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Background and Objectives: Recent studies suggest that bacteria influence the pathogenesis of primary colorectal cancer (CRC), yet their role in recurrence after resection is largely unknown. We have discovered that collagenase-producing bacteria promote cancer recurrence in mice, and that antibiotic bowel decontamination decreases colonization of these same organisms in humans. We hypothesized that preoperative combined mechanical and oral antibiotic bowel preparation would improve disease-free survival (DFS) in patients undergoing surgery for CRC., Methods: We reviewed a cancer registry of patients treated for CRC at a tertiary center. Patients who received bowel preparation were compared to those that did not via a 1:1-propensity score matched for follow-up, age, sex, BMI, stage, location, chemoradiation, infection, anastomotic leak, and blood transfusion., Results: One thousand two hundred and seventy-nine patients met inclusion criteria. Following propensity score matching, 264 patients receiving bowel prep were matched to 264 patients who did not. Kaplan-Meier estimates showed that patients who received bowel prep had a significantly improved 5-year DFS compared to those that did not (76.3% vs. 64.2%; p < .01). Cox regression demonstrated that bowel prep was associated with improved DFS (HR, 0.57; 95% CI, 0.37-0.89; p < .01)., Conclusion: Combined mechanical and oral antibiotic bowel preparation is independently associated with improved recurrence-free survival in patients undergoing surgery for CRC., (© 2021 Wiley Periodicals LLC.)

Targeted and immunotherapy regimens have revolutionized the treatment of advanced melanoma patients. Despite this, only a subset of patients respond durably. Recently, combination strategies of BRAF/MEK inhibitors with immune checkpoint inhibitor monotherapy (α-CTLA-4 or α-PD-1) have increased the rate of durable responses. Based on evidence from our group and others, these therapies appear synergistic, but at the cost of significant toxicity. We know from other treatment paradigms (e.g. hematologic malignancies) that combination strategies with multi-drug regimens (>4 drugs) are associated with more durable disease control. To better understand the mechanism of these improved outcomes, and to identify and prioritize new strategies for testing, we studied several multi-drug regimens combining BRAF/MEK targeted therapy and immunotherapy combinations in a Braf -mutant murine melanoma model ( Braf V600E /Pten -/- ). Short-term treatment with α-PD-1 and α-CTLA-4 monotherapies were relatively ineffective, while treatment with α-OX40 demonstrated some efficacy [17% of mice with no evidence of disease, (NED), at 60-days]. Outcomes were improved in the combined α-OX40/α-PD-1 group (42% NED). Short-term treatment with quadruplet therapy of immunotherapy doublets in combination with targeted therapy [dabrafenib and trametinib (DT)] was associated with excellent tumor control, with 100% of mice having NED after combined DT/α-CTLA-4/α-PD-1 or DT/α-OX40/α-PD-1. Notably, tumors from mice in these groups demonstrated a high proportion of effector memory T cells, and immunologic memory was maintained with tumor re-challenge. Together, these data provide important evidence regarding the potential utility of multi-drug therapy in treating advanced melanoma and suggest these models can be used to guide and prioritize combinatorial treatment strategies., Competing Interests: MCA reports advisory board participation and honoraria from Merck Sharp and Dohme, outside the submitted work. MAD has been a consultant to Roche/Genentech, Array, Novartis, BMS, GlaxoSmithKline (GSK), Sanofi-Aventis, Vaccinex and Apexigen, and he has been the PI of research grants to UT MD Anderson by Roche/Genentech, GSK, Sanofi-Aventis, Merck, Myriad, and Oncothyreon. JEG reports advisory board participation with Merck, Regeneron, BMS, Novartis, and Syndax. AJL reports personal fees from BMS, Novartis, Genentech/Roche, and Merck; personal fees and non-financial support from ArcherDX and Beta-Cat; grants and non-financial support from Medimmune/AstraZeneca and Sanofi; grants, personal fees and non-financial support from Janssen, all outside the submitted work. MTT reports personal fees from Myriad Genetics, Seattle Genetics and Novartis, all outside the submitted work. ZAC is currently an employee of AstraZeneca outside the submitted work. JAW reports speaker fees from Imedex, Dava Oncology, Omniprex, Illumina, Gilead, MedImmune and BMS; consultant/advisor roles or advisory board membership for Roche-Genentech, Novartis, AstraZeneca, GSK, BMS, Merck/MSD, Biothera Pharma, and Microbiome DX; and receives clinical trial support from GSK, Roche-Genentech, BMS, and Novartis, all outside the current work. The remaining authors declare no competing interests., (© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Metastatic melanoma is a deadly malignancy with poor outcomes historically. Immuno-oncology (IO) agents, targeting immune checkpoint molecules such as cytotoxic T-lymphocyte associated protein-4 (CTLA-4) and programmed cell death-1 (PD-1), have revolutionized melanoma treatment and outcomes, achieving significant response rates and remarkable long-term survival. Despite these vast improvements, roughly half of melanoma patients do not achieve long-term clinical benefit from IO therapies and there is an urgent need to understand and mitigate mechanisms of resistance. MicroRNAs are key post-transcriptional regulators of gene expression that regulate many aspects of cancer biology, including immune evasion. We used network analysis to define two core microRNA-mRNA networks in melanoma tissues and cell lines corresponding to 'MITF-low' and 'Keratin' transcriptomic subsets of melanoma. We then evaluated expression of these core microRNAs in pre-PD-1-inhibitor-treated melanoma patients and observed that higher expression of miR-100-5p and miR-125b-5p were associated with significantly improved overall survival. These findings suggest that miR-100-5p and 125b-5p are potential markers of response to PD-1 inhibitors, and further evaluation of these microRNA-mRNA interactions may yield further insight into melanoma resistance to PD-1 inhibitors.

The use of heated intraperitoneal chemotherapy (HIPEC) in conjunction with cytoreductive surgery has been gaining increasing traction in treating gastric adenocarcinoma with metastasis to the peritoneum in recent years. The addition of laparoscopic HIPEC (LS-HIPEC) to these treatment algorithms has increased the flexibility and adaptability of HIPEC integrating into treatment sequencing, allowing for iterative protocols of LS-HIPEC prior to cytoreduction as neoadjuvant treatment, as well as in the palliation of patients with unresectable disease and uncontrolled ascites. As the use of HIPEC in gastric adenocarcinoma continues to be refined, LS-HIPEC algorithms should continue to be considered and utilized both in curative treatment algorithms as well as in patients in the palliative setting. Given that LS-HIPEC remains a relatively nascent treatment modality, we advocate for its use in the setting of a clinical trial when feasible.

The application of minimally invasive surgery (MIS) techniques in the treatment of hepatobiliary malignancies offers advantages of shorter length of stay, quicker functional recovery, and decreased need for postoperative opioids. However, MIS completion radical cholecystectomy for incidentally diagnosed gallbladder cancer can be challenging due to a reoperative field and lack of tactile feedback. This video demonstrates the utility of the robotic platform and highlights the ways in which it assists surgeons in overcoming these limitations. These include (1) versatile wristed instruments and excellent visualization that facilitate a thorough regional lymphadenectomy; and (2) built-in fluorescence imaging technology that can be used with intravenous indocyanine green (ICG) to confirm porta hepatis anatomy in a reoperative field. ICG pharmacokinetics enable fluorescence angiography 15-20 s after ICG injection and fluorescence cholangiography 15-20 min after ICG injection as the dye accumulates in the biliary system. Systematic and intentional application of these techniques allows for the safe performance of robotic completion radical cholecystectomy following sound oncologic principles, with excellent perioperative outcomes., (© 2021. Society of Surgical Oncology.)

