Citations

Success in pharmaceutical development led to a record 51 drugs approved in the past year, surpassing every previous year since 1950. Technology innovation enabled identification and exploitation of increasingly precise disease targets ensuring next generation diagnostic and therapeutic products for patient management. The expanding biopharmaceutical portfolio stands, however, in contradistinction to the unsustainable costs that reflect remarkable challenges of clinical development programs. This annual Therapeutic Innovations issue juxtaposes advances in translating molecular breakthroughs into transformative therapies with essential considerations for lowering attrition and improving the cost‐effectiveness of the drug‐development paradigm. Realizing the discovery‐translation‐application continuum mandates a congruent approval, adoption, and access triad.

Calcineurin inhibitors (CNIs), including tacrolimus and cyclosporine, are immune‐modulating agents used in autoimmune disorders, glomerulonephritides, and after transplantation. CNIs are implicated as diabetogenic drugs but the mechanism is not clearly elucidated. Calcineurin is a cytosolic‐phosphatase critical for T‐lymphocyte activation. Calcineurin is widely distributed in different tissues responsible for glucose‐regulation including pancreas, liver, skeletal muscle, adipocytes, brain, and gut. We describe the pharmacologic effects of CNIs in different tissues and impact on glucose regulation.

Objectives To determine the cross‐sectional association between cerebral amyloid‐beta (A β ) deposition and gait. Design Cross‐sectional. Setting Population‐based cohort study in Olmsted County, MN . Participants Cognitively normal individuals (n = 611), aged 50 to 69 years, enrolled in the Mayo Clinic Study of Aging with concurrent PiB‐ PET imaging and gait assessment. Participants with a history of stroke, alcoholism, Parkinson's disease, subdural hematoma, traumatic brain injury, or normal pressure hydrocephalus were excluded. Measurements PiB‐ PET SUVR was measured in prefrontal, orbitofrontal, parietal, temporal, anterior cingulate, posterior cingulate, and motor‐specific regions of interest ( ROI s). Gait parameters (speed, cadence, stride length, double support time, and intra‐individual stance time variability) were measured using GAITR ite ® instrumentation. Linear regression models were adjusted for age, sex, body mass index, education, APOE ε 4 allele, Charlson comorbidity index, and depression. In secondary analyses, we additionally adjusted for neurodegeneration (hippocampal volume, FDG PET SUVR , and cortical thickness) in AD ‐associated regions. Results In fully adjusted models including neuroimaging measures of neurodegeneration, higher PiB‐ PET SUVR across all ROI s was associated with slower gait speed ( P < .05 except for the parietal ROI ), lower cadence and longer double support time ( P ≤ .05 except for the motor ROI ), and greater stance time variability ( P < .05). In sex‐stratified analyses, the association between higher PiB‐ PET SUVR across all ROI s and measures of gait was only present among women. Conclusion PiB‐ PET SUVR across ROI s, independent of general measures of AD ‐associated neurodegeneration, is associated with poorer performance on multiple gait parameters among cognitively normal women, aged 50 to 69 years. Longitudinal studies are needed to determine whether A β predicts gait decline in both women and men.

ObjectivePatients with probable dementia with Lewy bodies (DLB) often have Alzheimer's disease (AD)‐related pathology. Our objective was to determine the pattern of positron emission tomography (PET) tau tracer AV‐1451 uptake in patients with probable DLB, compared to AD, and its relationship to β‐amyloid deposition on PET.MethodsConsecutive patients with clinically probable DLB (n = 19) from the Mayo Clinic Alzheimer's Disease Research Center underwent magnetic resonance imaging, AV‐1451, and Pittsburgh compound‐B (PiB) PET examinations. Age‐ and sex‐matched groups of AD dementia (n = 19) patients and clinically normal controls (n = 95) from an epidemiological cohort served as a comparison groups. Atlas‐ and voxel‐based analyses were performed.ResultsThe AD dementia group had significantly higher AV‐1451 uptake than the probable DLB group, and medial temporal uptake completely distinguished AD dementia from probable DLB. Patients with probable DLB had greater AV‐1451 uptake in the posterior temporoparietal and occipital cortex compared to clinically normal controls, and in probable DLB, the uptake in these regions correlated with global cortical PiB uptake (Spearman rho = 0.63; p = 0.006).InterpretationMedial temporal lobe AV‐1451 uptake distinguishes AD dementia from probable DLB, which may be useful for differential diagnosis. Elevated posterior temporoparietal and occipital AV‐1451 uptake in probable DLB and its association with global cortical PiB uptake suggest an atypical pattern of tau deposition in DLB. ANN NEUROL 2017;81:58–67

