The utility of whole-exome sequencing (WES) for the diagnosis and management of adult-onset constitutional disorders has not been adequately studied. Genetic diagnostics may be advantageous in adults ...with chronic kidney disease (CKD), in whom the cause of kidney failure often remains unknown.
To study the diagnostic utility of WES in a selected referral population of adults with CKD.
Observational cohort.
A major academic medical center.
92 adults with CKD of unknown cause or familial nephropathy or hypertension.
The diagnostic yield of WES and its potential effect on clinical management.
Whole-exome sequencing provided a diagnosis in 22 of 92 patients (24%), including 9 probands with CKD of unknown cause and encompassing 13 distinct genetic disorders. Among these, loss-of-function mutations were identified in PARN in 2 probands with tubulointerstitial fibrosis. PARN mutations have been implicated in a short telomere syndrome characterized by lung, bone marrow, and liver fibrosis; these findings extend the phenotype of PARN mutations to renal fibrosis. In addition, review of the American College of Medical Genetics actionable genes identified a pathogenic BRCA2 mutation in a proband who was diagnosed with breast cancer on follow-up. The results affected clinical management in most identified cases, including initiation of targeted surveillance, familial screening to guide donor selection for transplantation, and changes in therapy.
The small sample size and recruitment at a tertiary care academic center limit generalizability of findings among the broader CKD population.
Whole-exome sequencing identified diagnostic mutations in a substantial number of adults with CKD of many causes. Further study of the utility of WES in the evaluation and care of patients with CKD in additional settings is warranted.
New York State Empire Clinical Research Investigator Program, Renal Research Institute, and National Human Genome Research Institute of the National Institutes of Health.
Background
While a shift to minimally invasive techniques in rectal cancer surgery has occurred, non-inferiority of laparoscopy in terms of oncological outcomes has not been definitely demonstrated. ...Transanal total mesorectal excision (TaTME) has been pioneered to potentially overcome difficulties experienced when operating with a pure abdominal approach deep down in the pelvis. This study aimed to compare short-term oncological results of TaTME versus laparoscopic TME (lapTME), based on a strict anatomical definition for low rectal cancer on MRI.
Methods
From June 2013, all consecutive TaTME cases were included and compared to lapTME in a single institution. Propensity score-matching was performed for nine relevant factors. Primary outcome was resection margin involvement (R1), secondary outcomes included intra- and post-operative outcomes.
Results
After matching, forty-one patients were included in each group; no significant differences were observed in patient and tumor characteristics. The resection margin was involved in 5 cases (12.2%) in the laparoscopic group, versus 2 (4.9%) TaTME cases (
P
= 0.432). The TME specimen quality was complete in 84.0% of the laparoscopic cases and in 92.7% of the TaTME cases (
P
= 0.266). Median distance to the circumferential resection margin (CRM) was 5 mm in lapTME and 10 mm in TaTME (
P
= 0.065). Significantly more conversions took place in the laparoscopic group, 9 (22.0%) compared to none in the TaTME group (
P
< 0.001). Other clinical outcomes did not show any significant differences between the two groups.
Conclusion
This is the first study to compare results of TaTME with lapTME in a highly selected patient group with MRI-defined low rectal tumors. A significant decrease in R1 rate could not be demonstrated, although conversion rate was significantly lower in this TaTME cohort.
There remains a lack of international consensus on the appropriate management of lateral nodal disease. Although the East manages this more aggressively with lateral lymph node dissections, the West ...aims to eradicate small-volume disease with neoadjuvant chemoradiotherapy and lateral nodal disease is not considered for routine surgical treatment. However, recent studies have shown that, despite neoadjuvant treatment, a significant number of patients with lateral nodal disease develop local recurrence in the lateral compartment after total mesorectal excision.
The aim of this study is to assess the role of the pretreatment features of lateral nodes on MRI in regard to local recurrence.
All patients operated on for low locally advanced rectal cancer over a 5-year period were evaluated retrospectively.
This study was conducted at a single expert center.
