Milk intake and incident stroke and CHD in populations of European descent: a Mendelian randomisation study.

Higher milk intake has been associated with a lower stroke risk, but not with risk of CHD. Residual confounding or reverse causation cannot be excluded. Therefore, we estimated the causal association of milk consumption with stroke and CHD risk through instrumental variable (IV) and gene-outcome analyses. IV analysis included 29 328 participants (4611 stroke; 9828 CHD) of the European Prospective Investigation into Cancer and Nutrition (EPIC)-CVD (eight European countries) and European Prospective Investigation into Cancer and Nutrition-Netherlands (EPIC-NL) case-cohort studies. rs4988235, a lactase persistence (LP) SNP which enables digestion of lactose in adulthood was used as genetic instrument. Intake of milk was first regressed on rs4988235 in a linear regression model. Next, associations of genetically predicted milk consumption with stroke and CHD were estimated using Prentice-weighted Cox regression. Gene-outcome analysis included 777 024 participants (50 804 cases) from MEGASTROKE (including EPIC-CVD), UK Biobank and EPIC-NL for stroke, and 483 966 participants (61 612 cases) from CARDIoGRAM, UK Biobank, EPIC-CVD and EPIC-NL for CHD. In IV analyses, each additional LP allele was associated with a higher intake of milk in EPIC-CVD (ß = 13·7 g/d; 95 % CI 8·4, 19·1) and EPIC-NL (36·8 g/d; 95 % CI 20·0, 53·5). Genetically predicted milk intake was not associated with stroke (HR per 25 g/d 1·05; 95 % CI 0·94, 1·16) or CHD (1·02; 95 % CI 0·96, 1·08). In gene-outcome analyses, there was no association of rs4988235 with risk of stroke (OR 1·02; 95 % CI 0·99, 1·05) or CHD (OR 0·99; 95 % CI 0·95, 1·03). Current Mendelian randomisation analysis does not provide evidence for a causal inverse relationship between milk consumption and stroke or CHD risk.

Volume-outcome relationships in open and endovascular repair of abdominal aortic aneurysm: administrative data 2006-2018.

BACKGROUND: The aim of this study was to use recent evidence to investigate and update volume-outcome relationships after open surgical repair (OSR) and endovascular repair (EVAR) of abdominal aortic aneurysm in England. METHODS: Hospital Episode Statistics (HES) data from April 2006 to March 2018 were obtained. The primary outcome was in-hospital death. Other outcomes included duration of hospital stay, readmissions within 30 days, and critical care requirements. Case-mix adjustment included age, sex, HES year, deprivation index, weekend admission, mode of admission, type of procedure and co-morbidities. RESULTS: Annual volume of all repairs combined appeared to be an appropriate measure of volume. After case-mix adjustment, a significant relationship between volume and in-hospital mortality was seen for OSR (P < 0·001) but not for EVAR (P = 0·169 for emergency and P = 0·363 for elective). The effect appeared to extend beyond 60 repairs per year to volumes above 100 repairs per year. There was no significant relationship between volume and duration of hospital stay or 30-day readmissions. In patients receiving emergency OSR, higher volume was associated with longer stay in critical care. CONCLUSION: Higher annual all-procedure volumes were associated with significantly lower in-hospital mortality for OSR, but such a relationship was not significant for EVAR. There was not enough evidence for a volume effect on other outcomes.

Dietary intake of advanced glycation end products (AGEs) and changes in body weight in European adults.