Background and Aims: Skeletal muscle index (SMI) from computed tomography (CT) reliably assesses sarcopenia, however, it is expensive and involves serial radiation exposure. Phase angle (PhA) from bioimpedance analysis (BIA) is a noninvasive, low cost, bedside nutritional tool used to monitor changes to nutritional interventions. We aimed to compare the performance of PhA with SMI to assess sarcopenia in cirrhosis., Methods: Ambispective cohort study. Consecutive patients with cirrhosis and available images from abdominal CT scan were included. Monofrequency BIA was performed within 2 weeks CT. Spearman's correlation, ROC curve, and survival analysis with Kaplan-Meier, Cox and competing-risk regression were performed., Results: 136 patients were included with a mean age of 54.5 years (60% female). Most had decompensated disease (66%) with ascites in 47%, and a mean MELD of 14 ± 6. We found positive correlations between SMI and PhA (r = 0.58 , P < .001), irrespective of the presence of ascites. The AUROC of PhA-sarcopenia in all patients was 0.702; (0.748 in males,0.677 in females). The best cutoffs of PhA for diagnosing sarcopenia were ≤5.6° in males and ≤5.4° in females. SMI and PhA were significantly associated with survival in Kaplan-Meier curves. In multivariable analyses, SMI was outperformed by age and MELD, whereas PhA remained independently associated with mortality. Considering transplantation as a competing risk, regression analysis showed both SMI and PhA to be independent predictors of mortality (sHR:0.95 [0.90-0.99] and sHR:0.61 [0.42-0.88])., Conclusion: PhA moderately correlates with SMI for the identification of sarcopenia in patients with cirrhosis. However, its prognostic accuracy is comparable to that of SMI, and it is not influenced by ascites., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

The structures formed by the deposition of mass-selected niobium oxide clusters, Nb 3 O y ( y  = 5, 6, 7), onto Au(111) were studied by scanning tunneling microscopy. The as-deposited Nb 3 O 7 clusters assemble into large dendritic structures that grow on the terraces as well as extend from the top and bottom of step edges. The Nb 3 O 6 cluster also forms dendritic assemblies but they are generally much smaller in size. The assemblies are composed of smaller discrete structures (<1 nm) which are likely to be single clusters. The dendritic assemblies for both the Nb 3 O 7 and Nb 3 O 6 clusters have fractal dimensions of about 1.7 which is very close to that expected for simple diffusion limited aggregation. Annealing the Nb 3 O 7,6 /Au(111) surfaces up to 550 K results in changes in assembly sizes and increases in heights, while heating to 700 results in the disruption of the assemblies into smaller structures. By contrast, the as-deposited Nb 3 O 5 /Au(111) surface at RT exhibits compact cluster structures which become 3D nanoparticles when annealed above 550 K. Differences in the observed surface structures and thermal stability are attributed to differences in metal-oxygen stoichiometry which can influence cluster binding energies, mobility and inter-cluster interactions., (© 2021 IOP Publishing Ltd.)

Background: This study investigated the safety and feasibility of intraoperative portal vein blood (PVB) collection at the time of pancreatic ductal adenocarcinoma (PDAC) resection. Relationships of circulating tumor cells (CTCs) in PVB and peripheral blood (PB) with overall survival (OS) and recurrence-free survival were studied., Methods: Patients undergoing PDAC resection were offered enrollment in a prospective liquid biopsy protocol. The patients had PB drawn before incision and PVB drawn before tumor mobilization, then again immediately after resection. Using standard CellSearch protocols, CTCs were identified and compared with OS., Results: Of the 34 patients enrolled in this study, 23 (68%) underwent pancreaticoduodenectomy, 8 (23%) underwent distal pancreatectomy, and 3 (9%) underwent total pancreatectomy. Peripheral blood was available for 22 (65%) and PVB for 31 (91%) of the patients. No bleeding or thrombotic complications occurred with the PVB draws. The CTC counts per 7.5 mL of PVB collected before and after resection were highly correlated (R 2  = 0.89). The study found CTCs in 11 (50%) of 22 PB samples and 22 (71%) of 31 PVB samples. The OS rate at 18 months was 92% for the patients with < 3 CTCs, 71% for the patients with ≥ 3 CTCs per 7.5 mL of PB (p = 0.30), 100% for the patients without PVB CTCs, and 70% for the patients with PVB CTCs (p < 0.01)., Conclusions: Collection of PVB during PDAC resection is safe. In this pilot study, PVB CTC counts but not PB CTC counts were significantly correlated with OS. This opens the door for future studies on selective omission of adjuvant chemotherapy for patients treated preoperatively and tailored surveillance intensity for patients without PVB CTCs at PDAC resection.

Treatment with combined immune checkpoint blockade (CICB) targeting CTLA-4 and PD-1 is associated with clinical benefit across tumor types, but also a high rate of immune-related adverse events. Insights into biomarkers and mechanisms of response and toxicity to CICB are needed. To address this, we profiled the blood, tumor and gut microbiome of 77 patients with advanced melanoma treated with CICB, with a high rate of any ≥grade 3 immune-related adverse events (49%) with parallel studies in pre-clinical models. Tumor-associated immune and genomic biomarkers of response to CICB were similar to those identified for ICB monotherapy, and toxicity from CICB was associated with a more diverse peripheral T-cell repertoire. Profiling of gut microbiota demonstrated a significantly higher abundance of Bacteroides intestinalis in patients with toxicity, with upregulation of mucosal IL-1β in patient samples of colitis and in pre-clinical models. Together, these data offer potential new therapeutic angles for targeting toxicity to CICB., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Programmed death-ligand 1 (PD-L1) expression has been described in patients with malignant peritoneal mesothelioma (MPM), but treatment strategies utilising immune checkpoint inhibition are yet to be defined. Here, we examine levels of PD-L1 expression in MPM patients treated with systemic and/or intraperitoneal chemotherapy using tissue from patient tumour biopsies or resections at multiple time points. We found the mean PD-L1 expression was higher in those with a germline mutation and/or those with a higher somatic mutation burden. Moreover, PD-L1 expression was lower in patients who had received prior chemotherapy as compared to the treatment-naive cohort. Twenty patients who received chemotherapy, either systemic and/or peritoneal, between PD-L1 measurements showed marked heterogeneity. Six (30%) patients demonstrated upregulation of PD-L1, while eight (40%) demonstrated downregulation. Heterogeneity in PD-L1 expression in MPM before and after cytotoxic therapies may present an additional consideration when initiating immune checkpoint inhibition in this rare and challenging disease.

The design and performance of a room temperature electrical substitution radiometer for use as an absolute standard for measuring continuous-wave laser power over a wide range of wavelengths, beam diameters, and powers are described. The standard achieves an accuracy of 0.46% (k = 2) for powers from 10 mW to 100 mW and 0.83% (k = 2) for powers from 1 mW to 10 mW and can accommodate laser beam diameters (1/e 2 ) up to 11 mm and wavelengths from 300 nm to 2 μm. At low power levels, the uncertainty is dominated by sensitivity to fluctuations in the thermal environment. The core of the instrument is a planar, silicon microfabricated bolometer with vertically aligned carbon nanotube absorbers, commercial surface mount thermistors, and an integrated heater. Where possible, commercial electronics and components were used. The performance was validated by comparing it to a National Institute of Standards and Technology primary standard through a transfer standard silicon trap detector and by comparing it to the legacy "C-series" standards in operation at the U.S. Air Force Metrology and Calibration Division (AFMETCAL).

