPaLM, and the proportion of the cohort with FQ-R. Compared to the standard of care, 6 months of BPaLM would be expected to save Moldova's national TB program budget $7.1 million (95% UI: [1.3 million, 15.4 million] p = 0.002) over the 5-year period from implementation. Our analysis did not account for all possible interactions between specific drugs with regard to treatment outcomes, resistance acquisition, or the consequences of specific types of severe adverse events, nor did we model how the intervention may affect TB transmission dynamics. CONCLUSIONS: Compared to standard of care, longer regimens, the implementation of the 6-month BPaLM regimen could improve the cost-effectiveness of care for individuals diagnosed with RR-TB, particularly in settings with a high burden of drug-resistant TB. Further research may be warranted to explore the impact and cost-effectiveness of shorter RR-TB regimens across settings with varied drug-resistant TB burdens and national income levels.

Predictive power of wastewater for nowcasting infectious disease transmission: A retrospective case study of five sewershed areas in Louisville, Kentucky.

BACKGROUND: Epidemiological nowcasting traditionally relies on count surveillance data. The availability and quality of such count data may vary over time, limiting representation of true infections. Wastewater data correlates with traditional surveillance data and may provide additional value for nowcasting disease trends. METHODS: We obtained SARS-CoV-2 case, death, wastewater, and serosurvey data for Jefferson County, Kentucky (USA), between August 2020 and March 2021, and parameterized an existing nowcasting model using combinations of these data. We assessed the predictive performance and variability at the sewershed level and compared the effects of adding or replacing wastewater data to case and death reports. FINDINGS: Adding wastewater data minimally improved the predictive performance of nowcasts compared to a model fitted to case and death data (Weighted Interval Score (WIS) 0.208 versus 0.223), and reduced the predictive performance compared to a model fitted to deaths data (WIS 0.517 versus 0.500). Adding wastewater data to deaths data improved the nowcasts agreement to estimates from models using cases and deaths data. These findings were consistent across individual sewersheds as well as for models fit to the aggregated total data of 5 sewersheds. Retrospective reconstructions of epidemiological dynamics created using different combinations of data were in general agreement (coverage >75%). INTERPRETATION: These findings show wastewater data may be valuable for infectious disease nowcasting when clinical surveillance data are absent, such as early in a pandemic or in low-resource settings where systematic collection of epidemiologic data is difficult.

Changes in Population Immunity Against Infection and Severe Disease From Severe Acute Respiratory Syndrome Coronavirus 2 Omicron Variants in the United States Between December 2021 and November 2022.

BACKGROUND: Although a substantial fraction of the US population was infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during December 2021-February 2022, the subsequent evolution of population immunity reflects the competing influences of waning protection over time and acquisition or restoration of immunity through additional infections and vaccinations. METHODS: Using a Bayesian evidence synthesis model of reported coronavirus disease 2019 (COVID-19) data (diagnoses, hospitalizations), vaccinations, and waning patterns for vaccine- and infection-acquired immunity, we estimate population immunity against infection and severe disease from SARS-CoV-2 Omicron variants in the United States, by location (national, state, county) and week. RESULTS: By 9 November 2022, 97% (95%-99%) of the US population were estimated to have prior immunological exposure to SARS-CoV-2. Between 1 December 2021 and 9 November 2022, protection against a new Omicron infection rose from 22% (21%-23%) to 63% (51%-75%) nationally, and protection against an Omicron infection leading to severe disease increased from 61% (59%-64%) to 89% (83%-92%). Increasing first booster uptake to 55% in all states (current US coverage: 34%) and second booster uptake to 22% (current US coverage: 11%) would increase protection against infection by 4.5 percentage points (2.4-7.2) and protection against severe disease by 1.1 percentage points (1.0-1.5). CONCLUSIONS: Effective protection against SARS-CoV-2 infection and severe disease in November 2022 was substantially higher than in December 2021. Despite this high level of protection, a more transmissible or immune evading (sub)variant, changes in behavior, or ongoing waning of immunity could lead to a new SARS-CoV-2 wave.

Population Immunity to Pre-Omicron and Omicron Severe Acute Respiratory Syndrome Coronavirus 2 Variants in US States and Counties Through 1 December 2021.

