Medicinal cannabis for Australian patients with chronic refractory pain including arthritis.

Objectives: To examine the tolerability and effectiveness of medicinal cannabis prescribed to patients for chronic, refractory pain, with a subset analysis on arthritis. Methods: This was an interim analysis of the CA Clinics Observational Study investigating self-reported adverse events (AEs) and changes in health-related quality of life (HRQoL) outcomes over time after commencing medicinal cannabis. Patients were prescribed medicinal cannabis by a medical practitioner, containing various ratios of Δ9-tetrahydrocannabinol (THC) and/or cannabidiol (CBD). Results: The overall chronic pain cohort, and specifically the balanced CBD:THC products, were associated with significantly reduced pain intensity scores (p = 0.003, p = 0.025), with 22% of patients reporting a clinically meaningful reduction in pain intensity. Patients in the arthritis subset (n = 199) reported significantly reduced pain intensity scores (p = 0.005) overall, and specifically for those taking CBD-only (p = 0.018) and balanced products (p = 0.005). Other HRQoL outcomes, including pain interference and pain impact scores were significantly improved depending on the CBD:THC ratio. Products that contained a balanced ratio of CBD:THC were associated with improvements in the most number of PROMIS-29 domains. Approximately half (n = 364; 51%) of the chronic pain cohort experienced at least one AE, the most common being dry mouth (24%), somnolence (19%) or fatigue (12%). These findings were similar in the arthritis subset. Discussion: Medicinal cannabis was observed to improve pain intensity scores and HRQoL outcomes in patients with chronic, refractory pain, providing real-world insights into medicinal cannabis' therapeutic potential.

Medicinal cannabis for patients with chronic non-cancer pain: analysis of safety and concomitant medications.

OBJECTIVES: This study aimed to explore the incidence of adverse events (AEs) reported by patients when initiating medicinal cannabis treatment for chronic pain, and the association of cannabis constituents, dose and concomitant medicines with AE incidence. METHODS: Patient demographics, cannabis products and AE data were collected as part of the Cannabis Access Clinics Observational Study, and concomitant medicines were obtained from patient health summaries provided by referring doctors. Cannabis products were grouped by their constituents as either cannabidiol-only or containing both cannabidiol and Δ-9-tetrahydrocannabinol. KEY FINDINGS: From a total of 275 patients, each had a median of six concomitant medicines, with opioids (n = 179; 65%) the most common. A total of 35.6% patients took 10 or more other medicines, and they were associated with a 3.6 times higher likelihood to report the AE of fatigue (P = 0.048). Patients who received concomitant gabapentinoids were 2.4 times more likely to report dizziness (P = 0.036), patients on tricyclic antidepressants were 1.8 times more likely to report somnolence (P = 0.034) and 3.4 times more likely to report anxiety (P = 0.04), when compared with patients who were not prescribed those classes of medications. Those patients who were prescribed products containing both cannabidiol and Δ-9-tetrahydrocannabinol were 1.5 times more likely (P = 0.004) to have experienced an AE when compared with those prescribed only cannabidiol. CONCLUSIONS: These findings show that certain concomitant medications and cannabis constituents may be associated with AE incidence when initiating medicinal cannabis. These potential pharmacokinetic and pharmacodynamic interactions require further study to develop guidance for prescribers and pharmacists.

Exome Sequencing Reveals a Putative Role for HLA-C*03:02 in Control of HIV-1 in African Pediatric Populations.

Human leucocyte antigen (HLA) class I molecules present endogenously processed antigens to T-cells and have been linked to differences in HIV-1 disease progression. HLA allelotypes show considerable geographical and inter-individual variation, as does the rate of progression of HIV-1 disease, with long-term non-progression (LTNP) of disease having most evidence of an underlying genetic contribution. However, most genetic analyses of LTNP have occurred in adults of European ancestry, limiting the potential transferability of observed associations to diverse populations who carry the burden of disease. This is particularly true of HIV-1 infected children. Here, using exome sequencing (ES) to infer HLA allelotypes, we determine associations with HIV-1 LTNP in two diverse African pediatric populations. We performed a case-control association study of 394 LTNPs and 420 rapid progressors retrospectively identified from electronic medical records of pediatric HIV-1 populations in Uganda and Botswana. We utilized high-depth ES to perform high-resolution HLA allelotyping and assessed evidence of association between HLA class I alleles and LTNP. Sixteen HLA alleles and haplotypes had significantly different frequencies between Uganda and Botswana, with allelic differences being more prominent in HLA-A compared to HLA-B and C allelotypes. Three HLA allelotypes showed association with LTNP, including a novel association in HLA-C (HLA-B∗57:03, aOR 3.21, Pc = 0.0259; B∗58:01, aOR 1.89, Pc = 0.033; C∗03:02, aOR 4.74, Pc = 0.033). Together, these alleles convey an estimated population attributable risk (PAR) of non-progression of 16.5%. We also observed novel haplotype associations with HLA-B∗57:03-C∗07:01 (aOR 5.40, Pc = 0.025) and HLA-B∗58:01-C∗03:02 (aOR 4.88, Pc = 0.011) with a PAR of 9.8%, as well as a previously unreported independent additive effect and heterozygote advantage of HLA-C∗03:02 with B∗58:01 (aOR 4.15, Pc = 0.005) that appears to limit disease progression, despite weak LD (r 2 = 0.18) between these alleles. These associations remained irrespective of gender or country. In one of the largest studies of HIV in Africa, we find evidence of a protective effect of canonical HLA-B alleles and a novel HLA-C association that appears to augment existing HIV-1 control alleles in pediatric populations. Our findings outline the value of using multi-ethnic populations in genetic studies and offer a novel HIV-1 association of relevance to ongoing vaccine studies.

