Baseline and early digital [¹⁸F]FDG PET/CT and multiparametric MRI contain promising features to predict response to neoadjuvant therapy in locally advanced rectal cancer patients:a pilot study

Objective In this pilot study, we investigated the feasibility of response prediction using digital [18F]FDG PET/computed tomography (CT) and multiparametric MRI before, during, and after neoadjuvant chemoradiation therapy in locally advanced rectal cancer (LARC) patients and aimed to select the most promising imaging modalities and timepoints for further investigation in a larger trial. Methods Rectal cancer patients scheduled to undergo neoadjuvant chemoradiation therapy were prospectively included in this trial, and underwent multiparametric MRI and [18F]FDG PET/CT before, 2 weeks into, and 6-8 weeks after chemoradiation therapy. Two groups were created based on pathological tumor regression grade, that is, good responders (TRG1-2) and poor responders (TRG3-5). Using binary logistic regression analysis with a cutoff value of P ≤ 0.2, promising predictive features for response were selected. Results Nineteen patients were included. Of these, 5 were good responders, and 14 were poor responders. Patient characteristics of these groups were similar at baseline. Fifty-seven features were extracted, of which 13 were found to be promising predictors of response. Baseline [T2: volume, diffusion-weighted imaging (DWI): apparent diffusion coefficient (ADC) mean, DWI: difference entropy], early response (T2: volume change, DWI: ADC mean change) and end-of-treatment presurgical evaluation MRI (T2: gray level nonuniformity, DWI: inverse difference normalized, DWI: gray level nonuniformity normalized), as well as baseline (metabolic tumor volume, total lesion glycolysis) and early response PET/CT (Δ maximum standardized uptake value, Δ peak standardized uptake value corrected for lean body mass), were promising features. Conclusion Both multiparametric MRI and [18F]FDG PET/CT contain promising imaging features to predict response to neoadjuvant chemoradiotherapy in LARC patients. A future larger trial should investigate baseline, early response, and end-of-treatment presurgical evaluation MRI and baseline and early response PET/CT.</p

Twelve-year outcomes of watchful waiting versus surgery of mildly symptomatic or asymptomatic inguinal hernia in men aged 50 years and older:a randomised controlled trial

Background: Inguinal hernia belongs to the most common surgical pathology worldwide. Approximately, one third is asymptomatic. The value of watchful waiting (WW) in patients with asymptomatic or mildly symptomatic inguinal hernia has been established in a few randomised controlled trials (RCTs). The aim of this study was to assess long-term outcomes of a RCT comparing WW and elective surgery.Methods: In the original study, men aged ≥50 years with an asymptomatic or mildly symptomatic inguinal hernia were randomly assigned to WW or elective repair. In the present study, the primary outcome was the 12-year crossover rate to surgery, secondary outcomes were time-to-crossover, patient regret, pain, quality of life and incarceration. Dutch Trial Registry: NTR629. Findings: Out of 496 originally analysed patients, 488 (98.4%) were evaluable for chart review (WW: n = 258, surgery: n = 230), and 200 (41.0%) for telephone contact (WW: n = 106, surgery: n = 94) between November 2021 and March 2022 with a median 12 years follow-up (IQR 9–14). After 12 years, the estimated cumulative crossover rate to surgery was 64.2%, which was higher in mildly symptomatic than in asymptomatic patients (71.7% versus 60.4%, HR 1.451, 95% CI: 1.064–1.979). Time-to-crossover was longer in asymptomatic patients (50% after 6.0 years versus 2.0 years, p = 0.019). Patient regret was higher in the WW group (37.7 versus 18.0%, p = 0.002), as well as pain/discomfort (p = 0.031). Quality of life did not differ (p = 0.737). In the WW group, incarceration occurred in 10/255 patients (3.9%). Interpretation: During 12-year follow-up, most WW patients crossed over to surgery, significantly earlier with mildly symptomatic hernia. Considering the relatively low incarceration rate, WW might still be an option in asymptomatic patients with a clear preference and being well-informed about pros and cons.</p

Twelve-year outcomes of watchful waiting versus surgery of mildly symptomatic or asymptomatic inguinal hernia in men aged 50 years and older:a randomised controlled trial

