Matthew J. Anderson

Pancreatic ductal adenocarcinoma (PDAC) can be divided into transcriptomic subtypes with two broad lineages referred to as classical (pancreatic) and squamous. We find that these two subtypes are driven by distinct metabolic phenotypes. Loss of genes that drive endodermal lineage specification, HNF4A and GATA6, switch metabolic profiles from classical (pancreatic) to predominantly squamous, with glycogen synthase kinase 3 beta (GSK3β) a key regulator of glycolysis. Pharmacological inhibition of GSK3β results in selective sensitivity in the squamous subtype; however, a subset of these squamous patient-derived cell lines (PDCLs) acquires rapid drug tolerance. Using chromatin accessibility maps, we demonstrate that the squamous subtype can be further classified using chromatin accessibility to predict responsiveness and tolerance to GSK3β inhibitors. Our findings demonstrate that distinct patterns of chromatin accessibility can be used to identify patient subgroups that are indistinguishable by gene expression profiles, highlighting the utility of chromatin-based biomarkers for patient selection in the treatment of PDAC.

Developmental dysplasia of the hip (DDH) encompasses a wide spectrum of hip disorders, including neonatal instability, acetabular dysplasia, hip subluxation, and frank dislocation of the hip. It is a common disorder, with a reported incidence of between 0.1% and >10% of live births. Coordinated, interdisciplinary care is important to achieving successful outcomes. This starts with accurate assessment of risk factors in the prenatal period, thorough clinical examination by the primary care provider at all well-child visits, and early referral to a pediatric orthopaedic surgeon for prompt diagnosis and treatment. Early diagnosis and prompt treatment is critical for an excellent outcome. Ongoing, open communication between clinicians is essential for the effective coordination of care. Treatment options vary depending on the age of presentation. A Pavlik harness (dynamic hip abduction orthosis) is used for children up to 6 months of age. A more rigid abduction orthosis may be used if treatment with a Pavlik harness is unsuccessful, with a closed reduction and spica cast being the next step if needed for children up to 18 months of age. Finally, open reduction with possible concomitant femoral and/or pelvic osteotomies is the surgical option in an older child, when necessary. In general, the later the child is diagnosed with and treated for DDH, the greater the risk of a nonoptimal outcome. Depending on the severity of the condition, children with DDH may need to be followed closely until skeletal maturity so as not to miss the diagnosis of asymptomatic residual hip dysplasia, which can predispose patients to early hip arthritis.

Correction to: Nature Genetics https://doi.org/10.1038/s41588-019-0558-9, published online 05 February 2020.

Antimalarial medications are recommended for chemoprevention as part of malaria control programs to decrease the morbidity and mortality related to more than 200 million infections each year. We sought to evaluate patient and provider acceptability of malaria chemoprevention in a long-acting formulation. We administered questionnaires to patients and providers in malaria endemic districts in Kenya and Zambia. Questions explored preferences and concerns around long-acting antimalarial formulations compared with oral formulations. We recruited 202 patient respondents (Kenya, n = 102; Zambia, n = 100) and 215 provider respondents (Kenya, n = 105; Zambia, n = 110). Long-acting injection was preferred to oral pills, whereas oral pills were preferred to implant or transdermal administration by patient respondents. Of 202 patient respondents, 80% indicated that they 'definitely would try' malaria chemoprevention offered by injection instead of oral pills. Of parents or guardians, 84% of 113 responded that they 'definitely would' have their child age < 12 years and 90% of 88 'definitely would' have their child ≥12 years receive an injection for malaria prevention. Provider respondents indicated that they would be more likely to prescribe a long-acting injectable product compared with an oral product for malaria chemoprevention in adults (70%), adolescents ages 12 years and older (67%), and children <12 years (81%). Potential for prolonged adverse effects with long-acting products was the highest concern for patient respondents, while higher medication-related cost was cited as the most concerning barrier to implementation by providers. Overall, these findings indicate enthusiasm for the development of long-acting injectable antimalarials to provide individual delivery method options across age groups.