Australian Genomics: Outcomes of a 5-year national program to accelerate the integration of genomics in healthcare.

Australian Genomics is a national collaborative partnership of more than 100 organizations piloting a whole-of-system approach to integrating genomics into healthcare, based on federation principles. In the first five years of operation, Australian Genomics has evaluated the outcomes of genomic testing in more than 5,200 individuals across 19 rare disease and cancer flagship studies. Comprehensive analyses of the health economic, policy, ethical, legal, implementation and workforce implications of incorporating genomics in the Australian context have informed evidence-based change in policy and practice, resulting in national government funding and equity of access for a range of genomic tests. Simultaneously, Australian Genomics has built national skills, infrastructure, policy, and data resources to enable effective data sharing to drive discovery research and support improvements in clinical genomic delivery.

Shariant platform: Enabling evidence sharing across Australian clinical genetic-testing laboratories to support variant interpretation.

Sharing genomic variant interpretations across laboratories promotes consistency in variant assertions. A landscape analysis of Australian clinical genetic-testing laboratories in 2017 identified that, despite the national-accreditation-body recommendations encouraging laboratories to submit genotypic data to clinical databases, fewer than 300 variants had been shared to the ClinVar public database. Consultations with Australian laboratories identified resource constraints limiting routine application of manual processes, consent issues, and differences in interpretation systems as barriers to sharing. This information was used to define key needs and solutions required to enable national sharing of variant interpretations. The Shariant platform, using both the GRCh37 and GRCh38 genome builds, was developed to enable ongoing sharing of variant interpretations and associated evidence between Australian clinical genetic-testing laboratories. Where possible, two-way automated sharing was implemented so that disruption to laboratory workflows would be minimized. Terms of use were developed through consultation and currently restrict access to Australian clinical genetic-testing laboratories. Shariant was designed to store and compare structured evidence, to promote and record resolution of inter-laboratory classification discrepancies, and to streamline the submission of variant assertions to ClinVar. As of December 2021, more than 14,000 largely prospectively curated variant records from 11 participating laboratories have been shared. Discrepant classifications have been identified for 11% (28/260) of variants submitted by more than one laboratory. We have demonstrated that co-design with clinical laboratories is vital to developing and implementing a national variant-interpretation sharing effort. This approach has improved inter-laboratory concordance and enabled opportunities to standardize interpretation practices.

Persons with HIV Develop Spike-Specific Lymph Node Germinal Center Responses following SARS-CoV-2 Vaccination.

COVID-19 disproportionately affects persons with HIV (PWH) in worldwide locations with limited access to SARS-CoV-2 vaccines. PWH exhibit impaired immune responses to some, but not all, vaccines. Lymph node (LN) biopsies from PWH demonstrate abnormal LN structure, including dysregulated germinal center (GC) architecture. It is not clear whether LN dysregulation prevents PWH from mounting Ag-specific GC responses in the draining LN following vaccination. To address this issue, we longitudinally collected blood and draining LN fine needle aspiration samples before and after SARS-CoV-2 vaccination from a prospective, observational cohort of 11 PWH on antiretroviral therapy: 2 who received a two-dose mRNA vaccine series and 9 who received a single dose of the Ad26.COV2.S vaccine. Following vaccination, we observed spike-specific Abs, spike-specific B and T cells in the blood, and spike-specific GC B cell and T follicular helper cell responses in the LN of both mRNA vaccine recipients. We detected spike-specific Abs in the blood of all Ad26.COV2.S recipients, and one of six sampled Ad26.COV2.S recipients developed a detectable spike-specific GC B and T follicular helper cell response in the draining LN. Our data show that PWH can mount Ag-specific GC immune responses in the draining LN following SARS-CoV-2 vaccination. Due to the small and diverse nature of this cohort and the limited number of available controls, we are unable to elucidate all potential factors contributing to the infrequent vaccine-induced GC response observed in the Ad26.COV2.S recipients. Our preliminary findings suggest this is a necessary area of future research.

