Association of Opioid Use Disorder Diagnosis With Use of Physical Therapy and Chiropractic Care Among Chronic Low Back Pain Patients: A Group-Based Trajectory Analysis.

Nonpharmacologic approaches are recommended as first-line treatment for chronic pain, and their importance is heightened among individuals with co-occurring opioid use disorder (OUD), in whom opioid therapies may be particularly detrimental. Our objectives were to assess the receipt and trajectories of nonpharmacologic pain treatment and determine the association of OUD diagnosis with these trajectories. This retrospective cohort study used Medicare claims data from 2016 to 2018 and applied group-based trajectory models to identify distinct patterns of physical therapy (PT) or chiropractic care treatment over the 12 months following a new episode of chronic low back pain. We used logistic regression models to estimate the association of co-occurring OUD with group membership in PT and chiropractic trajectories. Our sample comprised 607,729 beneficiaries at least 18 years of age, of whom 11.4% had a diagnosis of OUD. The 12-month prevalence of PT and chiropractic treatment receipt was 24.7% and 27.1%, respectively, and lower among Medicare beneficiaries with co-occurring OUD (PT: 14.6%; chiropractic: 6.8%). The final models identified 3 distinct trajectories each for PT (no/little use [76.6% of sample], delayed and increasing use [8.2%], and early and declining use [15.2%]); and chiropractic (no/little use [75.0% of sample], early and declining use [17.3%], and early and sustained use [7.7%]). People with OUD were more likely to belong in trajectories with little/no PT or chiropractic care as compared to other trajectories. The findings indicate that people with co-occurring chronic pain and OUD often do not receive early or any nonpharmacologic pain therapies as recommended by practice guidelines. PERSPECTIVE: PT and chiropractic care use were low overall and even lower among Medicare beneficiaries with co-occurring OUD compared with those without OUD. As updated guidelines on pain management are promulgated, targeted interventions (eg, insurance policy, provider, and patient education) are needed to ensure equitable access to guideline-recommended pain therapies.

Comparing community and hospital data of snakebite in North Bihar: a community incidence survey and a parallel hospital-based clinical study.

In Bihar, an estimated 4500 snakebite deaths occur per year, but community data are scarce. Using a multi-stage cluster design, 4159 households were interviewed across six Community Development (CD) blocks in North Bihar, identifying 206 snakebites and 254 deaths between the Chhaat festivals of 2014 and 2015. Concurrently, 357 snakebite victims presented to Duncan Hospital from this area. None of the 254 verbal autopsies were attributed to snakebite envenoming. The annual community snakebite incidence was 643/100,000 person-years (95% confidence interval [CI] = 556-730) with peak incidence in women aged 30-39 years at 1323/100,000 person-years (95% CI = 837-1809). Two-thirds of snakebite victims attended traditional healers first for help (95% CI = 59.9-73.2). The community envenomation rate was 24.9/100,000 person-years (95% CI = 7.6-42.2). The hospital envenomation rate was 4.6% (95% CI = 3.5-5.7). Of the hospital snakebite deaths, 91% (10/11) were aged <16 years. Only 4.6% (95% CI = 4.1-5.1) of snakebite victims from this area presented at the local hospital.

Identification of an Immunogenic Broadly Inhibitory Surface Epitope of the Plasmodium vivax Duffy Binding Protein Ligand Domain.

The Plasmodium vivax Duffy binding protein region II (DBPII) is a vital ligand for the parasite's invasion of reticulocytes, thereby making this molecule an attractive vaccine candidate against vivax malaria. However, strain-specific immunity due to DBPII allelic variation in Bc epitopes may complicate vaccine efficacy, suggesting that an effective DBPII vaccine needs to target conserved epitopes that are potential targets of strain-transcending neutralizing immunity. The minimal epitopes reactive with functionally inhibitory anti-DBPII monoclonal antibody (MAb) 3C9 and noninhibitory anti-DBPII MAb 3D10 were mapped using phage display expression libraries, since previous attempts to deduce the 3C9 epitope by cocrystallographic methods failed. Inhibitory MAb 3C9 binds to a conserved conformation-dependent epitope in subdomain 3, while noninhibitory MAb 3D10 binds to a linear epitope in subdomain 1 of DBPII, consistent with previous studies. Immunogenicity studies using synthetic linear peptides of the minimal epitopes determined that the 3C9 epitope, but not the 3D10 epitope, could induce functionally inhibitory anti-DBPII antibodies. Therefore, the highly conserved binding-inhibitory 3C9 epitope offers the potential as a component in a broadly inhibitory, strain-transcending DBP subunit vaccine.IMPORTANCE Vivax malaria is the second leading cause of malaria worldwide and the major cause of non-African malaria. Unfortunately, efforts to develop antimalarial vaccines specifically targeting Plasmodium vivax have been largely neglected, and few candidates have progressed into clinical trials. The Duffy binding protein is considered a leading blood-stage vaccine candidate because this ligand's recognition of the Duffy blood group reticulocyte surface receptor is considered essential for infection. This study identifies a new target epitope on the ligand's surface that may serve as the target of vaccine-induced binding-inhibitory antibody (BIAb). Understanding the potential targets of vaccine protection will be important for development of an effective vaccine.