BACKGROUND: Both severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (COVID-19) vaccination contribute to population-level immunity against SARS-CoV-2. This study estimated the immunological exposure and effective protection against future SARS-CoV-2 infection in each US state and county over 2020-2021 and how this changed with the introduction of the Omicron variant. METHODS: We used a Bayesian model to synthesize estimates of daily SARS-CoV-2 infections, vaccination data and estimates of the relative rates of vaccination conditional on infection status to estimate the fraction of the population with (1) immunological exposure to SARS-CoV-2 (ever infected with SARS-CoV-2 and/or received ≥1 doses of a COVID-19 vaccine), (2) effective protection against infection, and (3) effective protection against severe disease, for each US state and county from 1 January 2020 to 1 December 2021. RESULTS: The estimated percentage of the US population with a history of SARS-CoV-2 infection or vaccination as of 1 December 2021 was 88.2% (95% credible interval [CrI], 83.6%-93.5%). Accounting for waning and immune escape, effective protection against the Omicron variant on 1 December 2021 was 21.8% (95% CrI, 20.7%-23.4%) nationally and ranged between 14.4% (13.2%-15.8%; West Virginia) and 26.4% (25.3%-27.8%; Colorado). Effective protection against severe disease from Omicron was 61.2% (95% CrI, 59.1%-64.0%) nationally and ranged between 53.0% (47.3%-60.0%; Vermont) and 65.8% (64.9%-66.7%; Colorado). CONCLUSIONS: While more than four-fifths of the US population had prior immunological exposure to SARS-CoV-2 via vaccination or infection on 1 December 2021, only a fifth of the population was estimated to have effective protection against infection with the immune-evading Omicron variant.

Changes in population immunity against infection and severe disease from SARS-CoV-2 Omicron variants in the United States between December 2021 and November 2022.

Importance: While a substantial fraction of the US population was infected with SARS-CoV-2 during December 2021 - February 2022, the subsequent evolution of population immunity against SARS-CoV-2 Omicron variants reflects the competing influences of waning protection over time and acquisition or restoration of immunity through additional infections and vaccinations. Objective: To estimate changes in population immunity against infection and severe disease due to circulating SARS-CoV-2 Omicron variants in the United States from December 2021 to November 2022, and to quantify the protection against a potential 2022-2023 winter SARS-CoV-2 wave. Design setting participants: Bayesian evidence synthesis of reported COVID-19 data (diagnoses, hospitalizations), vaccinations, and waning patterns for vaccine- and infection-acquired immunity, using a mathematical model of COVID-19 natural history. Main Outcomes and Measures: Population immunity against infection and severe disease from SARS-CoV-2 Omicron variants in the United States, by location (national, state, county) and week. Results: By November 9, 2022, 94% (95% CrI, 79%-99%) of the US population were estimated to have been infected by SARS-CoV-2 at least once. Combined with vaccination, 97% (95%-99%) were estimated to have some prior immunological exposure to SARS-CoV-2. Between December 1, 2021 and November 9, 2022, protection against a new Omicron infection rose from 22% (21%-23%) to 63% (51%-75%) nationally, and protection against an Omicron infection leading to severe disease increased from 61% (59%-64%) to 89% (83%-92%). Increasing first booster uptake to 55% in all states (current US coverage: 34%) and second booster uptake to 22% (current US coverage: 11%) would increase protection against infection by 4.5 percentage points (2.4-7.2) and protection against severe disease by 1.1 percentage points (1.0-1.5). Conclusions and Relevance: Effective protection against SARS-CoV-2 infection and severe disease in November 2022 was substantially higher than in December 2021. Despite this high level of protection, a more transmissible or immune evading (sub)variant, changes in behavior, or ongoing waning of immunity could lead to a new SARS-CoV-2 wave. Key points: Question: How did population immunity against SARS-CoV-2 infection and subsequent severe disease change between December 2021, and November 2022?Findings: On November 9, 2022, the protection against a SARS-CoV-2 infection with the Omicron variant was estimated to be 63% (51%-75%) in the US, and the protection against severe disease was 89% (83%-92%).Meaning: As most of the newly acquired immunity has been accumulated in the December 2021-February 2022 Omicron wave, risk of reinfection and subsequent severe disease remains present at the beginning of the 2022-2023 winter, despite high levels of protection.