Barriers and facilitators to smartwatch-based prehabilitation participation among frail surgery patients: a qualitative study.

BACKGROUND: For older, frail adults, exercise before surgery through prehabilitation (prehab) may hasten return recovery and reduce postoperative complications. We developed a smartwatch-based prehab program (BeFitMe) for older adults that encourages and tracks at-home exercise. The objective of this study was to assess patient perceptions about facilitators and barriers to prehab generally and to using a smartwatch prehab program among older adult thoracic surgery patients to optimize future program implementation. METHODS: We recruited patients, aged ≥50 years who had or were having surgery and were screened for frailty (Fried's Frailty Phenotype) at a thoracic surgery clinic at a single academic institution. Semi-structured interviews were conducted by telephone after obtaining informed consent. Participants were given a description of the BeFitMe program. The interview questions were informed by The Five "Rights" of Clinical Decision-Making framework (Information, Person, Time, Channel, and Format) and sought to identify the factors perceived to influence smartwatch prehab program participation. Interview transcripts were transcribed and independently coded to identify themes in for each of the Five "Rights" domains. RESULTS: A total of 29 interviews were conducted. Participants were 52% men (n = 15), 48% Black (n = 14), and 59% pre-frail (n = 11) or frail (n = 6) with a mean age of 68 ± 9 years. Eleven total themes emerged. Facilitator themes included the importance of providers (right person) clearly explaining the significance of prehab (right information) during the preoperative visit (right time); providing written instructions and exercise prescriptions; and providing a preprogrammed and set-up (right format) Apple Watch (right channel). Barrier themes included pre-existing conditions and disinterest in exercise and/or technology. Participants provided suggestions to overcome the technology barrier, which included individualized training and support on usage and responsibilities. CONCLUSIONS: This study reports the perceived facilitators and barriers to a smartwatch-based prehab program for pre-frail and frail thoracic surgery patients. The future BeFitMe implementation protocol must ensure surgical providers emphasize the beneficial impact of participating in prehab before surgery and provide a written prehab prescription; must include a thorough guide on smartwatch use along with the preprogrammed device to be successful. The findings are relevant to other smartwatch-based interventions for older adults.

Adjuvant chemotherapy following chemoradiotherapy as primary treatment for locally advanced cervical cancer versus chemoradiotherapy alone (OUTBACK): an international, open-label, randomised, phase 3 trial.

