High-affinity autoreactive plasma cells disseminate through multiple organs in patients with immune thrombocytopenic purpura

The major therapeutic goal for immune thrombocytopenic purpura (ITP) is to restore normal platelet counts using drugs to promote platelet production or by interfering with mechanisms responsible for platelet destruction. Eighty percent of patients with ITP possess anti–integrin αIIbβ3 IgG autoantibodies that cause platelet opsonization and phagocytosis. The spleen is considered the primary site of autoantibody production by autoreactive B cells and platelet destruction. The immediate failure in approximately 50% of patients to recover a normal platelet count after anti-CD20 rituximab-mediated B cell depletion and splenectomy suggests that autoreactive, rituximab-resistant, IgG-secreting B cells (IgG-SCs) reside in other anatomical compartments. We analyzed more than 3,300 single IgG-SCs from spleen, bone marrow, and/or blood of 27 patients with ITP, revealing high interindividual variability in affinity for αIIbβ3, with variations over 3 logs. IgG-SC dissemination and range of affinities were, however, similar for each patient. Longitudinal analysis of autoreactive IgG-SCs upon treatment with the anti-CD38 mAb daratumumab demonstrated variable outcomes, from complete remission to failure with persistence of high-affinity anti–αIIbβ3 IgG-SCs in the bone marrow. This study demonstrates the existence and dissemination of high-affinity autoreactive plasma cells in multiple anatomical compartments of patients with ITP that may cause the failure of current therapies.     

Global strategies to reduce the price of antiretroviral medicines: evidence from transactional databases

Objective

To estimate the impact of global strategies, such as pooled procurement arrangements, third-party price negotiation and differential pricing, on reducing the price of antiretrovirals (ARVs), which currently hinders universal access to HIV/AIDS treatment.

Methods

We estimated the impact of global strategies to reduce ARV prices using data on 7253 procurement transactions (July 2002–October 2007) from databases hosted by WHO and the Global Fund to Fight AIDS, Tuberculosis and Malaria.

Findings

For 19 of 24 ARV dosage forms, we detected no association between price and volume purchased. For the other five ARVs, high-volume purchases were 4–21% less expensive than medium- or low-volume purchases. Nine of 13 generic ARVs were priced 6–36% lower when purchased under the Clinton Foundation HIV/AIDS Initiative (CHAI). Fifteen of 18 branded ARVs were priced 23–498% higher for differentially priced purchases compared with non-CHAI generic purchases. However, two branded, differentially priced ARVs were priced 63% and 73% lower, respectively, than generic non-CHAI equivalents.

Conclusion

Large purchase volumes did not necessarily result in lower ARV prices. Although current plans for pooled procurement will further increase purchase volumes, savings are uncertain and should be balanced against programmatic costs. Third-party negotiation by CHAI resulted in lower generic ARV prices. Generics were less expensive than differentially priced branded ARVs, except where little generic competition exists. Alternative strategies for reducing ARV prices, such as streamlining financial management systems, improving demand forecasting and removing barriers to generics, should be explored.     

Risky Party and Nightclub Attendance during the COVID-19 Nightlife Shutdown in New York City

From March 2020 through May 2021, nightlife venues were shut down and large gatherings were deemed illegal in New York City (NYC) due to COVID-19. This study sought to determine the extent of risky party attendance during the COVID-19 shutdown among people who attend electronic dance music parties in NYC. During the first four months that venues were permitted to reopen (June through September 2021), time–space sampling was used to survey adults (n = 278) about their party attendance during the first year of the shutdown (March 2020–March 2021). We examined prevalence and correlates of attendance and mask-wearing at such parties. A total of 43.9% attended private parties with more than 10 people, 27.3% attended nightclubs, and 20.5% attended other parties such as raves. Among those who attended any, 32.3% never wore a mask and 19.3% reported attending parties in which no one wore a mask. Past-year ecstasy use was associated with increased risk for attending private (aPR = 1.51, 95% CI: 1.00–2.28) or other parties (aPR = 2.75, 95% CI: 1.48–5.13), and use of 2C series drugs was associated with increased risk for attending nightclubs (aPR = 2.67, 95% CI: 1.24–5.77) or other parties (aPR = 2.50, 95% CI: 1.06–5.87). Attending >10 parties was associated with increased risk for never wearing a mask (aPR = 2.74, 95% CI: 1.11–6.75) and for no other attendees wearing masks (aPR = 4.22, 95% CI: 1.26–14.07). Illegal dance parties continued in NYC during the COVID-19 shutdown. Prevention and harm reduction efforts to mitigate risk of COVID-19 transmission during such shutdowns are sorely needed.     