Results of a Pilot Study on the Safety and Early Efficacy of Novel Polymethyl Methacrylate Microspheres and a Hyaluronic Acid Device for the Treatment of Low Back Pain Caused by Degenerative and Diseased Intervertebral Discs of the Lumbar Spine.

Background Low back pain (LBP) costs the healthcare system billions of dollars each year. Intervertebral disc (IVD) degeneration is a significant cause of LBP, due to structural defects, biomechanical instability, and inflammation. First-line therapy for patients with LBP includes physical therapy, medication, and steroid injections. DiscSealTM was developed to provide patients who are refractory to first-line therapy with a minimally invasive treatment alternative to invasive surgical procedures. The product is a combination of poly-methyl methacrylate (PMMA) microspheres in hyaluronic acid (HA) that is injected under modified discography into the IVD. Methods Two pain specialist centers in Australia recruited eligible participants who were followed up for 180 days post-procedure. The procedure was conducted using a modified discography technique. Low back and leg pain was reported using the Visual Analogue Scale (VAS) while other endpoints included were Oswestry Disability Index (ODI), Clinician and Patient Global Impact of Change, and Patient Rating of Overall Health Status. The general analytical approach for all endpoints was descriptive in nature and 95% confidence intervals of means were estimated. Results The pilot study achieved its primary objective which was an absence of peri-treatment or post-treatment device-related Serious Adverse Events (SAE) during the first 90 days. There were no device-related serious adverse events recorded throughout the study. The mean LBP percentage change from baseline at 90 and 180 days was -27.0% and -42.3% respectively. The mean ODI percentage change from baseline at 90 and 180 days was -22.3 and -14.2% respectively. End of study improvements shows a 67.8% (20.83) increase in Overall Health Status, as well as positive results for Participant and Clinician Global Impact of Change. These results were achieved based on treating one diseased IVD, although 83.3% of patients were diagnosed with multiple diseased IVDs. Conclusions The results from this pilot study showed that DiscSealTM is safe and well-tolerated. Early efficacy shows that DiscSealTM may be a promising treatment option for people suffering from discogenic LBP that have not responded to first-line treatment options. A larger, statistically powered study where all diseased discs are treated should be completed to validate the promising results from this early feasibility study.

Whole-Exome Sequencing Reveals Uncaptured Variation and Distinct Ancestry in the Southern African Population of Botswana.

Large-scale, population-based genomic studies have provided a context for modern medical genetics. Among such studies, however, African populations have remained relatively underrepresented. The breadth of genetic diversity across the African continent argues for an exploration of local genomic context to facilitate burgeoning disease mapping studies in Africa. We sought to characterize genetic variation and to assess population substructure within a cohort of HIV-positive children from Botswana-a Southern African country that is regionally underrepresented in genomic databases. Using whole-exome sequencing data from 164 Batswana and comparisons with 150 similarly sequenced HIV-positive Ugandan children, we found that 13%-25% of variation observed among Batswana was not captured by public databases. Uncaptured variants were significantly enriched (p = 2.2 × 10-16) for coding variants with minor allele frequencies between 1% and 5% and included predicted-damaging non-synonymous variants. Among variants found in public databases, corresponding allele frequencies varied widely, with Botswana having significantly higher allele frequencies among rare (<1%) pathogenic and damaging variants. Batswana clustered with other Southern African populations, but distinctly from 1000 Genomes African populations, and had limited evidence for admixture with extra-continental ancestries. We also observed a surprising lack of genetic substructure in Botswana, despite multiple tribal ethnicities and language groups, alongside a higher degree of relatedness than purported founder populations from the 1000 Genomes project. Our observations reveal a complex, but distinct, ancestral history and genomic architecture among Batswana and suggest that disease mapping within similar Southern African populations will require a deeper repository of genetic variation and allelic dependencies than presently exists.