BACKGROUND: Standard treatment for locally advanced cervical cancer is chemoradiotherapy, but many patients relapse and die of metastatic disease. We aimed to determine the effects on survival of adjuvant chemotherapy after chemoradiotherapy. METHODS: The OUTBACK trial was a multicentre, open-label, randomised, phase 3 trial done in 157 hospitals in Australia, China, Canada, New Zealand, Saudi Arabia, Singapore, and the USA. Eligible participants were aged 18 year or older with histologically confirmed squamous cell carcinoma, adenosquamous cell carcinoma, or adenocarcinoma of the cervix (FIGO 2008 stage IB1 disease with nodal involvement, or stage IB2, II, IIIB, or IVA disease), Eastern Cooperative Oncology Group performance status 0-2, and adequate bone marrow and organ function. Participants were randomly assigned centrally (1:1) using a minimisation approach and stratified by pelvic or common iliac nodal involvement, requirement for extended-field radiotherapy, FIGO 2008 stage, age, and site to receive standard cisplatin-based chemoradiotherapy (40 mg/m2 cisplatin intravenously once-a-week for 5 weeks, during radiotherapy with 45·0-50·4 Gy external beam radiotherapy delivered in fractions of 1·8 Gy to the whole pelvis plus brachytherapy; chemoradiotherapy only group) or standard cisplatin-based chemoradiotherapy followed by adjuvant chemotherapy with four cycles of carboplatin (area under the receiver operator curve 5) and paclitaxel (155 mg/m2) given intravenously on day 1 of a 21 day cycle (adjuvant chemotherapy group). The primary endpoint was overall survival at 5 years, analysed in the intention-to-treat population (ie, all eligible patients who were randomly assigned). Safety was assessed in all patients in the chemoradiotherapy only group who started chemoradiotherapy and all patients in the adjuvant chemotherapy group who received at least one dose of adjuvant chemotherapy. The OUTBACK trial is registered with ClinicalTrials.gov, NCT01414608, and the Australia New Zealand Clinical Trial Registry, ACTRN12610000732088. FINDINGS: Between April 15, 2011, and June 26, 2017, 926 patients were enrolled and randomly assigned to the chemoradiotherapy only group (n=461) or the adjuvant chemotherapy group (n=465), of whom 919 were eligible (456 in the chemoradiotherapy only group and 463 in the adjuvant chemotherapy group; median age 46 years [IQR 37 to 55]; 663 [72%] were White, 121 [13%] were Black or African American, 53 [6%] were Asian, 24 [3%] were Aboriginal or Pacific islander, and 57 [6%] were other races) and included in the analysis. As of data cutoff (April 12, 2021), median follow-up was 60 months (IQR 45 to 65). 5-year overall survival was 72% (95% CI 67 to 76) in the adjuvant chemotherapy group (105 deaths) and 71% (66 to 75) in the chemoradiotherapy only group (116 deaths; difference 1% [95% CI -6 to 7]; hazard ratio 0·90 [95% CI 0·70 to 1·17]; p=0·81). In the safety population, the most common clinically significant grade 3-4 adverse events were decreased neutrophils (71 [20%] in the adjuvant chemotherapy group vs 34 [8%] in the chemoradiotherapy only group), and anaemia (66 [18%] vs 34 [8%]). Serious adverse events occurred in 107 (30%) in the adjuvant chemotherapy group versus 98 (22%) in the chemoradiotherapy only group, most commonly due to infectious complications. There were no treatment-related deaths. INTERPRETATION: Adjuvant carboplatin and paclitaxel chemotherapy given after standard cisplatin-based chemoradiotherapy for unselected locally advanced cervical cancer increased short-term toxicity and did not improve overall survival; therefore, it should not be given in this setting. FUNDING: National Health and Medical Research Council and National Cancer Institute.

Costs and Health Care Utilization Analysis of Medical Group Visits for Adults With Type 2 Diabetes in Community Health Centers.

OBJECTIVE: We evaluated the economic impact of group visits (GVs) in adults with uncontrolled diabetes in community health centers (CHCs) in the United States. RESEARCH DESIGN AND METHODS: In this prospective controlled trial, we implemented 6 monthly GV sessions in 5 CHCs and compared intervention patients (n=49) to control patients (n=72) receiving usual care within the same CHCs. We conducted patient chart reviews to obtain health care utilization data for the prior 6 months at baseline, 6 months (during the GV implementation), and 12 months (after the implementation). We also collected monthly logs of CHC expenses and staff time spent on activities related to GVs. Per-patient total costs included CHCs' expenses and costs associated with staff time and patients' health care use. For group comparison, we used the Wilcoxon rank-sum test and the bootstrapping method that was to bootstrap generalized estimating equation models. RESULTS: The GV group had fewer 6-month hospitalizations (mean: GV: 0.06 vs. control: 0.24, rate: 6.1% vs. 19.4%) ( P ≤ 0.04) and similar emergency department visits at 12 months than the control group. Implementing GV incurred $1770 per-patient. The intervention cost $1597 more than the control at 6 months ($3021 vs. $1424) but saved $1855 at 12 months ($857 vs. $2712) ( P =0.002). CONCLUSIONS: The diabetes GV care model reduced hospitalizations and had cost savings at 12 months, while it improved patients' diabetes-related quality of life and glucose control. Future studies should assess its lifetime cost-effectiveness through a randomized controlled trial.

Whole-genome landscape of pancreatic neuroendocrine tumours.

The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling.

Corrigendum: Whole-genome landscape of pancreatic neuroendocrine tumours.