An engineered vaccine of the Plasmodium vivax Duffy binding protein enhances induction of broadly neutralizing antibodies.

Plasmodium vivax invasion into human reticulocytes is a complex process. The Duffy binding protein (DBP) dimerization with its cognate receptor is vital for junction formation in the invasion process. Due to its functional importance, DBP is considered a prime vaccine candidate, but variation in B-cell epitopes at the dimer interface of DBP leads to induction of strain-limited immunity. We believe that the polymorphic residues tend to divert immune responses away from functionally conserved epitopes important for receptor binding or DBP dimerization. As a proof of concept, we engineered the vaccine DEKnull to ablate the dominant Bc epitope to partially overcome strain-specific immune antibody responses. Additional surface engineering on the next generation immunogen, DEKnull-2, provides an immunogenicity breakthrough to conserved protective epitopes. DEKnull-2 elicits a stronger broadly neutralizing response and reactivity with long-term persistent antibody responses of acquired natural immunity. By using novel engineered DBP immunogens, we validate that the prime targets of protective immunity are conformational epitopes at the dimer interface. These successful results indicate a potential approach that can be used generally to improve efficacy of other malaria vaccine candidates.

"Sometimes What They Think is Helpful is Not Really Helpful": Understanding Engagement in the Program of Assertive Community Treatment (PACT).

This exploratory study recruited a purposive sample of twelve clinical staff from a Program of Assertive Community Treatment (PACT) team in central Virginia to understand the perceptions and experiences related to assertive engagement. The researchers coded the transcribed data initially as twenty-three sub-themes and further refined the data into four overarching themes: characteristics of assertive engagement, PACT engagement strategies and engagement strategies for difficult to engage clients. Further analysis emphasized that PACT team members emphasized the importance of the therapeutic relationship for engagement, which proves challenging for hard-to-engage clients.

Immunogenicity of a synthetic vaccine based on Plasmodium vivax Duffy binding protein region II.

Molecules that play a role in Plasmodium merozoite invasion of host red blood cells represent attractive targets for blood-stage vaccine development against malaria. In Plasmodium vivax, merozoite invasion of reticulocytes is mediated by the Duffy binding protein (DBP), which interacts with its cognate receptor, the Duffy antigen receptor for chemokines, on the surface of reticulocytes. The DBP ligand domain, known as region II (DBPII), contains the critical residues for receptor recognition, making it a prime target for vaccine development against blood-stage vivax malaria. In natural infections, DBP is weakly immunogenic and DBPII allelic variation is associated with strain-specific immunity, which may compromise vaccine efficacy. In a previous study, a synthetic vaccine termed DEKnull that lacked an immunodominant variant epitope in DBPII induced functional antibodies to shared neutralizing epitopes on the native Sal1 allele. Anti-DEKnull antibody titers were lower than anti-Sal1 titers but produced more consistent, strain-transcending anti-DBPII inhibitory responses. In this study, we further characterized the immunogenicity of DEKnull, finding that immunization with recombinant DEKnull produced an immune response comparable to that obtained with native recombinant DBP alleles. Further investigation of DEKnull is necessary to enhance its immunogenicity and broaden its specificity.

Immunogenicity of single versus mixed allele vaccines of Plasmodium vivax Duffy binding protein region II.

The Duffy binding protein (DBP) of Plasmodium vivax is vital for host erythrocyte invasion. DBP region II (DBPII) contains critical residues for receptor recognition and anti-DBPII antibodies have been shown to inhibit erythrocyte binding and invasion, thereby making the molecule an attractive vaccine candidate against P. vivax blood stages. Similar to other blood-stage antigens, allelic variation within the DBPII and associated strain-specific immunity is a major challenge for development of a broadly effective vaccine against P. vivax malaria. We hypothesized that immunization with a vaccine composed of multiple DBP alleles or a modified epitope DBP (DEKnull) will be more effective in producing a broadly reactive and inhibitory antibody response to diverse DBPII alleles than a single allele vaccine. In this study, we compared single, naturally occurring DBPII allele immunizations (Sal1, 7.18, P) and DEKnull with a combination of (Sal1, 7.18, P) alleles. Quantitative analysis by ELISA demonstrated that the multiple allele vaccine tend to be more immunogenic than any of the single allele vaccines when tested for reactivity against a panel of DBPII allelic variants whereas DEKnull was less immunogenic than the mixed-allele vaccine but similar in reactivity to the single allele vaccines. Further analysis for functional efficacy by in vitro erythrocyte-binding inhibition assays demonstrated that the multiple allele immunization produced a stronger strain-neutralizing response than the other vaccination strategies even though inhibition remained biased toward some alleles. Overall, there was no correlation between antibody titer and functional inhibition. These data suggest that a multiple allele vaccine may enhance immunogenicity of a DBPII vaccine but further investigation is required to optimize this vaccine strategy to achieve broader coverage against global P. vivax strains.