PURPOSE: Advanced glycation end products (AGEs) can be formed in foods by the reaction of reducing sugars with proteins, and have been shown to induce insulin resistance and obesity in experimental studies. We examined the association between dietary AGEs intake and changes in body weight in adults over an average of 5 years of follow-up. METHODS: A total of 255,170 participants aged 25-70 years were recruited in ten European countries (1992-2000) in the PANACEA study (Physical Activity, Nutrition, Alcohol, Cessation of smoking, Eating out of home in relation to Anthropometry), a sub-cohort of the EPIC (European Prospective Investigation into Cancer and Nutrition). Body weight was measured at recruitment and self-reported between 2 and 11 years later depending on the study center. A reference database for AGEs was used containing UPLC-MS/MS-measured Nε-(carboxymethyl)-lysine (CML), Nε-(1-carboxyethyl)-lysine (CEL), and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) in 200 common European foods. This reference database was matched to foods and decomposed recipes obtained from country-specific validated dietary questionnaires in EPIC and intake levels of CEL, CML, and MG-H1 were estimated. Associations between dietary AGEs intake and body weight change were estimated separately for each of the three AGEs using multilevel mixed linear regression models with center as random effect and dietary AGEs intake and relevant confounders as fixed effects. RESULTS: A one-SD increment in CEL intake was associated with 0.111 kg (95% CI 0.087-0.135) additional weight gain over 5 years. The corresponding additional weight gain for CML and MG-H1 was 0.065 kg (0.041-0.089) and 0.034 kg (0.012, 0.057), respectively. The top six food groups contributing to AGEs intake, with varying proportions across the AGEs, were cereals/cereal products, meat/processed meat, cakes/biscuits, dairy, sugar and confectionary, and fish/shellfish. CONCLUSION: In this study of European adults, higher intakes of AGEs were associated with marginally greater weight gain over an average of 5 years of follow-up.

QTc interval prolongation during recovery from brief high-intensity intermittent exercise in obese adults.

The risk of malignant arrhythmias is higher during extremely intense exercise and after its cessation. It is still unclear whether high-intensity interval exercise (HIE), an increasingly popular option in preventive and rehabilitative medicine, can lead to an impaired electrophysiological milieu, as revealed by QT interval prolongation on an electrocardiogram. This study investigated heart rate-corrected QT interval (QTc) dynamics during recovery from HIE in obese adults. In total, 13 obese males (age: 24.3 ± 4.6 years old; body mass index: 31.6 ± 4.1 kg/m2) underwent: (1) HIE: an HIE session of four 30-s all-out cycling efforts interspersed with 4­min recovery periods; (2) REC: a recovery session 24 h after HIE; and (3) CON: a control session of no treatment. The QT interval was measured before HIE, REC, and CON, and then at 30-min intervals thereafter, for up to 3 h. QTc values were obtained using Bazett, Fridericia, Framingham, Hodges, and Rautaharju correction formulas. Acute HIE led to a significant increase in QTc for each correction (by 5-47 ms, all p < 0.05), and QTc was significantly longer during early recovery from acute exercise (HIE) compared with CON corrected with the Bazett (by 49 ms), Fridericia (by 11 ms), Hodges (by 27 ms), and Rautaharju (by 15 ms) formulas (all p < 0.05). Further, the QTc for each correction at most of the observation points in the REC trial was significantly longer (by 5-10 ms, all p < 0.05) than the corresponding value of the CON. In conclusion, in obese adults, the risk of QTc prolongation increased after brief HIE, and the risk may be sustained for more than 24 h.

[Long-term outcomes of Bryan artificial cervical disc replacement for degenerative cervical spondylosis].