Background: Follow-up clinics after ICU admission have demonstrated limited benefit. However, existing trials have evaluated heterogeneous cohorts and used physicians who had limited training in outpatient care., Research Question: What are the effects of a "shared-care" intensivist-endocrinologist clinic for ICU survivors with type 2 diabetes on process measures and clinical outcomes 6 months after hospital discharge, and is it feasible to conduct a larger trial?, Study Design and Methods: This was a prospective, randomized, single-center pilot study with blinded outcome assessment. Patients with type 2 diabetes, who required ≥ 5 days of ICU care (mixed medical-surgical ICU) and survived to ICU discharge, were eligible. Participants were randomized to attendance at the shared-care clinic 1 month after hospital discharge or usual care. Six months after hospital discharge, participants were assessed for outcomes including glycated hemoglobin, neuropathy, nephropathy, quality of life, return to employment, frailty, and health-care use. The primary outcome was participant recruitment and retention., Results: During an 18-month period, 42 of 82 eligible patients (51%) were recruited. Four participants (10%) withdrew before assessment at 6 months and 11 (26%) died. At 6 months, only 18 of 38 participants who did not withdraw (47%) were living independently without support, and 24 (63%) required at least one subsequent hospital admission. In the intervention group (n = 21), 16 (76%) attended the clinic. Point estimates did not indicate that the intervention improved glycated hemoglobin (+5.6 mmol/mol; 95% CI, -6.3 to 17; P = .36) or quality of life (36-Item Short Form Survey physical summary score, 32 [9] vs. 32 [7]; P = 1.0)., Interpretation: Outcomes for ICU survivors with type 2 diabetes are poor. Because of low participation and high mortality, a larger trial of a shared-care follow-up clinic in this cohort, using the present design, does not appear feasible., Trial Registry: Australian New Zealand Clinical Trials Registry (ANZCTR); No.: ACTRN12616000206426; URL: www.anzctr.org.au., (Copyright © 2020 American College of Chest Physicians. All rights reserved.)

The evaluation of surgically resected papillary thyroid carcinomas (PTC) by immunohistochemistry (IHC) for BRAF mutation has diagnostic, prognostic and therapeutic implications. The goal of this meta-analysis was to perform a systematic review of studies using the VE1 clone (specific for detection of the BRAF V600E mutation) on formalin-fixed paraffin embedded (FFPE) thyroid surgical resection specimens for primary papillary thyroid carcinoma. The authors' molecular techniques, immunohistochemistry protocols, and scoring methods for VE1 immunostaining were also evaluated. This study included 4079 PTCs representing data from 23 studies. The results extracted from each study were split into two different groups, direct sequencing group or PCR group, based on the molecular "gold standard" method used to compare VE1 IHC staining. In the direct sequencing group, the IHC sensitivity was 100% (95% CI 0.97-1.00) and specificity 84% (95% 0.72-0.91). In the PCR group the sensitivity was 98% (95% CI 0.96-0.99) and specificity 89% (95% CI 0.82-0.94). Although immunohistochemical procedures varied by author, the overall performance of the VE1 clone shows that it is highly sensitive and relatively specific for detecting the BRAF V600E mutation in surgical resection specimens. However, standardization of immunohistochemical procedural method and scoring/interpretation criteria may improve the reliability and reproducibility for the use of VE1 clone for future practice.

Purpose: Although laparoscopic hyperthermic intraperitoneal chemotherapy (LS-HIPEC) has been proven safe in patients with gastric adenocarcinoma and carcinomatosis or positive cytology, patient selection criteria remain unclear. Thus, we perform a retrospective analysis to identify factors associated with improved survival and resection rates., Patients and Methods: Data for all patients undergoing LS-HIPEC for stage IV gastric adenocarcinoma between June 2014 and November 2018 were collected prospectively and analyzed for associations with survival and resection using uni- and multivariate logistic regression, Cox proportional hazards models, and Kaplan-Meier survival functions., Results: Of 70 patients who underwent LS-HIPEC, 43 (61%) received two drugs (mitomycin C and cisplatin), and 27 (39%) received three drugs (mitomycin C, cisplatin, and paclitaxel). The two groups' demographic and oncologic differences were not significant, although the three-drug group had a significantly lower rate of radiation therapy use (58% vs. 15%; p < 0.01). Univariate analysis revealed that poor differentiation [Cox hazard ratio (HR) 2.75; 95% confidence interval (CI) 1.34-5.63; p < 0.01], gross carcinomatosis (HR 3.10; 95% CI 1.52-6.30; p = 0.03), and ascites (HR 3.43; 95% CI 1.88-6.26; p < 0.01) were associated with shorter median survival. Gastrectomy was associated with improved overall survival (HR 0.32; 95% CI 0.15-0.70; p < 0.01). The resection rate of the 45 patients without ascites (38%) was significantly higher than that of the 25 patients with ascites (0%; p < 0.01)., Conclusions: Our findings identify ascites as a significant prognostic factor for gastric cancer patients with peritoneal metastases undergoing LS-HIPEC. Our findings can be used to help identify patients who are unlikely to proceed to resection after LS-HIPEC and are good candidates for novel therapeutic approaches or clinical trials.

Introduction: A decline in physical function is highly prevalent and a poor prognostic factor in cirrhosis. We assessed the benefits of a home-based physical activity program (HB-PAP) in patients with cirrhosis with a randomized pilot trial., Methods: All participants received a personal activity tracker to monitor daily activities and were given 12 g/day of an essential amino acid supplement. The HB-PAP intervention consisted of biweekly counseling sessions to increase physical activity for 12 weeks. Six-minute walk test (6MWT) and cardiopulmonary exercise testing (CPET) assessed changes in aerobic fitness. Different anthropometric measuring tools were used for skeletal muscle and adiposity assessment., Results: Seventeen patients (60% male; 29% nonalcoholic steatohepatitis/cryptogenic, 29% hepatitis C, 24% alcohol, 18% other) were randomized, 9 to HB-PAP group. There were no significant differences in MELD-sodium between HB-PAP and controls at baseline or after the 12-week intervention. By the end of study, there was a significant between-group difference in daily step count favoring the active group (2627 [992-4262], p = 0.001), with less sedentary patients in the active group (33-17% vs. 25-43%, p = 0.003). The 6MWT improved in the HB-PAP group (423 ± 26 m vs. 482 ± 35 m), while the controls had a nonsignificant drop (418 ± 26 m vs. 327 ± 74 m) with a significant between-group difference. CPET did not change. Other than an improvement in psoas muscle index, there were no differences in anthropometry, or in quality of life., Conclusions: HB-PAP maintained physical performance and improved aerobic fitness according to 6MWT but not CPET, supporting the use of personal activity trackers to monitor/guide home-based prehabilitation programs in cirrhosis.