Reconstructing the course of the COVID-19 epidemic over 2020 for US states and counties: Results of a Bayesian evidence synthesis model.

Reported COVID-19 cases and deaths provide a delayed and incomplete picture of SARS-CoV-2 infections in the United States (US). Accurate estimates of both the timing and magnitude of infections are needed to characterize viral transmission dynamics and better understand COVID-19 disease burden. We estimated time trends in SARS-CoV-2 transmission and other COVID-19 outcomes for every county in the US, from the first reported COVID-19 case in January 13, 2020 through January 1, 2021. To do so we employed a Bayesian modeling approach that explicitly accounts for reporting delays and variation in case ascertainment, and generates daily estimates of incident SARS-CoV-2 infections on the basis of reported COVID-19 cases and deaths. The model is freely available as the covidestim R package. Nationally, we estimated there had been 49 million symptomatic COVID-19 cases and 404,214 COVID-19 deaths by the end of 2020, and that 28% of the US population had been infected. There was county-level variability in the timing and magnitude of incidence, with local epidemiological trends differing substantially from state or regional averages, leading to large differences in the estimated proportion of the population infected by the end of 2020. Our estimates of true COVID-19 related deaths are consistent with independent estimates of excess mortality, and our estimated trends in cumulative incidence of SARS-CoV-2 infection are consistent with trends in seroprevalence estimates from available antibody testing studies. Reconstructing the underlying incidence of SARS-CoV-2 infections across US counties allows for a more granular understanding of disease trends and the potential impact of epidemiological drivers.

Population immunity to pre-Omicron and Omicron SARS-CoV-2 variants in US states and counties through December 1, 2021.

Prior infection and vaccination both contribute to population-level SARS-CoV-2 immunity. We used a Bayesian model to synthesize evidence and estimate population immunity to prevalent SARS-CoV-2 variants in the United States over the course of the epidemic until December 1, 2021, and how this changed with the introduction of the Omicron variant. We used daily SARS-CoV-2 infection estimates and vaccination coverage data for each US state and county. We estimated relative rates of vaccination conditional on previous infection status using the Census Bureau’s Household Pulse Survey. We used published evidence on natural and vaccine-induced immunity, including waning and immune escape. The estimated percentage of the US population with a history of SARS-CoV-2 infection or vaccination as of December 1, 2021, was 88.2% (95%CrI: 83.6%-93.5%), compared to 24.9% (95%CrI: 18.5%-34.1%) on January 1, 2021. State-level estimates for December 1, 2021, ranged between 76.9% (95%CrI: 67.6%-87.6%, West Virginia) and 94.4% (95%CrI: 91.2%-97.3%, New Mexico). Accounting for waning and immune escape, the effective protection against the Omicron variant on December 1, 2021, was 21.8% (95%CrI: 20.7%-23.4%) nationally and ranged between 14.4% (95%CrI: 13.2%-15.8%, West Virginia), to 26.4% (95%CrI: 25.3%-27.8%, Colorado). Effective protection against severe disease from Omicron was 61.2% (95%CrI: 59.1%-64.0%) nationally and ranged between 53.0% (95%CrI: 47.3%-60.0%, Vermont) and 65.8% (95%CrI: 64.9%-66.7%, Colorado). While over three-quarters of the US population had prior immunological exposure to SARS-CoV-2 via vaccination or infection on December 1, 2021, only a fifth of the population was estimated to have effective protection to infection with the immune-evading Omicron variant. Significance: Both SARS-CoV-2 infection and COVID-19 vaccination contribute to population-level immunity against SARS-CoV-2. This study estimates the immunity and effective protection against future SARS-CoV-2 infection in each US state and county over 2020-2021. The estimated percentage of the US population with a history of SARS-CoV-2 infection or vaccination as of December 1, 2021, was 88.2% (95%CrI: 83.6%-93.5%). Accounting for waning and immune escape, protection against the Omicron variant was 21.8% (95%CrI: 20.7%-23.4%). Protection against infection with the Omicron variant ranged between 14.4% (95%CrI: 13.2%-15.8%%, West Virginia) and 26.4% (95%CrI: 25.3%-27.8%, Colorado) across US states. The introduction of the immune-evading Omicron variant resulted in an effective absolute increase of approximately 30 percentage points in the fraction of the population susceptible to infection.