This corrects the article DOI: 10.1038/nature21063.

Methotrexate-related central neurotoxicity: clinical characteristics, risk factors and genome-wide association study in children treated for acute lymphoblastic leukemia.

Symptomatic methotrexate-related central neurotoxicity (MTX neurotoxicity) is a severe toxicity experienced during acute lymphoblastic leukemia (ALL) therapy with potential long-term neurologic complications. Risk factors and long-term outcomes require further study. We conducted a systematic, retrospective review of 1,251 consecutive Australian children enrolled on Berlin-Frankfurt-Münster or Children's Oncology Group-based protocols between 1998-2013. Clinical risk predictors for MTX neurotoxicity were analyzed using regression. A genome-wide association study (GWAS) was performed on 48 cases and 537 controls. The incidence of MTX neurotoxicity was 7.6% (n=95 of 1,251), at a median of 4 months from ALL diagnosis and 8 days after intravenous or intrathecal MTX. Grade 3 elevation of serum aspartate aminotransferase (P=0.005, odds ratio 2.31 [range, 1.28-4.16]) in induction/consolidation was associated with MTX neurotoxicity, after accounting for the only established risk factor, age ≥10 years. Cumulative incidence of CNS relapse was increased in children where intrathecal MTX was omitted following symptomatic MTX neurotoxicity (n=48) compared to where intrathecal MTX was continued throughout therapy (n=1,174) (P=0.047). Five-year central nervous system relapse-free survival was 89.2 4.6% when intrathecal MTX was ceased compared to 95.4 0.6% when intrathecal MTX was continued. Recurrence of MTX neurotoxicity was low (12.9%) for patients whose intrathecal MTX was continued after their first episode. The GWAS identified single-nucletide polymorphism associated with MTX neurotoxicity near genes regulating neuronal growth, neuronal differentiation and cytoskeletal organization (P<1x10-6). In conclusion, increased serum aspartate aminotransferase and age ≥10 years at diagnosis were independent risk factors for MTX neurotoxicity. Our data do not support cessation of intrathecal MTX after a first MTX neurotoxicity event.

Elements of Integrated Behavioral Health Associated with Primary Care Provider Confidence in Managing Depression at Community Health Centers.

BACKGROUND: Depression is most often treated by primary care providers (PCPs), but low self-efficacy in caring for depression may impede adequate management. We aimed to identify which elements of integrated behavioral health (BH) were associated with greater confidence among PCPs in identifying and managing depression. DESIGN: Mailed cross-sectional surveys in 2016. PARTICIPANTS: BH leaders and PCPs caring for adult patients at community health centers (CHCs) in 10 midwestern states. MAIN MEASURES: Survey items asked about depression screening, systems to support care, availability and integration of BH, and PCP attitudes and experiences. PCPs rated their confidence in diagnosing, assessing severity, providing counseling, and prescribing medication for depression on a 5-point scale. An overall confidence score was calculated (range 4 (low) to 20 (high)). Multilevel linear mixed models were used to identify factors associated with confidence. KEY RESULTS: Response rates were 60% (N=77/128) and 52% (N=538/1039) for BH leaders and PCPs, respectively. Mean overall confidence score was 15.25±2.36. Confidence was higher among PCPs who were satisfied with the accuracy of depression screening (0.38, p=0.01), worked at CHCs with depression tracking systems (0.48, p=0.045), had access to patients' BH treatment plans (1.59, p=0.002), and cared for more patients with depression (0.29, p=0.003). PCPs who reported their CHC had a sufficient number of psychiatrists were more confident diagnosing depression (0.20, p=0.02) and assessing severity (0.24, p=0.03). Confidence in prescribing was lower at CHCs with more patients living below poverty (-0.66, p<0.001). Confidence in diagnosing was lower at CHCs with more Black/African American patients (-0.20, p=0.03). CONCLUSIONS: PCPs who had access to BH treatment plans, a system for tracking patients with depression, screening protocols, and a sufficient number of psychiatrists were more confident identifying and managing depression. Efforts are needed to address disparities and support PCPs caring for vulnerable patients with depression.