Background: To achieve goals, organisms are often faced with complex tasks that require enhanced control of cognitive faculties for optimal performance. However, the neural circuit mechanisms underlying this ability are unclear. The claustrum is proposed to mediate a variety of functions ranging from sensory binding to cognitive control of action, but direct functional assessments of this telencephalic nucleus are lacking., Methods: Here, we employed the Gnb4 (guanine nucleotide-binding subunit beta-4) cre driver line in mice to selectively monitor and manipulate claustrum projection neurons during 1-choice versus 5-choice serial reaction time task performance., Results: Using fiber photometry, we found elevated claustrum activity prior to an expected cue during correct performance on the cognitively demanding 5-choice response assay relative to the less demanding 1-choice version of the task. Claustrum activity during reward acquisition was also enhanced when task demand was higher. Furthermore, optogenetically inhibiting the claustrum prior to the onset of the cue reduced choice accuracy on the 5-choice task but not on the 1-choice task., Conclusions: These results suggest that the claustrum supports a cognitive control function necessary for optimal behavioral performance under cognitively demanding conditions., (Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Recent work by Kadosh et al. (2020) suggests that mutant p53 activity in gut epithelia is influenced by local production of microbial metabolites. The switch of p53 from tumor suppressor to oncogene is location-dependent and is impacted by microbially derived gallic acid., Competing Interests: Declaration of Interests J.A.W. is an inventor on a US patent application (PCT/US17/53.717) submitted by the University of Texas MD Anderson Cancer Center that covers methods to enhance immune checkpoint blockade responses by modulating the microbiome. J.A.W. reports compensation for speaker’s bureau and honoraria from Imedex, Dava Oncology, Omniprex, Illumina, Gilead, PeerView, Physician Education Resource, MedImmune, and Bristol-Myers Squibb. J.A.W. serves as a consultant/advisory board member for Roche/Genentech, Novartis, AstraZeneca, GlaxoSmithKline, Bristol-Myers Squibb, Merck, Biothera Pharmaceuticals, and Microbiome DX. J.A.W. also receives research support from GlaxoSmithKline, Roche/Genentech, Bristol-Myers Squibb, and Novartis., (Copyright © 2020 Elsevier Inc. All rights reserved.)

We demonstrate the capability to measure the absolute power responsivity of optical fiber-coupled detectors at an expanded uncertainty of 0.1%, by direct comparison with a cryogenic primary standard. To facilitate synchronous power measurements, commercial all-fiber beam-splitters direct laser diode light simultaneously to the device under test and the primary standard. We investigate the use of single-mode, polarisation maintaining, and photonic crystal fibers to access the cryogenic standard, and report a reduction in the temperature dependent effective refractive index of these fibers of 0.1%, 0.15% and 0.3% respectively in going from room temperature to 5 K. We also evaluate the polarisation dependent loss of the beam-splitters, the stability of the beam-splitter ratio between the cryogenic detector and the device under test and the temporal and modal stability of the Fabry-Pérot laser diode sources. It is shown that the stability of the optical fiber beam-splitters limits the overall performance of the measurement system to an expanded uncertainty of 0.1%.

Context: Although diabetes affects 40% to 50% of adults with cystic fibrosis, remarkably little is known regarding the underlying mechanisms leading to impaired pancreatic β-cell insulin secretion. Efforts toward improving the functional β-cell deficit in cystic fibrosis-related diabetes (CFRD) have been hampered by an incomplete understanding of whether β-cell function is intrinsically regulated by cystic fibrosis transmembrane conductance regulator (CFTR). Definitively excluding meaningful CFTR expression in human β-cells in situ would contribute significantly to the understanding of CFRD pathogenesis., Objective: To determine CFTR messenger ribonucleic acid (mRNA) and protein expression within β-cells in situ in the unmanipulated human pancreas of donors without any known pancreatic pathology., Design: In situ hybridization for CFTR mRNA expression in parallel with insulin immunohistochemical staining and immunofluorescence co-localization of CFTR with insulin and the ductal marker, Keratin-7 (KRT7), were undertaken in pancreatic tissue blocks from 10 normal adult, nonobese deceased organ donors over a wide age range (23-71 years) with quantitative image analysis., Results: CFTR mRNA was detectable in a mean 0.45% (range 0.17%-0.83%) of insulin-positive cells. CFTR protein expression was co-localized with KRT7. One hundred percent of insulin-positive cells were immunonegative for CFTR., Conclusions: For the first time, in situ CFTR mRNA expression in the unmanipulated pancreas has been shown to be present in only a very small minority (<1%) of normal adult β-cells. These data signal a need to move away from studying endocrine-intrinsic mechanisms and focus on elucidation of exocrine-endocrine interactions in human cystic fibrosis., (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

β-Cell dysfunction in type 2 diabetes (T2D) is associated with loss of cellular identity and mis-expression of alternative islet hormones, including glucagon. The molecular basis for these cellular changes has been attributed to dysregulation of core β-cell transcription factors, which regulate β-cell identity through activating and repressive mechanisms. The TLE1 gene lies near a T2D susceptibility locus and, recently, the glucagon repressive actions of this transcriptional coregulator have been demonstrated in vitro. We investigated whether TLE1 expression is disrupted in human T2D, and whether this is associated with increased islet glucagon-expressing cells. Automated image analysis following immunofluorescence in donors with (n = 7) and without (n = 7) T2D revealed that T2D was associated with higher islet α/β cell ratio (Control: 0.7 ± 0.1 vs T2D: 1.6 ± 0.4; P < .05) and an increased frequency of bihormonal (insulin+/glucagon+) cells (Control: 0.8 ± 0.2% vs T2D: 2.0 ± 0.4%, P < .05). In nondiabetic donors, the majority of TLE1-positive cells were mono-hormonal β-cells (insulin+/glucagon-: 98.2 ± 0.5%; insulin+/glucagon+: 0.7 ± 0.2%; insulin-/glucagon+: 1.1 ± 0.4%; P < .001). TLE1 expression was reduced in T2D (Control: 36 ± 2.9% vs T2D: 24 ± 2.6%; P < .05). Reduced islet TLE1 expression was inversely correlated with α/β cell ratio (r = -0.55; P < .05). TLE1 knockdown in EndoC-βH1 cells was associated with a 2.5-fold increase in glucagon gene mRNA and mis-expression of glucagon in insulin-positive cells. These data support TLE1 as a putative regulator of human β-cell identity, with dysregulated expression in T2D associated with increased glucagon expression potentially reflecting β- to α-cell conversion., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Institutional review boards (IRBs), duly constituted under the Office of Human Research Protection, have the federally mandated responsibility of reviewing research involving human subjects to ensure that a proposed protocol meets the appropriate ethical guidelines before subjects may be enrolled in any study. The road leading to the current regulations and ethical considerations has been long and checkered. Methods: This paper reviews the history of human subjects participating in research, including examples of egregious events, and the ethical analyses that precipitated the evolution of the mandated protections afforded participants in research under current federal regulations. Results: Key documents-from the Nuremberg Code in 1947 to the Belmont Report in 1978 to Moral Science: Protecting Participants in Human Subjects Research in 2011-that have informed the ethics debate regarding human subjects protection in research activities are presented in light of their historic significance, highlighting the complexity of the issues surrounding protection of human subjects in research. Conclusion: The examples from history and the scarcity of contemporary examples demonstrate that the regulations for the protection of humans participating in research have evolved in a way that minimizes the probability that subjects will be harmed when they choose to participate in research. The examples also reinforce the importance of individual responsibility. Failure of IRBs to provide appropriate review and oversight can lead to severe consequences, as can abrogation by the investigator to place the well-being of the subjects as the primary responsibility in any research protocol. Understanding how we arrived at the current approach and some of the failures that directed this course can support efforts to continually reevaluate and improve the safety of subjects who are willing to participate in research activities., (©2020 by the author(s); Creative Commons Attribution License (CC BY).)