Estimation of COVID-19 vaccine effectiveness against hospitalisation in individuals aged ≥ 65 years using electronic health registries; a pilot study in four EU/EEA countries,October 2021 to March 2022

By employing a common protocol and data from electronic health registries in Denmark, Navarre (Spain), Norway and Portugal, we estimated vaccine effectiveness (VE) against hospitalisation due to COVID-19 in individuals aged ≥ 65 years old, without previous documented infection, between October 2021 and March 2022. VE was higher in 65–79-year-olds compared with ≥ 80-year-olds and in those who received a booster compared with those who were primary vaccinated. VE remained high (ca 80%) between ≥ 12 and < 24 weeks after the first booster administration, and after Omicron became dominant.     

Repeated exposure to heterologous hepatitis C viruses associates with enhanced neutralizing antibody breadth and potency

A prophylactic hepatitis C virus (HCV) vaccine that elicits neutralizing antibodies could be key to HCV eradication. However, the genetic and antigenic properties of HCV envelope (E1E2) proteins capable of inducing anti-HCV broadly neutralizing antibodies (bNAbs) in humans have not been defined. Here, we investigated the development of bNAbs in longitudinal plasma of HCV-infected persons with persistent infection or spontaneous clearance of multiple reinfections. By measuring plasma antibody neutralization of a heterologous virus panel, we found that the breadth and potency of the antibody response increased upon exposure to multiple genetically distinct infections and with longer duration of viremia. Greater genetic divergence between infecting strains was not associated with enhanced neutralizing breadth. Rather, repeated exposure to antigenically related, antibody-sensitive E1E2s was associated with potent bNAb induction. These data reveal that a prime-boost vaccine strategy with genetically distinct, antibody-sensitive viruses is a promising approach to inducing potent bNAbs in humans.     

Investigation of COVID-19 Outbreak among Wildland Firefighters during Wildfire Response,Colorado, USA, 2020

A COVID-19 outbreak occurred among Cameron Peak Fire responders in Colorado, USA, during August 2020–January 2021. The Cameron Peak Fire was the largest recorded wildfire in Colorado history, lasting August–December 2020. At least 6,123 responders were involved, including 1,260 firefighters in 63 crews who mobilized to the fire camps. A total of 79 COVID-19 cases were identified among responders, and 273 close contacts were quarantined. State and local public health investigated the outbreak and coordinated with wildfire management teams to prevent disease spread. We performed whole-genome sequencing and applied social network analysis to visualize clusters and transmission dynamics. Phylogenetic analysis identified 8 lineages among sequenced specimens, implying multiple introductions. Social network analysis identified spread between and within crews. Strategies such as implementing symptom screening and testing of arriving responders, educating responders about overlapping symptoms of smoke inhalation and COVID-19, improving physical distancing of crews, and encouraging vaccinations are recommended.     

Manufacturing of a Magnetic Composite Flexible Filament and Optimization of a 3D Printed Wideband Electromagnetic Multilayer Absorber in X-Ku Frequency Bands

With the multiplication of electronic devices in our daily life, there is a need for tailored wideband electromagnetic (EM) absorbers that could be conformed on any type of surface-like antennas for interference attenuation or military vehicles for stealth applications. In this study, a wideband flexible flat electromagnetic absorber compatible with additive manufacturing has been studied in the X-Ku frequency bands. A multilayer structure has been optimized using a genetic algorithm (GA), adapting the restrictions of additive manufacturing and exploiting the EM properties of loaded and non-loaded filaments, of which the elaboration is described. After optimization, a bi-material multilayer absorber with a thickness of 4.1 mm has been designed to provide a reflectivity below −12 dB between 8 and 18 GHz. Finally, the designed multilayer structure was 3D-printed and measured in an anechoic chamber, achieving −11.8 dB between 7 and 18 GHz. Thus, the development of dedicated materials has demonstrated the strong potential of additive technologies for the manufacturing of thin wideband flexible EM absorbers.     

Prevalence of Thoracic Aortic Aneurysms in Patients with Degenerative Abdominal Aortic Aneurysms: Results from the Prospective ACTA Study

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