Sustainability Challenges and Opportunities in Oligonucleotide Manufacturing.

With a renewed and growing interest in therapeutic oligonucleotides across the pharmaceutical industry, pressure is increasing on drug developers to take more seriously the sustainability ramifications of this modality. With 12 oligonucleotide drugs reaching the market to date and hundreds more in clinical trials and preclinical development, the current state of the art in oligonucleotide production poses a waste and cost burden to manufacturers. Legacy technologies make use of large volumes of hazardous reagents and solvents, as well as energy-intensive processes in synthesis, purification, and isolation. In 2016, the American Chemical Society (ACS) Green Chemistry Institute Pharmaceutical Roundtable (GCIPR) identified the development of greener processes for oligonucleotide Active Pharmaceutical Ingredients (APIs) as a critical unmet need. As a result, the Roundtable formed a focus team with the remit of identifying green chemistry and engineering improvements that would make oligonucleotide production more sustainable. In this Perspective, we summarize the present challenges in oligonucleotide synthesis, purification, and isolation; highlight potential solutions; and encourage synergies between academia; contract research, development and manufacturing organizations; and the pharmaceutical industry. A critical part of our assessment includes Process Mass Intensity (PMI) data from multiple companies to provide preliminary baseline metrics for current oligonucleotide manufacturing processes.

Community Assessment of the Predictability of Cancer Protein and Phosphoprotein Levels from Genomics and Transcriptomics.

Cancer is driven by genomic alterations, but the processes causing this disease are largely performed by proteins. However, proteins are harder and more expensive to measure than genes and transcripts. To catalyze developments of methods to infer protein levels from other omics measurements, we leveraged crowdsourcing via the NCI-CPTAC DREAM proteogenomic challenge. We asked for methods to predict protein and phosphorylation levels from genomic and transcriptomic data in cancer patients. The best performance was achieved by an ensemble of models, including as predictors transcript level of the corresponding genes, interaction between genes, conservation across tumor types, and phosphosite proximity for phosphorylation prediction. Proteins from metabolic pathways and complexes were the best and worst predicted, respectively. The performance of even the best-performing model was modest, suggesting that many proteins are strongly regulated through translational control and degradation. Our results set a reference for the limitations of computational inference in proteogenomics. A record of this paper's transparent peer review process is included in the Supplemental Information.

The Korean Version of the Cognitive Assessment Scale for Stroke Patients (K-CASP): A Reliability and Validity Study.

OBJECTIVE: To develop the Korean version of the Cognitive Assessment Scale for Stroke Patients (K-CASP) and to evaluate the test reliability and validity of the K-CASP in stroke patients. METHODS: The original CASP was translated into Korean, back-translated into English, then reviewed and compared with the original version. Thirty-three stroke patients were assessed independently by two examiners using the K-CASP twice, with a one-day interval, for a total of four test results. To evaluate the reliability of the K-CASP, intra-class correlation coefficients were used. Pearson correlations were calculated and simple regression analyses performed with the Korean version of Mini-Mental State Examination (K-MMSE) and the aphasia quotient (AQ) to assess the validity. RESULTS: The mean score was 24.42±9.47 (total score 36) for the K-CASP and 21.50±7.01 (total score 30) for the K-MMSE. The inter-rater correlation coefficients of the K-CASP were 0.992 on the first day and 0.995 on the second day. The intra-rater correlation coefficients of the K-CASP were 0.997 for examiner 1 and 0.996 for examiner 2. In the Pearson correlation analysis, the K-CASP score significantly correlated with the K-MMSE score (r=0.825, p<0.001). The coefficients of determination (r2) of the AQ were 0.586 for the K-MMSE and 0.513 for the K-CASP in the simple regression analysis. CONCLUSION: The K-CASP is a reliable and valid instrument for cognitive dysfunction screening in post-stroke patients. It is more applicable than other cognitive assessment tools in stroke patients with aphasia.

A scalable and regioselective synthesis of 2-difluoromethyl pyridines from commodity chemicals.

A scalable de novo synthesis of difluoromethyl pyridines from inexpensive materials is reported. The pyridyl subunit is built around the difluoromethyl group rather than a late stage introduction of this moiety. This user-friendly approach allows access to a diverse range of substitution patterns on all positions on the ring system and on the difluoromethyl group.

25-Year summary of US malpractice claims for diagnostic errors 1986-2010: an analysis from the National Practitioner Data Bank.

BACKGROUND: We sought to characterise the frequency, health outcomes and economic consequences of diagnostic errors in the USA through analysis of closed, paid malpractice claims. METHODS: We analysed diagnosis-related claims from the National Practitioner Data Bank (1986-2010). We describe error type, outcome severity and payments (in 2011 US dollars), comparing diagnostic errors to other malpractice allegation groups and inpatient to outpatient within diagnostic errors. RESULTS: We analysed 350 706 paid claims. Diagnostic errors (n=100 249) were the leading type (28.6%) and accounted for the highest proportion of total payments (35.2%). The most frequent outcomes were death, significant permanent injury, major permanent injury and minor permanent injury. Diagnostic errors more often resulted in death than other allegation groups (40.9% vs 23.9%, p<0.001) and were the leading cause of claims-associated death and disability. More diagnostic error claims were outpatient than inpatient (68.8% vs 31.2%, p<0.001), but inpatient diagnostic errors were more likely to be lethal (48.4% vs 36.9%, p<0.001). The inflation-adjusted, 25-year sum of diagnosis-related payments was US$38.8 billion (mean per-claim payout US$386 849; median US$213 250; IQR US$74 545-484 500). Per-claim payments for permanent, serious morbidity that was 'quadriplegic, brain damage, lifelong care' (4.5%; mean US$808 591; median US$564 300), 'major' (13.3%; mean US$568 599; median US$355 350), or 'significant' (16.9%; mean US$419 711; median US$269 255) exceeded those where the outcome was death (40.9%; mean US$390 186; median US$251 745). CONCLUSIONS: Among malpractice claims, diagnostic errors appear to be the most common, most costly and most dangerous of medical mistakes. We found roughly equal numbers of lethal and non-lethal errors in our analysis, suggesting that the public health burden of diagnostic errors could be twice that previously estimated. Healthcare stakeholders should consider diagnostic safety a critical health policy issue.

Enhancing personal agency and competence in eating and moving: formative evaluation of a middle school curriculum--Choice, Control, and Change.

The purpose of this formative evaluation was to examine the impact of an innovative inquiry-based science education curriculum for middle school students, called Choice, Control, and Change, that is designed to foster healthful eating and physical activity and a healthy weight through enhancing agency and competence. The 24-session curriculum helps students develop understandings about the interactions between biology, personal behavior, and the environment and personal agency through cognitive self-regulation skills in navigating today's complex food system and sedentary environment. An extended theory of planned behavior served as the design framework. The study used a pretest-posttest evaluation design involving 278 middle school students in 19 science classes within 5 schools. Based on paired t tests, students significantly improved on several curriculum-specific eating and physical activity behaviors: they decreased several sedentary activities and increased their frequencies of fruit and vegetable intake. They decreased the frequency of sweetened beverages, packaged snacks, and eating at a fast-food restaurant, and ate and drank smaller portions of some items. Their outcome beliefs and overall self-efficacy, but not their attitudes, became more positive. A strategy based on fostering personal agency, cognitive self-regulation, and competence can be effective in increasing healthful eating and physical activity behaviors in middle school children and should be explored further.