Reconstructing the course of the COVID-19 epidemic over 2020 for US states and counties: results of a Bayesian evidence synthesis model.

Reported COVID-19 cases and deaths provide a delayed and incomplete picture of SARS-CoV-2 infections in the United States (US). Accurate estimates of both the timing and magnitude of infections are needed to characterize viral transmission dynamics and better understand COVID-19 disease burden. We estimated time trends in SARS-CoV-2 transmission and other COVID-19 outcomes for every county in the US, from the first reported COVID-19 case in January 13, 2020 through January 1, 2021. To do so we employed a Bayesian modeling approach that explicitly accounts for reporting delays and variation in case ascertainment, and generates daily estimates of incident SARS-CoV-2 infections on the basis of reported COVID-19 cases and deaths. The model is freely available as the covidestim R package. Nationally, we estimated there had been 49 million symptomatic COVID-19 cases and 400,718 COVID-19 deaths by the end of 2020, and that 27% of the US population had been infected. The results also demonstrate wide county-level variability in the timing and magnitude of incidence, with local epidemiological trends differing substantially from state or regional averages, leading to large differences in the estimated proportion of the population infected by the end of 2020. Our estimates of true COVID-19 related deaths are consistent with independent estimates of excess mortality, and our estimated trends in cumulative incidence of SARS-CoV-2 infection are consistent with trends in seroprevalence estimates from available antibody testing studies. Reconstructing the underlying incidence of SARS-CoV-2 infections across US counties allows for a more granular understanding of disease trends and the potential impact of epidemiological drivers.

All for one or some for all? Evaluating informative hypotheses using multiple N = 1 studies.

Analyses are mostly executed at the population level, whereas in many applications the interest is on the individual level instead of the population level. In this paper, multiple N = 1 experiments are considered, where participants perform multiple trials with a dichotomous outcome in various conditions. Expectations with respect to the performance of participants can be translated into so-called informative hypotheses. These hypotheses can be evaluated for each participant separately using Bayes factors. A Bayes factor expresses the relative evidence for two hypotheses based on the data of one individual. This paper proposes to "average" these individual Bayes factors in the gP-BF, the average relative evidence. The gP-BF can be used to determine whether one hypothesis is preferred over another for all individuals under investigation. This measure provides insight into whether the relative preference of a hypothesis from a pre-defined set is homogeneous over individuals. Two additional measures are proposed to support the interpretation of the gP-BF: the evidence rate (ER), the proportion of individual Bayes factors that support the same hypothesis as the gP-BF, and the stability rate (SR), the proportion of individual Bayes factors that express a stronger support than the gP-BF. These three statistics can be used to determine the relative support in the data for the informative hypotheses entertained. Software is available that can be used to execute the approach proposed in this paper and to determine the sensitivity of the outcomes with respect to the number of participants and within condition replications.

Tetris and Word games lead to fewer intrusive memories when applied several days after analogue trauma.

Background: Intrusive trauma memories are a key symptom of posttraumatic stress disorder (PTSD), so disrupting their recurrence is highly important. Intrusion development was hindered by visuospatial interventions administered up to 24 hours after analogue trauma. It is unknown whether interventions can be applied later, and whether modality or working-memory load are crucial factors. Objectives: This study tested: (1) whether a visuospatial task would lead to fewer intrusions compared to a reactivation-only group when applied after memory reactivation four days after analogue trauma exposure (extended replication), (2) whether both tasks (i.e. one aimed to be visuospatial, one more verbal) would lead to fewer intrusions than the reactivation-only group (intervention effect), and (3) whether supposed task modality (visuospatial or verbal) is a critical component (modality effect). Method: Fifty-four participants were randomly assigned to reactivation+Tetris (visuospatial), reactivation+Word games (verbal), or reactivation-only (no task). They watched an aversive film (day 0) and recorded intrusive memories of the film in diary A. On day 4, memory was reactivated, after which participants played Tetris, Word games, or had no task for 10 minutes. They then kept a second diary (B). Informative hypotheses were evaluated using Bayes factors. Results: Reactivation+Tetris and reactivation+Word games resulted in relatively fewer intrusions from the last day of diary A to the first day of diary B than reactivation-only (objective 1 and 2). Thus, both tasks were effective even when applied days after analogue trauma. Reactivation-only was not effective. Reactivation+Word games appeared to result in fewer intrusions than reactivation+Tetris (objective 3; modality effect), but this evidence was weak. Explorative analyses showed that Word games were more difficult than Tetris. Conclusions: Applying a task four days after the trauma film (during memory reconsolidation) was effective. The modality versus working-memory load issue is inconclusive.