The morphology and reactivity of mass-selected titania clusters, Ti 3 O 6 and Ti 3 O 5 , deposited onto Au(111) were studied by scanning tunneling microscopy and temperature programmed desorption. Despite differing by only one oxygen atom, the stoichiometric Ti 3 O 6 and the sub-stoichiometric ("reduced") Ti 3 O 5 clusters exhibit very different structures and preferred binding sites. The Ti 3 O 6 clusters bind at step edges and form small assemblies (2-4 clusters) on Au terraces, while the "reduced" Ti 3 O 5 clusters form much larger fractal-like assemblies that can extend across step boundaries. Annealing the Ti 3 O 5,6 /Au(111) systems to higher temperatures causes changes in the size-distributions of cluster assemblies, but does not lead to the formation of TiO x nanoislands for temperatures ≤700 K. Reactivity studies show that the reduced Ti 3 O 5 cluster has higher activity than Ti 3 O 6 for 2-propanol dehydration, although both clusters exhibit substantial activity for dehydrogenation to acetone. Calculations using DFT+U suggest that the differences in aggregate morphology and reactivity are associated with the number of undercoordinated Ti 3c sites in the supported clusters.

Cs is a promoter of Cu-based catalysts for the synthesis of alcohols from CO 2 hydrogenation. Scanning tunneling microscopy and ambient-pressure x-ray photoelectron spectroscopy were used to study the morphology and chemical properties of surfaces generated by the deposition of cesium on Cu 2 O/Cu(111) and Cu(111) substrates. CsO x nanostructures were formed after Cs metal was deposited on Cu 2 O/Cu(111) at 300 K. The formed CsO x protrude over the surface of copper oxide by 2-4 Å, with the dimension at the base of the nanostructures being in the range of 1-3 nm. Heating to elevated temperature induced significant changes in the size and dispersion of the CsO x nanostructures, and there was a clear reconstruction of the copper oxide substrate, which then exhibited long range order with a hexagonally packed structure. The as-deposited and annealed surfaces of CsO x /Cu 2 O/Cu(111) were more reactive toward CO 2 than plain Cu 2 O/Cu(111) or clean Cu(111). However, none of them were stable in the presence of H 2 , which fully reduced the copper oxide at 400-450 K. In CsO x /Cu(111), the CsO x nanoclusters were dispersed all over the metallic copper in no particular order. The CsO x species had an average width of 2 nm and ∼1 Å height. The CsO x /Cu(111) systems exhibited the highest activity for the binding and dissociation of CO 2 , suggesting that the CsO x -copper interface plays a key role in alcohol synthesis.

Using light energy to drive chemical reactions on semiconductor surfaces is the basis for technological applications ranging from the removal of organic pollutants to the generation of renewable solar fuels, yet our understanding of the mechanisms has been hindered by the multistep nature of the process and the wide range of time scales over which it occurs (femtoseconds to seconds). In this work, we use ultrafast laser pump-probe techniques to follow the time evolution of substrate-induced photooxidation of acetone on a titania surface. A UV light at 260 nm initiates carrier-induced fragmentation of adsorbed acetone on a TiO 2 (110) surface that was pretreated with oxygen. The photoreaction results in the ejection of methyl radicals into the gas-phase that are detected by the probe pulse via resonant multiphoton ionization. The time evolution of the methyl radicals leaving the surface exhibits ultrafast rise times, 300-700 fs, followed by a more gradual rise that plateaus by 10 ps, with faster rates at a low acetone coverage. These results are interpreted in terms of a time-dependent rate expression and a mechanism in which the fragmentation of the acetone surface species is driven by interactions with nonequilibrium, "hot" holes.

Striatal fast-spiking interneurons (FSIs) potently inhibit the output neurons of the striatum and, as such, powerfully modulate action learning. Through electrical synaptic coupling, FSIs are theorized to temporally coordinate their activity. This has important implications for their ability to temporally summate inhibition on downstream striatal projection neurons. While some in vivo single-unit electrophysiological recordings of putative FSIs support coordinated firing, others do not. Moreover, it is unclear as to what aspect of action FSIs encode. To address this, we used in vivo calcium imaging of genetically identified FSIs in freely moving mice and applied machine learning analyses to decipher the relationship between FSI activity and movement. We report that FSIs exhibit ensemble activity that encodes the speed of action sub-components, including ambulation and head movements. These results suggest FSI population dynamics fit within a Hebbian model for ensemble inhibition of striatal output guiding action.

Cystic fibrosis-related diabetes (CFRD) worsens CF lung disease leading to early mortality. Loss of beta cell area, even without overt diabetes or pancreatitis is consistently observed. We investigated whether short-term CFTR inhibition was sufficient to impact islet morphology and function in otherwise healthy mice. CFTR was inhibited in C57BL/6 mice via 8-day intraperitoneal injection of CFTRinh172. Animals had a 7-day washout period before measures of hormone concentration or islet function were performed. Short-term CFTR inhibition increased blood glucose concentrations over the course of the study. However, glucose tolerance remained normal without insulin resistance. CFTR inhibition caused marked reductions in islet size and in beta cell and non-beta cell area within the islet, which resulted from loss of islet cell size rather than islet cell number. Significant reductions in plasma insulin concentrations and pancreatic insulin content were also observed in CFTR-inhibited animals. Temporary CFTR inhibition had little long-term impact on glucose-stimulated, or GLP-1 potentiated insulin secretion. CFTR inhibition has a rapid impact on islet area and insulin concentrations. However, islet cell number is maintained and insulin secretion is unaffected suggesting that early administration of therapies aimed at sustaining beta cell mass may be useful in slowing the onset of CFRD.

Structural and functional analyses of the human claustrum, a poorly understood telencephalic gray matter structure, are hampered by its sheet-like anatomical arrangement. Here, we first describe a functional magnetic resonance imaging (fMRI) method to reveal claustrum signal with no linear relationship with adjacent regions in human subjects. We applied this approach to resting state functional connectivity (RSFC) analysis of the claustrum at high resolution (1.5 mm isotropic voxels) using a 7T dataset (n = 20) and a separate 3T dataset for replication (n = 35). We then assessed claustrum activation during performance of a cognitive task, the multi-source interference task, at 3T (n = 33). Extensive functional connectivity was observed between claustrum and cortical regions associated with cognitive control, including anterior cingulate, prefrontal and parietal cortices. Cognitive task performance was associated with widespread activation and deactivation that overlapped with the cortical areas showing functional connectivity to the claustrum. Furthermore, during high cognitive conflict conditions of the task, the claustrum was significantly activated at the onset of the task, but not during the remainder of the difficult condition. Both of these findings suggest that the human claustrum can be functionally isolated with fMRI, and that it may play a role in cognitive control, and specifically task switching, independent of sensorimotor processing., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The claustrum is structurally connected with many cortical areas.A major hurdle standing in the way of understanding claustrum function is the difficulty in assessing the global functional connectivity (FC) of this structure. The primary issues lie in the inability to isolate claustrum signal from the adjacent insular cortex (Ins), caudate/putamen (CPu), and endopiriform nucleus (Endo). To address this issue, we used (7T) fMRI in the rat and describe a novel analytic method to study claustrum without signal contamination from the surrounding structures. Using this approach, we acquired claustrum signal distinct from Ins, CPu, and Endo, and used this claustrum signal to determine whole brain resting state functional connectivity (RSFC). Claustrum RSFC was distinct from the adjacent structures and displayed extensive connections with sensory cortices and the cingulate cortex, consistent with known structural connectivity of the claustrum. These results suggest fMRI and improved analysis can be combined to accurately assay claustrum function.