Background: Inguinal hernia belongs to the most common surgical pathology worldwide. Approximately, one third is asymptomatic. The value of watchful waiting (WW) in patients with asymptomatic or mildly symptomatic inguinal hernia has been established in a few randomised controlled trials (RCTs). The aim of this study was to assess long-term outcomes of a RCT comparing WW and elective surgery. Methods: In the original study, men aged ≥50 years with an asymptomatic or mildly symptomatic inguinal hernia were randomly assigned to WW or elective repair. In the present study, the primary outcome was the 12-year crossover rate to surgery, secondary outcomes were time-to-crossover, patient regret, pain, quality of life and incarceration. Dutch Trial Registry: NTR629. Findings: Out of 496 originally analysed patients, 488 (98.4%) were evaluable for chart review (WW: n = 258, surgery: n = 230), and 200 (41.0%) for telephone contact (WW: n = 106, surgery: n = 94) between November 2021 and March 2022 with a median 12 years follow-up (IQR 9–14). After 12 years, the estimated cumulative crossover rate to surgery was 64.2%, which was higher in mildly symptomatic than in asymptomatic patients (71.7% versus 60.4%, HR 1.451, 95% CI: 1.064–1.979). Time-to-crossover was longer in asymptomatic patients (50% after 6.0 years versus 2.0 years, p = 0.019). Patient regret was higher in the WW group (37.7 versus 18.0%, p = 0.002), as well as pain/discomfort (p = 0.031). Quality of life did not differ (p = 0.737). In the WW group, incarceration occurred in 10/255 patients (3.9%). Interpretation: During 12-year follow-up, most WW patients crossed over to surgery, significantly earlier with mildly symptomatic hernia. Considering the relatively low incarceration rate, WW might still be an option in asymptomatic patients with a clear preference and being well-informed about pros and cons. Funding: The initial trial was funded by the Netherlands Organisation for Health Research and Development (ZonMW). This long-term study did not receive funding.</p

Consensus Recommendations for Clinical Outcome Assessments and Registry Development in Ataxias: Ataxia Global Initiative (AGI) Working Group Expert Guidance

To accelerate and facilitate clinical trials, the Ataxia Global Initiative (AGI) was established as a worldwide research platform for trial readiness in ataxias. One of AGI's major goals is the harmonization and standardization of outcome assessments. Clinical outcome assessments (COAs) that describe or reflect how a patient feels or functions are indispensable for clinical trials, but similarly important for observational studies and in routine patient care. The AGI working group on COAs has defined a set of data including a graded catalog of COAs that are recommended as a standard for future assessment and sharing of clinical data and joint clinical studies. Two datasets were defined: a mandatory dataset (minimal dataset) that can ideally be obtained during a routine clinical consultation and a more demanding extended dataset that is useful for research purposes. In the future, the currently most widely used clinician-reported outcome measure (ClinRO) in ataxia, the scale for the assessment and rating of ataxia (SARA), should be developed into a generally accepted instrument that can be used in upcoming clinical trials. Furthermore, there is an urgent need (i) to obtain more data on ataxia-specific, patient-reported outcome measures (PROs), (ii) to demonstrate and optimize sensitivity to change of many COAs, and (iii) to establish methods and evidence of anchoring change in COAs in patient meaningfulness, e.g., by determining patient-derived minimally meaningful thresholds of change

