Meeting the 2030 END TB goals in the wake of COVID-19: A modelling study of countries in the USAID TB portfolio.

Progress towards the 2030 End TB goals has seen severe setbacks due to disruptions arising from the COVID-19 pandemic. For governments and international partner organizations supporting the global TB response, there is a need to assess what level of effort is now needed to reach these goals. Using mathematical modelling, we addressed this question for the countries being supported by the United States Agency for International Development (USAID). We aggregated the 24 countries in the USAID portfolio into three geographical country groups: South Asia; sub-Saharan Africa; and Central Asian Republics/Europe (CAR/EU). From 2023 onwards we modelled a combination of interventions acting at different stages of the care cascade, including improved diagnostics; reducing the patient care seeking delay; and the rollout of a disease-preventing vaccine from 2025 onwards. We found that in all three country groups, meeting the End TB goals by 2030 will require a combination of interventions acting at stages of the TB care cascade. Specific priorities may depend on country settings, for example with public-private mix playing an important role in countries in South Asia and elsewhere. When a vaccine becomes available, its required coverage to meet the 2030 goals will vary by setting, depending on the amount of preventive therapy that has already been implemented. Monitoring the number-needed-to-test to identify 1 person with TB in community settings can provide a useful measure of progress towards the End TB goals.

Prolonged California aridity linked to climate warming and Pacific sea surface temperature.

California has experienced a dry 21(st) century capped by severe drought from 2012 through 2015 prompting questions about hydroclimatic sensitivity to anthropogenic climate change and implications for the future. We address these questions using a Holocene lake sediment record of hydrologic change from the Sierra Nevada Mountains coupled with marine sediment records from the Pacific. These data provide evidence of a persistent relationship between past climate warming, Pacific sea surface temperature (SST) shifts and centennial to millennial episodes of California aridity. The link is most evident during the thermal-maximum of the mid-Holocene (~8 to 3 ka; ka = 1,000 calendar years before present) and during the Medieval Climate Anomaly (MCA) (~1 ka to 0.7 ka). In both cases, climate warming corresponded with cooling of the eastern tropical Pacific despite differences in the factors producing increased radiative forcing. The magnitude of prolonged eastern Pacific cooling was modest, similar to observed La Niña excursions of 1(o) to 2 °C. Given differences with current radiative forcing it remains uncertain if the Pacific will react in a similar manner in the 21st century, but should it follow apparent past behavior more intense and prolonged aridity in California would result.

Towards tuberculosis elimination: an action framework for low-incidence countries.

This paper describes an action framework for countries with low tuberculosis (TB) incidence (<100 TB cases per million population) that are striving for TB elimination. The framework sets out priority interventions required for these countries to progress first towards "pre-elimination" (<10 cases per million) and eventually the elimination of TB as a public health problem (less than one case per million). TB epidemiology in most low-incidence countries is characterised by a low rate of transmission in the general population, occasional outbreaks, a majority of TB cases generated from progression of latent TB infection (LTBI) rather than local transmission, concentration to certain vulnerable and hard-to-reach risk groups, and challenges posed by cross-border migration. Common health system challenges are that political commitment, funding, clinical expertise and general awareness of TB diminishes as TB incidence falls. The framework presents a tailored response to these challenges, grouped into eight priority action areas: 1) ensure political commitment, funding and stewardship for planning and essential services; 2) address the most vulnerable and hard-to-reach groups; 3) address special needs of migrants and cross-border issues; 4) undertake screening for active TB and LTBI in TB contacts and selected high-risk groups, and provide appropriate treatment; 5) optimise the prevention and care of drug-resistant TB; 6) ensure continued surveillance, programme monitoring and evaluation and case-based data management; 7) invest in research and new tools; and 8) support global TB prevention, care and control. The overall approach needs to be multisectorial, focusing on equitable access to high-quality diagnosis and care, and on addressing the social determinants of TB. Because of increasing globalisation and population mobility, the response needs to have both national and global dimensions.

Randomized controlled trial of health maintenance reminders provided directly to patients through an electronic PHR.