Glutamatergic projections of the thalamic rostral intralaminar nuclei of the thalamus (rILN) innervate the dorsal striatum (DS) and are implicated in dopamine (DA)-dependent incubation of drug seeking. However, the mechanism by which rILN signaling modulates reward seeking and striatal DA release is unknown. We find that activation of rILN inputs to the DS drives cholinergic interneuron burst-firing behavior and DA D2 receptor-dependent post-burst pauses in cholinergic interneuron firing. In vivo, optogenetic activation of this pathway drives reinforcement in a DA D1 receptor-dependent manner, and chemogenetic suppression of the rILN reduces dopaminergic nigrostriatal terminal activity as measured by fiber photometry. Altogether, these data provide evidence that the rILN activates striatal cholinergic interneurons to enhance the pursuit of reward through local striatal DA release and introduce an additional level of complexity in our understanding of striatal DA signaling., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Primary aldosteronism is a common but underdiagnosed cause of hypertension. Patients with this disorder have worse morbidity compared with those with essential hypertension, but with timely diagnosis and appropriate intervention these patients are potentially cured and may have reversal of target organ damage. The goal of this study was to determine if hypertensive patients considered high risk were checked for primary aldosteronism., Methods: We reviewed electronic health records to identify patients age 18 years or older with coexisting hypertension and hypokalemia or hypertension and sleep apnea, then determined if they had been investigated with measurement of aldosterone or renin. We built regression models to identify explanatory variables for screening in these 2 high-risk groups., Results: Of nearly 37,000 patients with hypertension and hypokalemia, only 2.7% were ever screened for primary aldosteronism. Most opportunities for case detection were during inpatient hospitalizations, yet in this setting, patients were less likely than clinic patients be screened. Similarly, 3.0% of hypertensive patients with sleep apnea were screened since the inclusion of this group in case detection recommendations., Conclusion: Uptake of practice guidelines by hospital physicians, fueled by support from their specialty societies, may help to identify many more patients with unrecognized primary aldosteronism., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Management of large thyroid nodules is controversial, as data are conflicting regarding overall rates of malignancy (ROM) in all nodules and frequency of false-negative fine-needle aspiration results (FNR) in cytologically benign nodules. This meta-analysis aimed to evaluate and compare ROM and FNR in small versus large nodules published in the literature. Methods: Articles indexed in PubMed, written in English, published electronically or in print on or prior to December 8 2017 were searched for "false negative thyroid size or cm" and "malignancy rates benign thyroid nodules." Three hundred fifty-two unique citations were identified. Multiple reviewers selected a final set of 35 articles that contained nodules stratified by size (3, 4, or 5 cm), with benign or all cytologic diagnoses, and with postsurgical histologic diagnoses. Multiple observers extracted data, including numbers of total, cytologically benign, and histologically malignant nodules. Size cutoffs of 3, 4, and/or 5 cm were analyzed in 14, 24, and 1 article, respectively. Results: ROM in all nodules ≥3 cm (13.1%) and ≥4 cm (20.9%) was lower than those <3 cm (19.6%) and <4 cm (19.9%; odds ratio [OR] = 0.72 [confidence interval (CI) 0.64-0.81] and OR = 0.85 [CI 0.77-0.95]). FNR in nodules ≥3 cm (7.2%) was not different from smaller nodules (5.7%; OR = 1.47 [CI 0.80-2.69]). FNR in nodules ≥4 cm (6.7%) was slightly higher than those <4 cm (4.5%; OR = 1.38 [CI 1.06-1.80]). The most frequently reported false-negative diagnosis was papillary thyroid carcinoma. Conclusions: Rates of malignancy and false-negative FNA results vary but, in most studies, are not higher in larger nodules. Patients with large, cytologically benign thyroid nodules need not undergo immediate surgical resection, as false-negative FNA rates are low and are expected to decrease in light of nomenclature revision of a subset of follicular variants of papillary thyroid carcinoma.

Anterior cingulate cortex (ACC) input to the claustrum is required for top-down cognitive control of action. By virtue of its widespread cortical connectivity, the claustrum is anatomically situated to process and broadcast top-down signals from ACC to downstream cortices. To gain a deeper understanding of claustrum processing mechanisms, it is first critical to identify the projection neuron subtypes within claustrum, the intrinsic and extrinsic components regulating their firing, and the differential innervation of cortex by projection neuron subtypes. To this end, we used whole-cell patch-clamp electrophysiology in adult mouse brain slices to distinguish two spiny projection neuron subtypes in claustrum, referred to as type I and II neurons, and three aspiny interneuron subtypes, referred to as type III, IV, and V neurons. In response to optogenetic ACC afferent stimulation, type II neurons preferentially burst fire relative to type I neurons. This burst firing is calcium-dependent and is optimized by voltage-gated potassium channels. Finally, we find that visual cortices, parietal association cortex, and ACC receive input from type I and II neurons in differing proportions. These data reveal the diversity of claustrum neurons and mechanisms by which claustrum processes ACC command for spatiotemporal coordination of the cerebral cortex.

Time- and Angle-resolved photoelectron spectroscopy from surfaces can be used to record the dynamics of electrons and holes in condensed matter on ultrafast time scales. However, ultrafast photoemission experiments using extreme-ultraviolet (XUV) light have previously been limited by either space-charge effects, low photon flux, or limited tuning range. In this article, we describe XUV photoelectron spectroscopy experiments with up to 5 nA of average sample current using a tunable cavity-enhanced high-harmonic source operating at 88 MHz repetition rate. The source delivers >10 11 photons/s in isolated harmonics to the sample over a broad photon energy range from 18 to 37 eV with a spot size of 58 × 100 μ m 2 . From photoelectron spectroscopy data, we place conservative upper limits on the XUV pulse duration and photon energy bandwidth of 93 fs and 65 meV, respectively. The high photocurrent, lack of strong space charge distortions of the photoelectron spectra, and excellent isolation of individual harmonic orders allow us to observe laser-induced modifications of the photoelectron spectra at the 10 -4 level, enabling time-resolved XUV photoemission experiments in a qualitatively new regime.

The claustrum is a telencephalic gray matter nucleus that is richly interconnected with the neocortex. This structure subserves top-down executive functions that require frontal cortical control of posterior cortical regions. However, functional anatomical support for the claustrum allowing for long-range intercortical communication is lacking. To test this, we performed a channelrhodopsin-assisted long-circuit mapping strategy in mouse brain slices. We find that anterior cingulate cortex input to the claustrum is transiently amplified by claustrum neurons that, in turn, project to parietal association cortex or to primary and secondary visual cortices. Additionally, we observe that claustrum drive of cortical neurons in parietal association cortex is layer-specific, eliciting action potential generation briefly in layers II/III, IV, and VI but not V. These data are the first to provide a functional anatomical substrate through claustrum that may underlie top-down functions, such as executive attention or working memory, providing critical insight to this most interconnected and enigmatic nucleus.

