CRISPR-Cas9-modified pfmdr1 protects Plasmodium falciparum asexual blood stages and gametocytes against a class of piperazine-containing compounds but potentiates artemisinin-based combination therapy partner drugs.

Emerging resistance to first-line antimalarial combination therapies threatens malaria treatment and the global elimination campaign. Improved therapeutic strategies are required to protect existing drugs and enhance treatment efficacy. We report that the piperazine-containing compound ACT-451840 exhibits single-digit nanomolar inhibition of the Plasmodium falciparum asexual blood stages and transmissible gametocyte forms. Genome sequence analyses of in vitro-derived ACT-451840-resistant parasites revealed single nucleotide polymorphisms in pfmdr1, which encodes a digestive vacuole membrane-bound ATP-binding cassette transporter known to alter P. falciparum susceptibility to multiple first-line antimalarials. CRISPR-Cas9 based gene editing confirmed that PfMDR1 point mutations mediated ACT-451840 resistance. Resistant parasites demonstrated increased susceptibility to the clinical drugs lumefantrine, mefloquine, quinine and amodiaquine. Stage V gametocytes harboring Cas9-introduced pfmdr1 mutations also acquired ACT-451840 resistance. These findings reveal that PfMDR1 mutations can impart resistance to compounds active against asexual blood stages and mature gametocytes. Exploiting PfMDR1 resistance mechanisms provides new opportunities for developing disease-relieving and transmission-blocking antimalarials.

Pain management among Dominican patients with advanced osteoarthritis: a qualitative study.

BACKGROUND: Advanced osteoarthritis and total joint replacement (TJR) recovery are painful experiences and often prompt opioid use in developed countries. Physicians participating in the philanthropic medical mission Operation Walk Boston (OpWalk) to the Dominican Republic have observed that Dominican patients require substantially less opioid medication following TJR than US patients. We conducted a qualitative study to investigate approaches to pain management and expectations for postoperative recovery in patients with advanced arthritis undergoing TJR in the Dominican Republic. METHODS: We interviewed 20 patients before TJR about their pain coping mechanisms and expectations for postoperative pain management and recovery. Interviews were conducted in Spanish, translated, and analyzed in English using content analysis. RESULTS: Patients reported modest use of pain medications and limited knowledge of opioids, and many relied on non-pharmacologic therapies and family support to cope with pain. They held strong religious beliefs that offered them strength to cope with chronic arthritis pain and prepare for acute pain following surgery. Patients exhibited a great deal of trust in powerful others, expecting God and doctors to cure their pain through surgery. CONCLUSION: We note the importance of understanding a patient's individual pain coping mechanisms and identifying strategies to support these coping behaviors in pain management. Such an approach has the potential to reduce the burden of chronic arthritis pain while limiting reliance on opioids, particularly for patients who do not traditionally utilize powerful analgesics.

Outcomes of Children Admitted to a Pediatric Observation Unit With a Psychiatric Comanagement Model.

This cohort study describes outcomes of children requiring admission for mental health emergencies who receive psychiatric cotreatment in a pediatric observation unit.

Postoperative Pain Management Among Dominican and American Health-Care Providers: A Qualitative Analysis.

BACKGROUND: U.S. practitioners have prescribed opioid analgesics increasingly in recent years, contributing to what has been declared an opioid epidemic by the U.S. Centers for Disease Control and Prevention (CDC). Opioids are used frequently in the preoperative and postoperative periods for patients undergoing total joint replacement in developed countries, but cross-cultural comparisons of this practice are limited. An international medical mission such as Operation Walk Boston, which provides total joint replacement to financially vulnerable patients in the Dominican Republic, offers a unique opportunity to compare postoperative pain management approaches in a developed nation and a developing nation. METHODS: We interviewed American and Dominican surgeons and nurses (n = 22) during Operation Walk Boston 2015. We used a moderator's guide with open-ended questions to inquire about postoperative pain management and factors influencing prescribing practices. Interviews were recorded and transcripts were analyzed using content analysis. RESULTS: Providers highlighted differences in the patient-provider relationship, pain medication prescribing variability, and access to medications. Dominican surgeons emphasized adherence to standardized pain protocols and employed a paternalistic model of care, and American surgeons reported prescribing variability and described shared decision-making with patients. Dominican providers described limited availability of potent opioid preparations in the Dominican Republic, in contrast to American providers, who discussed opioid accessibility in the United States. CONCLUSIONS: Our findings suggest that cross-cultural comparisons provide insight into how opioid prescribing practices, approaches to the patient-provider relationship, and medication access inform distinct pain management strategies in American and Dominican surgical settings. Integrating lessons from cross-cultural pain management studies may yield more effective pain management strategies for surgical procedures performed in the United States and abroad.