Planteamiento: Los recuerdos intrusivos de trauma son un síntoma clave del trastorno de estrés postraumático (TEPT), por lo que es muy importante interrumpir su recurrencia. Se obstaculizó el desarrollo de intrusiones mediante intervenciones visuoespaciales administradas hasta 24 horas después de un trauma analógico. Se desconoce si las intervenciones pueden ser aplicadas más adelante, y si la modalidad o la carga de la memoria de trabajo son factores cruciales. Objetivos: El estudio comprobaba: (1) si una tarea visuoespacial conduciría a menos intrusiones en comparación con un grupo de solo reactivación cuando se aplicaba después de la reactivación del recuerdo, 4 días después de la exposición al trauma analógico (replicación extendida); (2) si ambas tareas (una pretendía ser más visuoespacial y otra más verbal) darían lugar a menos intrusiones que el grupo de solo reactivación (efecto de la intervención), y 3) si la supuesta modalidad de la tarea (visuoespacial o verbal) es un componente fundamental (efecto de la modalidad). Método: Se asignaron aleatoriamente 54 participantes a reactivación + Tetris (visuoespacial), reactivación + juegos de palabras (verbal), o solo reactivación (sin tarea). Vieron una película aversiva (día 0) y registraron recuerdos intrusivos de la película en el diario A. El cuarto día, se reactivó el recuerdo, después de lo cual los participantes jugaron al Tetris, a juegos de palabras, o no hicieron ninguna tarea durante 10 minutos. Luego escribieron un segundo diario (B). Se evaluaron las hipótesis informativas con factores de Bayes. Resultados: Reactivación + Tetris y reactivación + juegos de palabras dieron como resultado relativamente menos intrusiones que sólo la reactivación (objetivo 1 y 2), desde el último día del diario A hasta el primer día del diario B. Por lo tanto, ambas tareas fueron eficaces incluso cuando se aplicaron días después del trauma analógico. La reactivación por separado no fue efectiva. Reactivación + juegos de palabras pareció resultar en menos intrusiones que reactivación + Tetris (objetivo 3, efecto de la modalidad), pero esta evidencia era débil. Los análisis exploratorios mostraron que los juegos de palabras eran más difíciles que el Tetris. Conclusiones: La aplicación de una tarea 4 días después de la película traumática (durante la reconsolidación de la memoria) fue efectiva. La modalidad versus el problema de la carga de memoria de trabajo no es concluyente.

A virtual reality paradigm as an analogue to real-life trauma: its effectiveness compared with the trauma film paradigm.

Background: The trauma film paradigm (TFP) is a well-established method to study the effects of analogue psychological trauma under controlled laboratory settings. It has been used to examine pre-, peri-, and post-trauma processes, and to create and test interventions. A possible drawback is that watching films is a somewhat passive endeavour that lacks active behavioural engagement. Virtual reality (VR) may provide a better alternative. Like the TFP, VR allows for experimental control. In addition, it can induce a greater 'feeling of presence' and allows interaction with the environment, enabling research on action-reaction associations. Objective: We aimed to validate the utility of a VR paradigm as an experimental model to study psychological trauma by comparing its effectiveness with the TFP. Method: One group of participants (N = 25) was shown an aversive film, and another group (N = 25) moved through a VR scene. Main outcome measures were intrusion frequency assessed with a 7-day diary and self-rated vividness and emotionality of recalled memories related to the film or VR scene. Results: The results indicate that the film and VR scene were equally effective in inducing vivid and intrusive memories. However, self-reported emotional intensity appeared to be higher for memories related to the film than for memories related to the VR scene. Conclusions: Perhaps the film was more effective in inducing emotional memories than the VR scene due to its more aversive content. However, the VR scene seemed equally effective in inducing vivid and intrusive memories, and merits further exploration in light of ethical considerations (less aversive content) and other presumably beneficial qualities (e.g. inducing a greater feeling of presence and allowing interaction with the environment).