BackgroundFunctional genomics employs dozens of OMICs technologies to explore the functions of DNA, RNA and protein regulators in gene regulation processes. Despite each of these technologies being powerful tools on their own, like the parable of blind men and an elephant, any one single technology has a limited ability to depict the complex regulatory system. Integrative OMICS approaches have emerged and become an important area in biology and medicine. It provides a precise and effective way to study gene regulations.ResultsThis article reviews current popular OMICs technologies, OMICs data integration strategies, and bioinformatics tools used for multi‐dimensional data integration. We highlight the advantages of these methods, particularly in elucidating molecular basis of biological regulatory mechanisms.ConclusionsTo better understand the complexity of biological processes, we need powerful bioinformatics tools to integrate these OMICs data. Integrating multi‐dimensional OMICs data will generate novel insights into system‐level gene regulations and serves as a foundation for further hypothesis‐driven research.

Background: Traumatic amputation of the digit requiring revision amputation at the level of the proximal phalanx provides the opportunity to improve flexor function via tenodesis of the remaining flexor digitorum superficialis (FDS) tendon. Salvage of the remaining FDS and performing flexor tenodesis to the proximal phalanx allows increased flexion at the metacarpophalangeal (MCP) joint. Methods: This series reviews FDS tenodesis, outlining its surgical technique with clinical and functional outcomes. Institutional review board–approved retrospective study was performed. Twelve digits in 8 patients were included. Results: Average flexion-extension arc of affected MCP joint was 82°, and average grip strength was 70% of unaffected extremity. No patients required revision surgery or revision amputation. One patient had a minor wound infection treated successfully with oral antibiotics. Conclusions: FDS tenodesis is a reliable motion-preserving procedure for patients with amputations at the level of the proximal phalanx to maintain flexion at the MCP joint.

Objective: The aim of the study was to evaluate associations between ADHD and comorbid psychiatric disorders among adults from a population-based birth cohort. Method: Participants were recruited from all children born between 1976 and 1982 remaining in Rochester, Minnesota, after age 5. Participants with childhood ADHD ( n = 232; M age = 27.0 years; 72% men) and non-ADHD controls ( n = 335; M age = 28.6 years; 63% men) completed a structured interview (M.I.N.I. International Neuropsychiatric Interview) assessing current ADHD status and comorbid psychiatric disorders. Results: Among 232 with childhood ADHD, 68 (49 men, 19 women) had persistent adult ADHD. Compared with non-ADHD controls and non-persistent ADHD participants, adults with persistent ADHD were significantly more likely to have any or each of 12 psychiatric comorbidities. The associations retained significant or marginally significant when stratified by gender. Externalizing psychiatric disorders were more common in men (74%) and internalizing disorders in women (58%). Conclusion: Persistent ADHD is associated with an increased risk of comorbid psychiatric disorders in adult men and women.

Purpose: Traditionally, determination of total lung capacity (TLC) by plethysmography (TLCpleth) has been important in the diagnosis of lung diseases. Alternatively, data acquired from computerized tomography (CT) can be utilized to calculate a measure of TLC (TLCCT). The clinical utility of TLCCT is not certain. We sought to determine, in a clinical setting, whether TLCCT correlates with TLCpleth across a range of lung diseases and scanning techniques. In addition, we determined whether TLCCT affects the interpretation of pulmonary function tests. Subjects and Methods: Records of 118 of 148 consecutive lung transplant recipients were reviewed and determined to have coinciding pulmonary function tests, including plethysmography as well as volumetric chest CT performed supine during full inspiration. CT images acquired with a wide range of scanning protocols were analyzed using CALIPER, a software program for lung and trachea extraction from a CT volume and volumetric tissue characterization of the lung. Segmentation of the lung was achieved by using completely automated dynamic thresholding and region-growing techniques developed to extract the relatively low-density lung and tracheal anatomy from the CT data set without user intervention. Results: TLCpleth and TLCCT were strongly related with a correlation coefficient of 0.88 (P<0.001). The efficacy of the CT-derived measure was not influenced by specific lung diagnoses, age, height, body mass index, or spirometric parameters. TLCCT did not misidentify any diagnosis of restrictive lung disease, nor hyperinflation. Conclusions: In a clinical setting, CT segmentation analysis provides a favorable determination of TLC compared with traditional plethysmography. The technique has general applicability across varying CT data acquisition protocols, lung diseases, and patient characteristics. TLCCT may substitute for TLCpleth in pulmonary function interpretation and may be preferable for some patients in whom plethysmography is difficult to perform, such as transplant subjects with severe pulmonary fibrosis.