Oceanic and terrestrial sources of continental precipitation

Author Posting. © American Geophysical Union, 2012. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Reviews of Geophysics 50 (2012): RG4003, doi:10.1029/2012RG000389.The most important sources of atmospheric moisture at the global scale are herein identified, both oceanic and terrestrial, and a characterization is made of how continental regions are influenced by water from different moisture source regions. The methods used to establish source-sink relationships of atmospheric water vapor are reviewed, and the advantages and caveats associated with each technique are discussed. The methods described include analytical and box models, numerical water vapor tracers, and physical water vapor tracers (isotopes). In particular, consideration is given to the wide range of recently developed Lagrangian techniques suitable both for evaluating the origin of water that falls during extreme precipitation events and for establishing climatologies of moisture source-sink relationships. As far as oceanic sources are concerned, the important role of the subtropical northern Atlantic Ocean provides moisture for precipitation to the largest continental area, extending from Mexico to parts of Eurasia, and even to the South American continent during the Northern Hemisphere winter. In contrast, the influence of the southern Indian Ocean and North Pacific Ocean sources extends only over smaller continental areas. The South Pacific and the Indian Ocean represent the principal source of moisture for both Australia and Indonesia. Some landmasses only receive moisture from the evaporation that occurs in the same hemisphere (e.g., northern Europe and eastern North America), while others receive moisture from both hemispheres with large seasonal variations (e.g., northern South America). The monsoonal regimes in India, tropical Africa, and North America are provided with moisture from a large number of regions, highlighting the complexities of the global patterns of precipitation. Some very important contributions are also seen from relatively small areas of ocean, such as the Mediterranean Basin (important for Europe and North Africa) and the Red Sea, which provides water for a large area between the Gulf of Guinea and Indochina (summer) and between the African Great Lakes and Asia (winter). The geographical regions of Eurasia, North and South America, and Africa, and also the internationally important basins of the Mississippi, Amazon, Congo, and Yangtze Rivers, are also considered, as is the importance of terrestrial sources in monsoonal regimes. The role of atmospheric rivers, and particularly their relationship with extreme events, is discussed. Droughts can be caused by the reduced supply of water vapor from oceanic moisture source regions. Some of the implications of climate change for the hydrological cycle are also reviewed, including changes in water vapor concentrations, precipitation, soil moisture, and aridity. It is important to achieve a combined diagnosis of moisture sources using all available information, including stable water isotope measurements. A summary is given of the major research questions that remain unanswered, including (1) the lack of a full understanding of how moisture sources influence precipitation isotopes; (2) the stationarity of moisture sources over long periods; (3) the way in which possible changes in intensity (where evaporation exceeds precipitation to a greater of lesser degree), and the locations of the sources, (could) affect the distribution of continental precipitation in a changing climate; and (4) the role played by the main modes of climate variability, such as the North Atlantic Oscillation or the El Niño–Southern Oscillation, in the variability of the moisture source regions, as well as a full evaluation of the moisture transported by low-level jets and atmospheric rivers.Luis Gimeno would like to thank the Spanish Ministry of Science and FEDER for their partial funding of this research through the project MSM. A. Stohl was supported by the Norwegian Research Council within the framework of the WATER‐SIP project. The work of Ricardo Trigo was partially supported by the FCT (Portugal) through the ENAC project (PTDC/AAC-CLI/103567/2008).2013-05-0

Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.

Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP

Specific activities of wild-type and mutant CpMan5B enzymes and the CbMan5D enzyme.

<p>Rates of product formation from either mannohexaose (Panels A, C) or cellohexaose (Panels B, D) were determined after 10 minutes and 8 hours, respectively, when the rates of product formation by the wild-type enzymes were linear with time. The amino acid changes in the x-axes labels indicate the site-specific mutants of the CpMan5B enzyme. Parenthetical values above the bars show the percentage of wild-type CpMan5B activity, and asterisks indicate that the raw data are significantly different (P<0.05, Student's paired t test) from those of the wild-type CpMan5B enzyme in the same experiment. Abbreviations: M1, mannose; M2, mannobiose; M3, mannotriose; G1, glucose; G2, cellobiose; G3, cellotriose; n.d., end product(s) was not detected under these assay conditions; IU, international units (μmol min^-1 mg^-1); mIU, milli-international units (nmol min^-1 mg^-1). Lower limits for detection were <2 IU mg^-1 for mannosaccharides and <2 mIU mg^-1 for cellosaccharides.</p

Structural comparison of CpMan5B with <i>Clostridium</i><i>thermocellum</i> cellulase (CtCel5C).

<p>A, The CtCel5C-cellobiose complex (green) is superimposed onto CpMan5B (tan). B, Close-up view of the active site. The figure is drawn in the same orientation as in A. The cellobiose molecule bound to CtCel5C is shown in a stick model colored yellow and red for carbon and oxygen atoms, respectively. Contacting residues of CtCel5C (green), and the corresponding residues of CpMan5B (tan) are shown in panel B. Sugar subsites are indicated in black font.</p