Impact of diabetes group visits on patient clinical and self-reported outcomes in community health centers.

BACKGROUND: Diabetes group visits (GVs) are a promising way to deliver high quality care but have been understudied in community health centers (CHCs), across multiple sites, or with a focus on patient-centered outcomes. METHODS: We trained staff and healthcare providers from six CHCs across five Midwestern states to implement a 6-month GV program at their sites. We assessed the impact of diabetes GVs on patient clinical and self-reported outcomes and processes of care compared to patients receiving usual care at these sites during the same period using a prospective controlled study design. RESULTS: CHCs enrolled 51 adult patients with diabetes with glycosylated hemoglobin (A1C) ≥ 8% for the GV intervention and conducted chart review of 72 patients receiving usual care. We analyzed A1C at baseline, 6, and 12 months, low-density lipoproteins (LDL), blood pressure, and patient-reported outcomes. GV patients had a larger decrease in A1C from baseline to 6 months (-1.04%, 95% CI: -1.64, -0.44) and 12 months (-1.76, 95% CI: -2.44, -1.07) compared to usual care; there was no change in blood pressure or LDL. GV patients had higher odds of receiving a flu vaccination, foot exam, eye exam, and lipid panel in the past year compared to usual care but not a dental exam, urine microalbumin test, or blood pressure check. For GV patients, diabetes distress decreased, diabetes-related quality of life improved, and self-reported frequency of healthy eating and checking blood sugar increased from baseline to 6 months, but there was no change in exercise or medication adherence. CONCLUSIONS: A diabetes GV intervention improved blood glucose levels, self-care behaviors, diabetes distress, and processes of care among adults with elevated A1Cs compared to patients receiving usual care. Future studies are needed to assess the sustainability of clinical improvements and costs of the GV model in CHCs.

Genomic analyses identify molecular subtypes of pancreatic cancer.

Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-ß, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63∆N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.

Assessing the effectiveness of a diabetes group visit training for health center staff: a pilot study of five Midwestern community health centers.

BACKGROUND: Diabetes group visits are shared appointments that include diabetes education in a group setting and individual visits with a medical provider. An 18-month pilot study was designed to evaluate organizational capacity and staff preparedness in implementing and sustaining diabetes group visits. RESULTS: Data were collected and analyzed from pre-post assessments and key informant interviews with community health center (CHC) staff (N = 26) from teams across five Midwestern states. Overall, participants demonstrated high baseline knowledge and awareness about diabetes group visit implementation. Changes in attitudes and practices did occur pertaining to familiarity with billing and increased awareness about potential barriers to diabetes group visit implementation. Key assets to diabetes group visit implementation were access to pre-designed resources and materials, a highly motivated team, and supportive leadership. Key obstacles were socioeconomic challenges experienced by patients, constraints on staff time dedicated to group visit implementation, and staff turnover. CONCLUSIONS: Results of the study provide a framework for implementation of diabetes group visit trainings for CHC staff. Future research is needed to assess the training program in a larger sample of CHCs.

Toxicological assessment of electronic cigarette vaping: an emerging threat to force health, readiness and resilience in the U.S. Army.