The MRIs of a total of 313 patients were reviewed, and only those with rectal cancers up to 8 cm from the anorectal junction, measured on MRI, were selected. This left 185 patients; of these, 58 patients had clinical T1 or T2 tumors as assessed on MRI, identifying 127 patients who had cT3/T4 tumors that were included in this study.
The primary outcomes measured were lateral local recurrence and multivariate analyses.
The lateral local recurrence rate was significantly higher (33.3% 4-year rate) in patients with nodes larger than 10 mm than in patients with smaller nodes (10.1%, p = 0.03), despite patients being irradiated in the lateral compartment.
Because this is a relatively uncommon disease, patient numbers are low, and a multicenter study is needed to further address lateral nodal disease in low rectal cancer.
Chemoradiotherapy with total mesorectal excision might not be sufficient in a selected group of patients. Further research is needed about which pretreatment features of the lateral nodes predict local recurrence and what is needed to prevent these from developing. See Video Abstract at http://links.lww.com/DCR/A338.
We tested the ability of a type 1 diabetes (T1D) genetic risk score (GRS) to predict progression of islet autoimmunity and T1D in at-risk individuals.
We studied the 1,244 TrialNet Pathway to ...Prevention study participants (T1D patients' relatives without diabetes and with one or more positive autoantibodies) who were genotyped with Illumina ImmunoChip (median range age at initial autoantibody determination 11.1 years 1.2-51.8, 48% male, 80.5% non-Hispanic white, median follow-up 5.4 years). Of 291 participants with a single positive autoantibody at screening, 157 converted to multiple autoantibody positivity and 55 developed diabetes. Of 953 participants with multiple positive autoantibodies at screening, 419 developed diabetes. We calculated the T1D GRS from 30 T1D-associated single nucleotide polymorphisms. We used multivariable Cox regression models, time-dependent receiver operating characteristic curves, and area under the curve (AUC) measures to evaluate prognostic utility of T1D GRS, age, sex, Diabetes Prevention Trial-Type 1 (DPT-1) Risk Score, positive autoantibody number or type, HLA DR3/DR4-DQ8 status, and race/ethnicity. We used recursive partitioning analyses to identify cut points in continuous variables.
Higher T1D GRS significantly increased the rate of progression to T1D adjusting for DPT-1 Risk Score, age, number of positive autoantibodies, sex, and ethnicity (hazard ratio HR 1.29 for a 0.05 increase, 95% CI 1.06-1.6;
= 0.011). Progression to T1D was best predicted by a combined model with GRS, number of positive autoantibodies, DPT-1 Risk Score, and age (7-year time-integrated AUC = 0.79, 5-year AUC = 0.73). Higher GRS was significantly associated with increased progression rate from single to multiple positive autoantibodies after adjusting for age, autoantibody type, ethnicity, and sex (HR 2.27 for GRS >0.295, 95% CI 1.47-3.51;
= 0.0002).
The T1D GRS independently predicts progression to T1D and improves prediction along T1D stages in autoantibody-positive relatives.
Aim
Outcomes following treatment for low rectal cancer still remain inferior to those for upper rectal cancer. A clear definition of ‘low’ rectal cancer is lacking and consensus is more likely using ...a definition based on MRI criteria. This study aimed to determine disease presentation and treatment outcome of low rectal cancer based on a strict anatomical definition.
Method
A low rectal cancer was defined as one with a lower border below the pelvic attachment of the levator muscles on sagittal MRI. One hundred and eighty consecutive patients with tumours defined by this criterion between 2006 and 2011 were identified from a prospectively managed departmental database.
Results
One hundred and eighteen patients (66%) underwent curative resection and 12 (7%) palliative resection. Eleven patients (6%) were entered into a ‘watch and wait’ (W&W) protocol; 10 others (5%) were not fit to undergo any operation. Some 26 patients (14%) had nonresectable local or metastatic disease. An R0 resection was the most important factor influencing survival after curative surgery. R+ resections occurred in 12% of non‐abdominoperineal excisions, 11% of abdominoperineal excisions and 47% of extended resections. Overall survival was similar in the curative resections compared with the W&W patients. In 23 of the 96 (24%) treated with neoadjuvant chemoradiotherapy there was a persistent clinical or a pathological complete response.