BACKGROUND: Provider and patient reminders can be effective in increasing rates of preventive screenings and vaccinations. However, the effect of patient-directed electronic reminders is understudied. OBJECTIVE: To determine whether providing reminders directly to patients via an electronic Personal Health Record (PHR) improved adherence to care recommendations. DESIGN: We conducted a cluster randomized trial without blinding from 2005 to 2007 at 11 primary care practices in the Partners HealthCare system. PARTICIPANTS: A total of 21,533 patients with access to a PHR were invited to the study, and 3,979 (18.5%) consented to enroll. INTERVENTIONS: Patients in the intervention arm received health maintenance (HM) reminders via a secure PHR "eJournal," which allowed them to review and update HM and family history information. Patients in the active control arm received access to an eJournal that allowed them to input and review information related to medications, allergies and diabetes management. MAIN MEASURES: The primary outcome measure was adherence to guideline-based care recommendations. KEY RESULTS: Intention-to-treat analysis showed that patients in the intervention arm were significantly more likely to receive mammography (48.6% vs 29.5%, p = 0.006) and influenza vaccinations (22.0% vs 14.0%, p = 0.018). No significant improvement was observed in rates of other screenings. Although Pap smear completion rates were higher in the intervention arm (41.0% vs 10.4%, p < 0.001), this finding was no longer significant after excluding women's health clinics. Additional on-treatment analysis showed significant increases in mammography (p = 0.019) and influenza vaccination (p = 0.015) for intervention arm patients who opened an eJournal compared to control arm patients, but no differences for any measure among patients who did not open an eJournal. CONCLUSIONS: Providing patients with HM reminders via a PHR may be effective in improving some elements of preventive care.

Effectiveness of health maintenance reminders provided directly to patients.

Provider-centric Electronic Health Records (EHRs) with clinical decision support have had a modest impact on improving quality care. However, they do not directly engage patients in promoting guideline adherence. Tethered Personal Health Records (PHRs) in contrast, can deliver decision support to both patients and providers. We conducted a randomized controlled trial to determine the effectiveness of providing seven screening reminders directly to patients via a PHR. Patients receiving the intervention were significantly more likely to receive Pap smears. No difference was seen for the other reminders.

Empowering patients to improve the quality of their care: design and implementation of a shared health maintenance module in a US integrated healthcare delivery network.

We describe a health maintenance module within a personal health record designed to improve the quality of routine preventive care for patients in a large integrated healthcare delivery network. This module allows patients and their providers to share an online medical record and decision support tools. Our preliminary results indicate that this approach is well-accepted by patients and their providers and has significant potential to facilitate patient-provider communication and improve the quality of routine health maintenance care. Further research will determine the long term impact and sustainability of this approach.

A patient-controlled journal for an electronic medical record: issues and challenges.

Partners Healthcare System, Boston, MA, has developed a patient Web portal that features a patient-controlled electronic "journal" to allow patients to interact with their physician's electronic medical record. Patients can view and respond to health reminders, critique electronic chart information maintained by their doctor's office, enter additional clinical information, and prepare information summaries before an office visit. Creating shared information resources to support a collaborative care model required analysis of the business, architectural, and workflow requirements of the patient-controlled clinical portal and the physician-controlled electronic medical record system. In this paper we describe the challenges in aligning the two systems and serving the different user groups. Coupling the Patient Gateway system, serving over 8700 patients of 90 physicians as of September, 2003, with the Longitudinal Medical Record system, serving over 4000 physicians, has required a clear definition of user goals and workflow, well-defined interfaces, and careful consideration of system assumptions to succeed.

Rational design of solid aerosols for immunoglobulin delivery by modulation of aerodynamic and release characteristics.

Parenteral administration of immunoglobulins (Ig) for prevention or treatment of respiratory diseases achieves only modest concentrations of antibody in the pulmonary interstitial tissue and airways. Aerosols, including spray-dried particles, must overcome two limiting factors in order to be effective vehicles for pulmonary delivery of Ig: (i) Fc receptor (FcR)-mediated scavenging by macrophages and (ii) clearance by the mucociliary system. Ig-incorporated spray-dried lipid microparticles (SDLM), coformulated with or without a biocompatible surfactant (1% w:w) to modulate protein release, were designed and tested for their capability to deliver Ig to the respiratory tract. To determine efficacy, rodents were immunized with SDLM containing antiinfluenza antibody followed by virus challenge and clinical parameters measured. Control of the release kinetics resulted in enhanced delivery of immunoglobulins to the respiratory tract and interstitial tissue with slow translocation into the systemic circulation. As much as 60% of the IgG delivered from nonretentive SDLM could be recovered from the lung interstitial tissue within 1 h after aerosol administration at a dose of 1 mg of Ig/kg of body weight. In addition, nonretentive rather than slow-release particles loaded with antiinfluenza antibody were effective in curbing virus replication with a resulting positive clinical outcome. Thus, controlled release of Ig by manipulating aerosol characteristics and composition allows for a significant increase in the efficiency of pulmonary delivery of antibodies.