Objective: To compare the long-term clinical effect and imaging results of Bryan artificial cervical disc replacement (ACDR) and anterior cervical discectomy and fusion (ACDF) and to explore whether ACDR can reduce the occurrence of postoperative adjacent segment degeneration (ASD) in the treatment of degenerative cervical spondylosis. Methods: It was a retrospective study. Total of 60 patients with degenerative cervical spondylosis, who had received operations by Bryan ACDR (n=27) and ACDF (n=33) in the Third Hospital of Hebei Medical University between January 2005 and December 2009 were enrolled in this study. The Japanese Orthopedic Association (JOA) scores, neck disability index (NDI), visual analogue scale (VAS), Odom's scale, cervical range of motion (ROM), surgical segment ROM, heterotopic ossification (HO) and ASD were used to evaluate the clinical and radiologic results. The indices abovementioned were compared between the two groups. Results: The VAS, NDI and JOA scores at each follow-up node in both ACDR and ACDF group were all significantly improved when compared with those before operation (all P<0.05), but there was no significant differences between the two groups (all P>0.05). Of all, 88.9%(24/27) of patients in ACDR group and 84.8%(28/33) of patients in ACDF group achieved excellent or good results, however, there was no significant difference in Odom's scale between the two groups (P>0.05). At the last follow-up, the cervical ROM in ACDR group was 43.2°±8.8°, which was slightly lower than that before operation (45.7°±10.4°), the difference was not statistically significant (t=0.954, P=0.345); the surgical segment ROM in ACDR group was 5.9°±3.6°, which was significantly reduced when compared with that before operation (8.8°±3.4°, t=3.043, P<0.01). However at the last follow-up, the cervical ROM in ACDF group was 36.4°±8.4°, which was significantly reduced when compared with that before operation (43.9°±11.1°), the difference was statistically significant (t=3.095, P<0.01). Although, there was no significant difference in the cervical ROM between the two groups before operation (t=0.643, P=0.523), and the difference was statistically significant at the last follow-up (t=3.054, P<0.01). At the last follow-up, the incidence of HO in ACDR group was 92.6%, and the high-grade HO was 37.0%. The incidence of ASD in ACDR group was 39.5%, which was much lower than that in ACDF group (61.1%, χ(2)=4.462, P=0.035). Conclusion: At minimum follow-up of 10 years, Bryan ACDR achieves a satisfactory clinical effect consistent with ACDF. In terms of advantages, ACDR could maintain the ROM of cervical and retain the ROM of the surgical segment, which reduces the occurrence of ASD by preserving motion.

Sex differences in national rates of repair of emergency abdominal aortic aneurysm.

BACKGROUND: The aim of this study was to assess the sex differences in both the rate and type of repair for emergency abdominal aortic aneurysm (AAA) in England. METHODS: Hospital Episode Statistics (HES) data sets from April 2002 to February 2015 were obtained. Clinical and administrative codes were used to identify patients who underwent primary emergency definitive repair of ruptured or intact AAA, and patients with a diagnosis of AAA who died in hospital without repair. These three groups included all patients with a primary AAA who presented as an emergency. Sex differences between repair rates and type of surgery (endovascular aneurysm repair (EVAR) versus open repair) over time were examined. RESULTS: In total, 15 717 patients (83·3 per cent men) received emergency surgical intervention for ruptured AAA and 10 276 (81·2 per cent men) for intact AAA; 12 767 (62·0 per cent men) died in hospital without attempted repair. The unadjusted odds ratio for no repair in women versus men was 2·88 (95 per cent c.i. 2·75 to 3·02). Women undergoing repair of ruptured AAA were older and had a higher in-hospital mortality rate (50·0 versus 41·0 per cent for open repair; 30·9 versus 23·5 per cent for EVAR). After adjustment for age, deprivation and co-morbidities, the odds ratio for no repair in women versus men was 1·34 (1·28 to 1·40). The in-hospital mortality rate after emergency repair of an intact AAA was also higher among women. CONCLUSION: Women who present as an emergency with an AAA are less likely to undergo repair than men. Although some of this can be explained by differences in age and co-morbidities, the differences persist after case-mix adjustment.

Local excision followed by early radical surgery in rectal cancer: long-term outcome.

BACKGROUND: In rectal cancers, radical surgery should follow local excisions, in cases of unexpected, unfavorable tumor characteristics. The oncological results of this completion surgery are inconsistent. This retrospective cohort study assessed the clinical and long-term oncological outcomes of patients that underwent completion surgery to clarify whether a local excision compromised the results of radical surgery. METHODS: Forty-six patients were included, and the reasons for completion surgery, intraoperative complications, residual tumors, local recurrences (LRs), distant metastases, and cancer-specific survival (CSS) were assessed. The results were compared to 583 patients that underwent primary surgery without adjuvant therapy, treated with a curative intention during the same time period. RESULTS: The median follow-up was 14.6 years. The reasons for undergoing completion surgery were positive resection margins (24%), high-risk cancer (30%), or both (46%). Intraoperative perforations occurred in 10/46 (22%) cases. Residual tumor in the rectal wall or lymph node involvement occurred in 12/46 (26%) cases. The risk of intraoperative perforation and residual tumor increased with the pT category. Intraoperative perforations did not increase postoperative complications, but they increased the risk of LRs in cases of intramural residual tumors (p = 0.003). LRs occurred in 2.6% of pT1/2 and 29% of pT3 tumors. Both the 5- and 10-year CSS rates were 88.8% (95% CI 80.0-98.6). Moreover, the LRs of patients with pT1/2 cancers were lower in patients with completion surgery than in patients with primary surgery. CONCLUSIONS: Rectal wall perforations at the local excision site and residual cancer were the main risks for poor oncological outcomes associated with completion surgery. Local excisions followed by early radical surgery did not appear to compromise outcomes compared to patients with primary surgery for pT1/2 rectal cancer. Improvements in clinical staging should allow more appropriate selection of patients that are eligible for a local excision of rectal cancer.