Background: Thyroid cancer is the fastest growing malignancy in the United States. Previous studies have shown a decrease in quality of life (QoL) after the treatment of thyroid cancer. To date, there have been no studies assessing physician perceptions regarding how a diagnosis of thyroid cancer affects QoL. Based on this and other findings from our study, we aim to assess physician perceptions on the effect of thyroid cancer on QoL., Materials and Methods: Physicians were recruited from two national organizations comprised physicians focusing on thyroid cancer. A 37-question survey was administered evaluating physician's perceptions of thyroid cancer patient satisfaction in various aspects of treatment, complications, and overall effects on QoL. QoL responses were categorized into overall QoL, physical, psychological, social, and spiritual well-being., Results: One hundred five physicians completed the survey. Physician's estimates of patient's overall QoL after thyroid cancer treatment was similar to overall QoL reported by patients. However, medical physicians overestimated the decrease in thyroid cancer survivor's QoL in several subcategories including physical, psychological, and social (P < 0.05). Both surgeons and medical physicians underestimated the percentage of patients with reported symptoms of temporary and permanent voice changes, temporary dry mouth, cold/heat sensitivity, and temporary and permanent hypocalcemia (P = 0.01-0.04)., Conclusions: Physicians have a varied estimation of the detrimental impact of thyroid cancer treatment on QoL. In addition, physicians underestimated the amount of physical symptoms associated with thyroid cancer treatments. Increased physician awareness of the detrimental effects of a thyroid cancer diagnosis on QoL should allow for a more accurate conversation about expected outcomes after thyroid cancer treatment., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Replacement of pancreatic β-cells through deceased donor islet transplantation is a proven therapy for preventing recurrent life-threatening hypoglycemia in type 1 diabetes. Although near-normal glucose levels and insulin independence can be maintained for many years following successful islet transplantation, restoration of normal functional β-cell mass has remained elusive. It has recently been proposed that dedifferentiation/plasticity towards other endocrine phenotypes may play an important role in stress-induced β-cell dysfunction in type 2 diabetes. Here we report loss of end-differentiated β-cell phenotype in 2 intraportal islet allotransplant recipients. Despite excellent graft function and sustained insulin independence, all examined insulin-positive cells had lost expression of the end-differentiation marker, urocortin-3, or appeared to co-express the α-cell marker, glucagon. In contrast, no insulin + /urocortin-3 - cells were seen in nondiabetic deceased donor control pancreatic islets. Loss of end-differentiated phenotype may facilitate β-cell survival during the stresses associated with islet isolation and culture, in addition to sustained hypoxia following engraftment. As further refinements in islet isolation and culture are made in parallel with exploration of alternative β-cell sources, graft sites, and ultimately fully vascularized bioengineered insulin-secreting microtissues, differentiation status immunostaining provides a novel tool to assess whether fully mature β-cell phenotype has been maintained., (© 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Cognitive abilities, such as volitional attention, operate under top-down, executive frontal cortical control of hierarchically lower structures. The circuit mechanisms underlying this process are unresolved. The claustrum possesses interconnectivity with many cortical areas and, thus, is hypothesized to orchestrate the cortical mantle for top-down control. Whether the claustrum receives top-down input and how this input may be processed by the claustrum have yet to be formally tested, however. We reveal that a rich anterior cingulate cortex (ACC) input to the claustrum encodes a preparatory top-down information signal on a five-choice response assay that is necessary for optimal task performance. We further show that ACC input monosynaptically targets claustrum inhibitory interneurons and spiny glutamatergic projection neurons, the latter of which amplify ACC input in a manner that is powerfully constrained by claustrum inhibitory microcircuitry. These results demonstrate ACC input to the claustrum is critical for top-down control guiding action., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Silica-supported model copper catalysts were prepared by supporting bis(1,5-diphenyl-1,3,5-pentanetrionato)dicopper(II), Cu 2 (dba) 2 , on Cab-O-Sil by a batch impregnation technique. This metal complex showed a strong affinity for the silica support, developing monolayer coverages near the value predicted from a consideration of the size and shape of the planar metal complex (2.6 wt % Cu). The supported catalysts were subsequently activated by decomposing the organic ligands at 400 °C in air followed by reduction with 2% H 2 /He at 250 °C. One sample was prepared having a loading of 3.70 wt % Cu 2 (dba) 2 /silica catalyst, and it was examined for the methanol synthesis reaction under the following conditions: 250 °C with an equimolar gas mixture of CO and H 2 in a high-pressure batch reactor. Kinetic data over the model catalyst were fit to a rate equation, second order in the limiting reactant (H 2 ), with a pseudo -second-order rate constant k 2 [CO] o [H 2 ] o = 0.0957 [h-g total Cu] -1 . A control experiment using a commercial catalyst, Cu/ZnO/Al 2 O 3 with a copper loading of 41.20 wt %, showed a value of k 2 [CO] o [H 2 ] o = 0.793 [h-g total Cu] -1 . A fresh sample of Cu 2 (dba) 2 /silica was examined for methanol decomposition reaction at 220 °C. The model catalyst shows a methanol decomposition first-order rate constant greater than that of the commercial Cu/ZnO/Al 2 O 3 catalyst: 1.59 × 10 -1 [min-g total Cu] -1 versus 9.6 × 10 -3 [min-g total Cu] -1 . X-ray diffraction analyzes confirm the presence of CuO particles in both catalysts after calcinations. Copper metal particles were found in both catalysts (fractional Cu dispersions were 0.11 and 0.16 on commercial and model catalysts, respectively) after the reduced catalysts were used in both the methanol synthesis and decomposition reactions. Using the values of copper dispersion found in these samples, we recalculated the rate constants for the two reactions per unit surface copper. These refined rate constants showed the same trends as those reported per total amount of Cu. One role of the promoter(s) in the commercial catalyst is the inhibition of the methanol decomposition reaction, thus allowing higher MeOH synthesis reaction rates in those regimes not controlled by thermodynamics., Competing Interests: The authors declare no competing financial interest.

Background: Patients diagnosed with a malignancy must decide whether to travel for care at an academic center or receive treatment at a nearby hospital. Here we examine differences in demographics, treatment, and outcomes of those traveling to academic centers for their care vs those not traveling, as well as compare travel for an aggressive vs indolent malignancy., Study Design: All patients with papillary thyroid carcinoma (PTC) or pancreatic ductal adenocarcinoma (PDAC) undergoing surgical resection and in the National Cancer Database were examined. Travel for care was abstracted from "crowfly" distance between patients' ZIP codes and treatment facility, region, county size, urban/metro/rural status, and facility type., Results: In total, 105,677 patients with PTC and 22,983 patients with PDAC were analyzed. There were no survival differences by travel in the PTC group. Survival was improved for patients with PDAC traveling from urban/rural settings (hazard ratio = 0.89; 95% CI 0.82 to 0.96; p = 0.002). Patients traveling with PDAC were more likely to have a complete resection and lymph node dissection. Those traveling were less likely to receive chemotherapy or radiotherapy (all p < 0.001). Those traveling with PTC were older, more likely to be male, have Medicare insurance, and had a higher stage of disease (all p < 0.001). Rates of radioactive iodine were lower, American Thyroid Association guidelines were more likely followed, and lymph node dissection was more common for those traveling for care of their PTC (all p < 0.001)., Conclusions: There are improvements in both quality and survival for those traveling to academic centers for their cancer care. In the case of PTC, this difference in quality did not affect overall survival. In PDAC, however, differences in quality translated to a survival advantage., (Copyright © 2017 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Thyroid-related mortality has remained constant despite the increasing incidence of thyroid carcinoma. Most thyroid nodules are benign; therefore, ultrasound and fine needle aspiration (FNA) are integral in cancer screening. We hypothesize that increased nodule size at ultrasound does not predict malignancy and correlation between nodule size at ultrasound and pathologic exam is good., Methods: Resected thyroids with preoperative ultrasounds were identified. Nodule size at ultrasound, FNA diagnosis by Bethesda category, size at pathologic examination, and final histologic diagnosis were recorded. Nodule characteristics at ultrasound and FNA diagnoses were correlated with gross characteristics and histologic diagnoses. Nodules for which correlation could not be established were excluded., Results: Of 1003 nodules from 659 patients, 26% were malignant. Nodules <2 cm had the highest malignancy rate (∼30%). Risk was similar (∼20%) for nodules ≥2 cm. Of the 548 subject to FNA, 38% were malignant. Decreasing malignancy rates were observed with increasing size (57% for nodules <1 cm to 20% for nodules >6 cm). At ultrasound size cutoffs of 2, 3, 4, and 5 cm, smaller nodules had higher malignancy rates than larger nodules. Of the 455 not subject to FNA, 11% were malignant. Ultrasound size alone is a poor predictor of malignancy, but a relatively good predictor of final pathologic size (R 2  = 0.748), with less correlation at larger sizes. In nodules subject to FNA, false negative diagnoses were highest (6-8%) in nodules 3-6 cm, mostly due to encapsulated follicular variant of papillary carcinoma., Conclusions: Thyroid nodule size is inversely related to malignancy risk, as larger nodules have lower malignancy rates. However, the relationship of size to malignancy varies by FNA status. All nodules (regardless of FNA status) demonstrate a risk trough at ≥2 cm. Nodules subject to FNA show step-wise decline in malignancy rates by size, demonstrating that size alone should not be considered as an independent risk factor. Size at ultrasound shows relatively good correlation with final pathologic size. False negative rates are low in this series. Lesions with the appropriate constellation of clinical and radiographic findings should undergo FNA regardless of size. Both size and FNA diagnosis should influence the clinical decision-making process.