Partner characteristics, intensity of the intercourse, and semen exposure during use of the female condom.

The objective of this study was to assess how characteristics of the intercourse and the couple relate to semen exposure during use of the female condom. From 1996 to 1998, 210 women in Birmingham, Alabama, were trained to use the female condom and follow study procedures during a group session and individually practiced inserting the device. The outcome was semen exposure as defined by comparing pre- and postcoital prostate-specific antigen levels in vaginal fluid. Women who had high income levels had lower rates of semen exposure (odds ratio (OR) = 0.3, 95% confidence interval (CI): 0.2, 0.7), while those in a relationship of less than 2 years were at greater risk (OR = 2.4, 95% CI: 1.3, 4.1). Couples with a large disparity in vaginal fundus size and penis size were at increased risk of semen exposure (OR = 2.7, 95% CI: 1.2, 6.0). Engaging in very active intercourse also increased the risk (OR = 1.7, 95% CI: 1.1, 2.6). Thus, the protective effect of the female condom appears to be a function of user- and intercourse-specific characteristics. Future studies of male condom efficacy should focus on collecting detailed data about the users and characteristics of intercourse to predict failure accurately.

Efficacy of the female condom as a barrier to semen during intercourse.

In 1996-1998, the authors measured prostate-specific antigen (PSA) in vaginal fluid to assess the frequency of female condom failure and to evaluate the association of self-reported failure with semen exposure. Women at low risk of sexually transmitted diseases (n = 210) were recruited in Birmingham, Alabama. They were trained to use the female condom, sample vaginal fluid before and after condom use, and complete forms to report problems during each use. Semen exposure was assessed by comparing pre- and postcoital PSA levels in vaginal fluid. A total of 175 women used 2,232 condoms. The rate of semen exposure ranged from 7% to 21% of condom uses, depending on the exposure criterion. Exposure was more likely (21-34%) and more intense (mean postcoital PSA, 24.7 ng/ml) if participants reported a mechanical problem versus other problems or no problems (exposure rate, 5-20% in both instances; mean postcoital PSA, 9.6 and 7.8 ng/ml, respectively). In logistic regression analyses for repeated measurements, user-reported problems accounted for less than 59% of the instances of semen exposure. The female condom prevented semen exposure in 79-93% of condom uses. Exposure was associated with user-reported problems but also occurred in their absence. Reported problems and semen exposure decreased with user experience.

Noncoding RNA danger motifs bridge innate and adaptive immunity and are potent adjuvants for vaccination.

The adaptive immune response is triggered by recognition of T and B cell epitopes and is influenced by "danger" motifs that act via innate immune receptors. This study shows that motifs associated with noncoding RNA are essential features in the immune response reminiscent of viral infection, mediating rapid induction of proinflammatory chemokine expression, recruitment and activation of antigen-presenting cells, modulation of regulatory cytokines, subsequent differentiation of Th1 cells, isotype switching, and stimulation of cross-priming. The heterogeneity of RNA-associated motifs results in differential binding to cellular receptors, and specifically impacts the immune profile. Naturally occurring double-stranded RNA (dsRNA) triggered activation of dendritic cells and enhancement of specific immunity, similar to selected synthetic dsRNA motifs. Based on the ability of specific RNA motifs to block tolerance induction and effectively organize the immune defense during viral infection, we conclude that such RNA species are potent danger motifs. We also demonstrate the feasibility of using selected RNA motifs as adjuvants in the context of novel aerosol carriers for optimizing the immune response to subunit vaccines. In conclusion, RNA-associated motifs produced during viral infection bridge the early response with the late adaptive phase, regulating the activation and differentiation of antigen-specific B and T cells, in addition to a short-term impact on innate immunity.