The first pilot study of expanded newborn screening for inborn errors of metabolism and survey of related knowledge and opinions of health care professionals in Hong Kong.

INTRODUCTION: Newborn screening is important for early diagnosis and effective treatment of inborn errors of metabolism (IEM). In response to a 2008 coroners' report of a 14-year-old boy who died of an undiagnosed IEM, the OPathPaed service model was proposed. In the present study, we investigated the feasibility of the OPathPaed model for delivering expanded newborn screening in Hong Kong. In addition, health care professionals were surveyed on their knowledge and opinions of newborn screening for IEM. METHODS: The present prospective study involving three regional hospitals was conducted in phases, from 1 October 2012 to 31 August 2014. The 10 steps of the OPathPaed model were evaluated: parental education, consent, sampling, sample dispatch, dried blood spot preparation and testing, reporting, recall and counselling, confirmation test, treatment and monitoring, and cost-benefit analysis. A fully automated online extraction system for dried blood spot analysis was also evaluated. A questionnaire was distributed to 430 health care professionals by convenience sampling. RESULTS: In total, 2440 neonates were recruited for newborn screening; no true-positive cases were found. Completed questionnaires were received from 210 respondents. Health care professionals supported implementation of an expanded newborn screening for IEM. In addition, there is a substantial need of more education for health care professionals. The majority of respondents supported implementing the expanded newborn screening for IEM immediately or within 3 years. CONCLUSION: The feasibility of OPathPaed model has been confirmed. It is significant and timely that when this pilot study was completed, a government-led initiative to study the feasibility of newborn screening for IEM in the public health care system on a larger scale was announced in the Hong Kong Special Administrative Region Chief Executive Policy Address of 2015.

Hysteroscopic excision of symptomatic myometrial adenomyosis: feasibility and effectiveness.

OBJECTIVE: To explore the feasibility and efficacy of hysteroscopic excision of myometrial adenomyotic lesions. DESIGN: A case-series study. SETTING: A university medical centre. POPULATION: 51 women with myometrial adenomyosis completed the study. METHODS: The patients underwent hysteroscopic excision of myometrial adenomyosis and were followed up for 24 months. The degree of symptoms, uterine volume, and serum CA125 concentrations were recorded. The degrees of menorrhagia and dysmenorrhea were evaluated. RESULTS: The mean MVJ and VAS score significantly decreased from the baseline. The uterine volume and the serum CA125 significantly reduced. CONCLUSIONS: Hysteroscopic excision of myometrial adenomyotic lesions is feasible and may be effective in improving symptoms. TWEETABLE ABSTRACT: Hysteroscopic excision is feasible for patients with symptomatic adenomyosisis.

Analysis of local recurrences after transanal endoscopic microsurgery for low risk rectal carcinoma.