The claustrum is a telencephalic gray matter structure with various proposed functions, including sensory integration and attentional allocation. Underlying these concepts is the reciprocal connectivity of the claustrum with most, if not all, areas of the cortex. What remains to be elucidated to inform functional hypotheses further is whether a pattern exists in the strength of connectivity between a given cortical area and the claustrum. To this end, we performed a series of retrograde neuronal tract tracer injections into rat cortical areas along the cortical processing hierarchy, from primary sensory and motor to frontal cortices. We observed that the number of claustrocortical projections increased as a function of processing hierarchy; claustrum neurons projecting to primary sensory cortices were scant and restricted in distribution across the claustrum, whereas neurons projecting to the cingulate cortex were densely packed and more evenly distributed throughout the claustrum. This connectivity pattern suggests that the claustrum may preferentially subserve executive functions orchestrated by the cingulate cortex. J. Comp. Neurol. 525:1347-1362, 2017. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Background: With over 110,000 bariatric operations performed in the United States annually, it is important to understand the biochemical abnormalities causing endocrine dysfunction associated with these procedures. Here we compare 2 malabsorptive procedures, duodenal switch and Roux-en-Y gastric bypass, to determine the role malabsorption plays in secondary hyperparathyroidism in this population., Methods: Data from all super-obese patients undergoing duodenal switch or Roux-en-Y gastric bypass between August 2002 and October 2005 were prospectively collected. Postoperatively, all patients received 1,200 mg of calcium citrate and 1,000 IU vitamin D3 per American Society for Metabolic and Bariatric Surgery guidelines. Beginning in 2007, duodenal switch patients were instructed to add daily vitamin D3 10,000 IU. Statistical analyses included Student t test, multivariate, and univariate logistic regression., Results: Of 283 patients with a body mass index ≥50, 170 (60.1%) underwent duodenal switch, while 113 (39.9%) underwent Roux-en-Y gastric bypass. Of 132 (46.6%) patients with secondary hyperparathyroidism, 101 (59.4%) had undergone duodenal switch and 31 (27.4%) had undergone Roux-en-Y gastric bypass. Symptoms were more common in the duodenal switch group (33 patients [19.4%]) than Roux-en-Y gastric bypass (11 patients [9.7%]). Multivariate logistic regression demonstrated that the extent of bypass and duration of follow-up were the only 2 independent predictive risk factors for developing secondary hyperparathyroidism. Although vitamin D levels improved with increased vitamin D3 supplementation in 2007, rates of secondary hyperparathyroidism increased., Conclusion: Despite routine postoperative calcium and vitamin D3 supplementation, secondary hyperparathyroidism is common after Roux-en-Y gastric bypass and duodenal switch. The degree of iatrogenic malabsorption correlates with the incidence of secondary hyperparathyroidism. These rates suggest current supplementation guidelines are not sufficient in preventing secondary hyperparathyroidism. Further work is needed to better define the sequelae of long-term hyperparathyroidism., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Normohormonal primary hyperparathyroidism presents diagnostic and intraoperative challenges, and current literature is conflicting about management. We aim to better define normohormonal primary hyperparathyroidism in order to improve the care for these patients., Methods: In the study, 516 consecutive patients undergoing parathyroidectomy for primary hyperparathyroidism were divided into 2 groups: classic primary hyperparathyroidism (classic primary hyperparathyroidism, increased serum levels of calcium, and parathyroid hormone) and normohormonal primary hyperparathyroidism (hypercalcemia, normal serum levels of parathyroid hormone). We evaluated inter-group differences in presentation, gland weight, pathology, and complications., Results: The normohormonal primary hyperparathyroidism group was comprised of 116 (22.5%) patients. Mean serum levels of parathyroid hormone and calcium were 62.1 pg/mL ± 10.1 and 10.6 mg/dL ± 0.63 in normohormonal primary hyperparathyroidism, and 142 ± 89.0pg/mL and 11.0 ± 0.88 (both P < .01) for classic primary hyperparathyroidism. Nephrolithiasis was more common in normohormonal primary hyperparathyroidism. Multigland hyperplasia was more common in normohormonal primary hyperparathyroidism 23 (19.8%) vs 44 (11%; P = .04). Concordant imaging studies were less likely in normohormonal primary hyperparathyroidism (82 [73.2%] vs 337 [87.1%; P < .01]), had a lesser total gland weight (531.8 mg ± 680.0 vs 1,039.6 mg ± 1,237.3; P < .01), and lesser 2-week parathyroid hormone (32.5 pg/mL ± 18.95 vs 41.0 pg/mL ± 27.8; P = .01). There was no difference in hypoparathyroidism (parathyroid hormone <15 pg/mL; P = .93) at 2 weeks postoperatively., Conclusion: Normohormonal primary hyperparathyroidism represents 22.5% of our primary hyperparathyroidism population, which is greater than reported previously. It is a distinct disease process from classic primary hyperparathyroidism in presentation, imaging, and operative findings. More hyperplasia and a lesser gland weight make it challenging to resect the ideal amount of tissue. Studies with long-term follow-up are needed to determine optimal operative management., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Integrated devices incorporating ultrasonic and bipolar technology have been used in laparoscopic surgery, however, are not yet incorporated into open operations. Here, we compare thermal spread and recurrent laryngeal nerve (RLN) functional data of the integrated THUNDERBEAT Open Fine Jaw device, the bipolar Ligasure Small Jaw, and the ultrasonic Harmonic Focus for open thyroidectomy., Materials and Methods: The three energy devices were compared in a live porcine model using three tissue types including liver, muscle, and thyroid. The devices were fired three times on each energy setting, and the thermal spread was measured by thermocouples that were inserted in surrounding tissues at 1-mm intervals. To determine RLN injury, devices were fired at successive 1-mm increments from the RLN until the monitor signal was lost., Results: When comparing heat generated across these devices at 1 mm, the peak temperature (Celsius) reached in liver tissue was observed with the ultrasonic device (115.4 ± 86.7), in muscle tissue with the integrated device (104.2 ± 82.1), and in thyroid with the bipolar device (81.4 ± 41.3). Temperatures generated at individual settings on each device were similar (P = 0.11-0.81). RLN injury occurred after firing on manually approximated tissue 1-mm away from the RLN for all devices; however, there was no signal loss at ≥2 mm., Conclusions: Heat transfer was similar among all devices with the exception of the ultrasonic device when used in the liver, which showed higher temperatures. Liver tissue showed the most consistent results. RLN injury did not occur if the devices were fired on manually approximated tissue ≥2 mm from the nerve., (Copyright © 2016 Elsevier Inc. All rights reserved.)