The Collaborative African Genomics Network (CAfGEN): Applying Genomic technologies to probe host factors important to the progression of HIV and HIV-tuberculosis infection in sub-Saharan Africa.

Background: Here, we describe how the Collaborative African Genomics Network ( CAfGEN) of the Human Heredity and Health in Africa (H3Africa) consortium is using genomics to probe host genetic factors important to the progression of HIV and HIV-tuberculosis (TB) coinfection in sub-Saharan Africa.   The H3Africa was conceived to facilitate the application of genomics technologies to improve health across Africa..          Methods: CAfGEN is an H3Africa collaborative centre comprising expertise from the University of Botswana; Makerere University; Baylor College of Medicine Children's Clinical Centers of Excellence (COEs) in Botswana, Uganda, and Swaziland; as well as Baylor College of Medicine, Texas. The COEs provide clinical expertise for community engagement, participant recruitment and sample collection while the three University settings facilitate processing and management of genomic samples and provide infrastructure and training opportunities to sustain genomics research. Results: The project has focused on utilizing whole-exome sequencing to identify genetic variants contributing to extreme HIV disease progression phenotypes in children, as well as RNA sequencing and integrated genomics to identify host genetic factors associated with TB disease progression among HIV-positive children. These cohorts, developed using the COEs' electronic medical records, are exceptionally well-phenotyped and present an unprecedented opportunity to assess genetic factors in individuals whose HIV was acquired by a different route than their adult counterparts in the context of a unique clinical course and disease pathophysiology. Conclusions: Our approach offers the prospect of developing a critical mass of well-trained, highly-skilled, continent-based African genomic scientists. To ensure long term genomics research sustainability in Africa, CAfGEN contributes to a wide range of genomics capacity and infrastructure development on the continent, has laid a foundation for genomics graduate programs at its institutions, and continues to actively promote genomics research through innovative forms of community engagement brokered by partnerships with governments and academia to support genomics policy formulation.

Characterization of a serine protease homologous to house dust mite group 3 allergens from the scabies mite Sarcoptes scabiei.

The scabies mite, Sarcoptes scabiei var. hominis, infests human skin, causing allergic reactions and facilitating bacterial infection by Streptococcus sp., with serious consequences such as rheumatic fever and rheumatic heart disease. To identify a possible drug target or vaccine candidate protein, we searched for homologues of the group 3 allergen of house dust mites, which we subsequently identified in a cDNA library. The native protein, designated Sar s 3, was shown to be present in the mite gut and excreted in fecal pellets into mite burrows within the upper epidermis. The substrate specificity of proteolytically active recombinant rSar s 3 was elucidated by screening a bacteriophage library. A preference for substrates containing a RS(G/A) sequence at the P1-P2' positions was revealed. A series of peptides synthesized as internally quenched fluorescent substrates validated the phage display data and high performance liquid chromatography/mass spectrometry analysis of the preferred cleaved substrate and confirmed the predicted cleavage site. Searches of the human proteome using sequence data from the phage display allowed the in silico prediction of putative physiological substrates. Among these were numerous epidermal proteins, with filaggrin being a particularly likely candidate substrate. We showed that recombinant rSar s 3 cleaves human filaggrin in vitro and obtained immunohistological evidence that the filaggrin protein is ingested by the mite. This is the first report elucidating the substrate specificity of Sar s 3 and its potential role in scabies mite biology.

Scabies mite inactivated serine protease paralogs inhibit the human complement system.

Infestation of skin by the parasitic itch mite Sarcoptes scabiei afflicts 300 million people worldwide and there is a need for novel and efficient therapies. We have previously identified a multigene family of serine proteases comprising multiple catalytically inactive members (scabies mite-inactivated protease paralogs (SMIPPs)), which are secreted into the gut of S. scabiei. SMIPPs are located in the mite gut and in feces excreted into the upper epidermis. Scabies mites feed on epidermal protein, including host plasma; consequently, they are exposed to host defense mechanisms both internally and externally. We found that two recombinantly expressed SMIPPs inhibited all three pathways of the human complement system. Both SMIPPs exerted their inhibitory action due to binding of three molecules involved in the three different mechanisms which initiate complement: C1q, mannose-binding lectin, and properdin. Both SMIPPs bound to the stalk domains of C1q, possibly displacing or inhibiting C1r/C1s, which are associated with the same domain. Furthermore, we found that binding of both SMIPPs to properdin resulted in prevention of assembly of the alternative pathway convertases. However, the SMIPPs were not able to dissociate already formed convertases. Immunohistochemical staining demonstrated the presence of C1q in the gut of scabies mites in skin burrows. We propose that SMIPPs minimize complement-mediated gut damage and thus create a favorable environment for the scabies mites.