The U.S. Army and U. S. Army Public Health Center are dedicated to protecting the health, and readiness of Department of the Army Service Members, civilians, and contractors. Despite implementation of health programs, policies and tobacco control interventions, the advent of electronic nicotine delivery systems (ENDS), including electronic cigarettes (e-cigs), represent unregulated and poorly defined systems to supplant or substitute use of conventional nicotine products (e.g., cigarettes and pipe tobacco). E-cigs present unique challenges to healthcare officials vested in preventive medicine. The health impact of an e-cig and vaping on an individual's acute or chronic disease susceptibility, performance and wellness, is fraught with uncertainty. Given the relatively recent emergence of e-cigs, high-quality epidemiological studies, and applied biological research studies are severely lacking. In sparsely available epidemiological studies of short-term cardiovascular and respiratory health outcomes, any attempt at addressing the etiology of acute and chronic health conditions from e-cig use faces incredible challenges. Until relatively recently, this was complicated by an absent national regulatory framework and health agency guidance on the manufacture, distribution, selling and use of e-cigs or similar ENDS devices and their chemical constituents. Two key issues underpin public health concern from e-cig use: 1) continued or emergent nicotine addiction and potential use of these devices for vaping controlled substances; and 2) inadvertent sudden-onset or chronic health effects from inhalational exposure to low levels of complex chemical toxicants from e-cig use and vaping the liquid. Herein, the health impacts from e-cig vaping and research supporting such effects are discussed.

Informing American Muslims about living donation through tailored health education: A randomized controlled crossover trial evaluating increase in biomedical and religious knowledge.

Biomedical and religious knowledge affects organ donation attitudes among Muslims. We tested the effectiveness of mosque-based, religiously tailored, ethically balanced education on organ donation among Muslim Americans. Our randomized, controlled, crossover trial took place at 4 mosques randomized to an early arm where organ donation education preceded a control educational workshop or a late arm with the order reversed. Primary outcomes were changes in biomedical (Rotterdam Renal Replacement Knowledge Test living donation subscale, R3KT) and religious (Islamic Knowledge of Living Organ Donation, IK-LOD) living kidney donation knowledge. Statistical analysis employed a 2 (Treatment Arm) X 3 (Time of Assessment) mixed-method analysis of variance. Of 158 participants, 59 were in the early arm and 99 in the late arm. A between group t test comparison at Period 1 (Time 1 - Time 2), demonstrated that the early arm had a significantly higher mean IK-LOD (7.11 v 5.19, P < .05) and R3KT scores (7.65 v 4.90, P < .05) when compared to the late arm. Late arm participants also had significant increases in mean IK-LOD (5.19 v 7.16, P < .05) and R3KT scores (4.90 v. 6.81, P < .05) postintervention (Time 2-Time 3). Our novel program thus yielded significant kidney donation-related knowledge gains among Muslim Americans (NCT04443114 Clinicaltrials.gov).

Provider-related barriers and enablers to the provision of hepatitis C treatment by general practitioners in Scotland: A behaviour change analysis.

The ease of direct-acting antiviral (DAA) medications for hepatitis C virus (HCV) has provided an opportunity to decentralize HCV treatment into community settings. However, the role of non-specialist clinicians in community-based pathways has received scant attention to date. This study examined barriers and enablers to expanding the role of general practitioners (GPs) in HCV treatment provision, using simple behaviour change theory as a conceptual framework. A maximum variation sample of 22 HCV treatment providers, GPs and HCV support workers participated in semi-structured interviews. Data were inductively coded, and the resulting codes deductively mapped into three principal components of behaviour change: capability, opportunity and motivation (COM-B). By this process, a number of provider- and systemic-level barriers and enablers were identified. Key barriers included the pre-treatment assessment of liver fibrosis, GP capacity and the 'speciality' of HCV care. Enablers included the simplicity of the drugs, existing GP/patient relationships and the provision of holistic care. In addition to these specific factors, the data also exposed an overarching provider understanding of 'HCV treatment' as triumvirate in nature, incorporating the assessment of liver fibrosis, the provision of holistic support and the treatment of disease. This understanding imposes a further fundamental barrier to GP-led treatment as each of these three components needs to be individually addressed. To enable sustainable models of HCV treatment provision by GPs, a pragmatic re-examination of the 'HCV treatment triumvirate' is required, and a paradigm shift from the 'refer and treat' status quo.

Integration of Diabetes and Depression Care Is Associated with Glucose Control in Midwestern Federally Qualified Health Centers.