Conclusion
In curative resections, a clear margin is the most important determinant of survival. In 24% of the patients treated with neoadjuvant chemoradiotherapy, surgery could potentially have been avoided. There is scope for improvement in the treatment of locally advanced rectal cancers.
This paper summarises key advances in defining the infectious reservoir for malaria and the measurement of transmission for research and programmatic use since the Malaria Eradication Research Agenda ...(malERA) publication in 2011. Rapid and effective progress towards elimination requires an improved understanding of the sources of transmission as well as those at risk of infection. Characterising the transmission reservoir in different settings will enable the most appropriate choice, delivery, and evaluation of interventions. Since 2011, progress has been made in a number of areas. The extent of submicroscopic and asymptomatic infections is better understood, as are the biological parameters governing transmission of sexual stage parasites. Limitations of existing transmission measures have been documented, and proof-of-concept has been established for new innovative serological and molecular methods to better characterise transmission. Finally, there now exists a concerted effort towards the use of ensemble datasets across the spectrum of metrics, from passive and active sources, to develop more accurate risk maps of transmission. These can be used to better target interventions and effectively monitor progress toward elimination. The success of interventions depends not only on the level of endemicity but also on how rapidly or recently an area has undergone changes in transmission. Improved understanding of the biology of mosquito-human and human-mosquito transmission is needed particularly in low-endemic settings, where heterogeneity of infection is pronounced and local vector ecology is variable. New and improved measures of transmission need to be operationally feasible for the malaria programmes. Outputs from these research priorities should allow the development of a set of approaches (applicable to both research and control programmes) that address the unique challenges of measuring and monitoring transmission in near-elimination settings and defining the absence of transmission.
Background
Ethanol (EtOH) and nicotine abuse are 2 leading causes of preventable mortality in the world, but little is known about the pharmacological mechanisms mediating co‐abuse. Few studies have ...examined the interaction of the acute effects of EtOH and nicotine. Here, we examine the effects of nicotine administration on the duration of EtOH‐induced loss of righting reflex (LORR) and characterize the nature of their pharmacological interactions in C57BL/6J mice.
Methods
We assessed the effects of EtOH and nicotine and the nature of their interaction in the LORR test using isobolographic analysis after acute injection in C57BL/6J male mice. Next, we examined the importance of receptor efficacy using nicotinic partial agonists varenicline and sazetidine. We evaluated the involvement of major nicotinic acetylcholine receptor (nAChR) subtypes using nicotinic antagonist mecamylamine and nicotinic α4‐ and α7‐knockout mice. The selectivity of nicotine's actions on EtOH‐induced LORR was examined by testing nicotine's effects on the hypnotic properties of ketamine and pentobarbital. We also assessed the development of tolerance after repeated nicotine exposure. Last, we assessed whether the effects of nicotine on EtOH‐induced LORR extend to hypothermia and EtOH intake in the drinking in the dark (DID) paradigm.
Results
We found that acute nicotine injection enhances EtOH's hypnotic effects in a synergistic manner and that receptor efficacy plays an important role in this interaction. Furthermore, tolerance developed to the enhancement of EtOH's hypnotic effects by nicotine after repeated exposure of the drug. α4* and α7 nAChRs seem to play an important role in nicotine–EtOH interaction in the LORR test. In addition, the magnitude of EtOH‐induced LORR enhancement by nicotine was more pronounced in C57BL/6J than DBA/2J mice. Furthermore, acute nicotine enhanced ketamine and pentobarbital hypnotic effects in the mouse. Finally, nicotine enhanced EtOH‐induced hypothermia but decreased EtOH intake in the DID test.
Conclusions
Our results demonstrate that nicotine synergistically enhances EtOH‐induced LORR in the mouse.
PDF