BACKGROUND: The 2016 American Diabetes Association position statement emphasized that psychosocial and medical care should be integrated and provided to all people with diabetes. OBJECTIVE: To determine whether better integration of diabetes and depression care is associated with better glycemic control. DESIGN: Cross-sectional surveys of Midwestern federally qualified health center (FQHC) leaders and primary care providers (PCPs) in 2016. Responses were linked to FQHC-level data on the percentage of patients with uncontrolled diabetes (glycated hemoglobin ≥ 9%; 75 mmol/mol). PARTICIPANTS: Midwest Clinicians' Network-affiliated FQHC leaders, and PCPs at the FQHCs. MAIN MEASURES: Multilevel models were used to determine associations between the percentage of patients with uncontrolled diabetes and FQHC and PCP characteristics; presence of diabetes and behavioral health care services; and PCPs' perception of the stage of integration between diabetes and depression care services based on the transtheoretical model (i.e., pre-contemplation, contemplation, preparation, action, or maintenance). KEY RESULTS: Response rates were 60% for the FQHC survey (N = 77) and 55% for the PCP survey (N = 538). In adjusted models, FQHCs in which PCPs perceived a higher stage of integration between diabetes and depression care had 3% fewer patients with uncontrolled diabetes per 1-level increase in integration stage (p = 0.01); on-site diabetes self-management education was associated with 7% fewer patients with uncontrolled diabetes (p < 0.01). CONCLUSIONS: At Midwestern FQHCs, a higher stage of perceived integration of diabetes and depression care was associated with better FQHC-level glycemic control. Future studies are needed to elucidate what defines integration of diabetes and depression care services.

Whole-genome characterization of chemoresistant ovarian cancer.

Patients with high-grade serous ovarian cancer (HGSC) have experienced little improvement in overall survival, and standard treatment has not advanced beyond platinum-based combination chemotherapy, during the past 30 years. To understand the drivers of clinical phenotypes better, here we use whole-genome sequencing of tumour and germline DNA samples from 92 patients with primary refractory, resistant, sensitive and matched acquired resistant disease. We show that gene breakage commonly inactivates the tumour suppressors RB1, NF1, RAD51B and PTEN in HGSC, and contributes to acquired chemotherapy resistance. CCNE1 amplification was common in primary resistant and refractory disease. We observed several molecular events associated with acquired resistance, including multiple independent reversions of germline BRCA1 or BRCA2 mutations in individual patients, loss of BRCA1 promoter methylation, an alteration in molecular subtype, and recurrent promoter fusion associated with overexpression of the drug efflux pump MDR1.

Whole genomes redefine the mutational landscape of pancreatic cancer.

Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded.

RNA-seq of newly diagnosed patients in the PADIMAC study leads to a bortezomib/lenalidomide decision signature.

Improving outcomes in multiple myeloma will involve not only development of new therapies but also better use of existing treatments. We performed RNA sequencing on samples from newly diagnosed patients enrolled in the phase 2 PADIMAC (Bortezomib, Adriamycin, and Dexamethasone Therapy for Previously Untreated Patients with Multiple Myeloma: Impact of Minimal Residual Disease in Patients with Deferred ASCT) study. Using synthetic annealing and the large margin nearest neighbor algorithm, we developed and trained a 7-gene signature to predict treatment outcome. We tested the signature in independent cohorts treated with bortezomib- and lenalidomide-based therapies. The signature was capable of distinguishing which patients would respond better to which regimen. In the CoMMpass data set, patients who were treated correctly according to the signature had a better progression-free survival (median, 20.1 months vs not reached; hazard ratio [HR], 0.40; confidence interval [CI], 0.23-0.72; P = .0012) and overall survival (median, 30.7 months vs not reached; HR, 0.41; CI, 0.21-0.80; P = .0049) than those who were not. Indeed, the outcome for these correctly treated patients was noninferior to that for those treated with combined bortezomib, lenalidomide, and dexamethasone, arguably the standard of care in the United States but not widely available elsewhere. The small size of the signature will facilitate clinical translation, thus enabling more targeted drug regimens to be delivered in myeloma.