AIM: Rates of local recurrence (LR) after transanal endoscopic microsurgery (TEM) for rectal carcinoma vary; the reasons remain unclear. We analyzed LR after TEM for low-risk pT1 (G1/2/X, L0/X) rectal carcinoma to investigate the influence of completeness of resection and occult lymph node metastasis on risk of LR. METHOD: LR location and stage, completeness of resection of primary carcinoma (minimal distance between tumor and resection line ≤1 mm vs >1 mm), and incidence of involved lymph nodes in resected LR specimens were collected, and tumor characteristics of LR were compared with primary carcinoma. Distant metastasis and overall and cancer-specific survival were determined. RESULTS: LR developed in 14 patients; in 2/4 with R1/X resection, in 3/8 (38%) with clear margins (R0) but a minimal distance of ≤1 mm, and in 9/88 (10%) with formally complete resection. Six of nine patients with formally complete resection underwent radical surgery for LR; in five out of these six, lymph nodes were not involved. In 5/14 patients, LR was poorly differentiated compared to primary carcinoma. Main LR causes were incomplete tumor resection or tumor persistence after formally complete resection. Overall (p = 0.008) and cancer-specific (p < 0.001) survival was lower in LR patients compared to non-LR patients, even if lymph nodes were uninvolved. CONCLUSIONS: The results suggest that most LRs after TEM for low-risk rectal cancer were caused by residual tumor at the previous excision site and not by undetected lymph node metastases. By improved standardization of surgical techniques to ensure complete resection of carcinomas and thorough pathological assessments, most LRs seem to be avoidable.

[Clinical significance and distribution of BRCA genes mutation in sporadic high grade serous ovarian cancer].

Objective: To investigate the mutations of BRCA genes in sporadic high grade serous ovarian cancer (HGSOC) and study its clinical significance. Methods: Sixty-eight patients between January 2015 and January 2016 from the Affiliated Cancer Hospital of Zhengzhou University were collected who were based on pathological diagnosis of ovarian cancer and had no reported family history, and all patients firstly hospitalized were untreated in other hospitals before. (1) The BRCA genes were detected by next-generation sequencing (NGS) method. (2) The serum tumor markers included carcinoembryonic antigen (CEA), CA(125), CA(199), and human epididymis protein 4 (HE4) were detected by the chemiluminescence methods, and their correlation was analyzed by Pearson linear correlation. Descriptive statistics and comparisons were performed using two-tailed t-tests, Pearson's chi square test, Fisher's exact tests or logistic regression analysis as appropriate to research the clinicopathologic features associated with BRCA mutations, including age, International Federation of Gynecology and Obstetrics (FIGO) stage, platinum-based chemotherapy sensitivity, distant metastases, serum tumor markers (STM) . Results: (1) Fifteen cases (22%, 15/68) BRCA mutations were identified (BRCA1: 11 cases; BRCA2: 4 cases), and four novel mutations were observed. (2) The levels of CEA, CA(199), and HE4 were lower in BRCA mutations compared to that in control group, while no significant differences were found (P>0.05), but the level of CA(125) was much higher in BRCA mutation group than that in controls (t=-3.536, P=0.003). Further linear regression analysis found that there was a significant linear correlation between CA(125) and HE4 group (r=0.494, P<0.01), and the same correlation as CEA and CA(199) group (r=0.897, P<0.01). (3) Single factor analysis showed that no significant differences were observed in onset age, FIGO stage, distant metastasis, and STM between BRCA(+) and BRCA(-) group (P>0.05), while significant differences were found in CA(125) and sensitivity to platinum-based chemotherapy between the patients with BRCA mutation and wild type (P<0.05). The multiple factors analysis showed that the high level of CA(125) was a independent risk factor of BRCA mutations in sporadic HGSOC (P=0.007). Conclusion: The combination of CA(125) with BRCA have great clinical significance, the mutation of BRCA gene could guild the clinical chemotherapy regiments.

Instantiated mixed effects modeling of Alzheimer's disease markers.

The assessment and prediction of a subject's current and future risk of developing neurodegenerative diseases like Alzheimer's disease are of great interest in both the design of clinical trials as well as in clinical decision making. Exploring the longitudinal trajectory of markers related to neurodegeneration is an important task when selecting subjects for treatment in trials and the clinic, in the evaluation of early disease indicators and the monitoring of disease progression. Given that there is substantial intersubject variability, models that attempt to describe marker trajectories for a whole population will likely lack specificity for the representation of individual patients. Therefore, we argue here that individualized models provide a more accurate alternative that can be used for tasks such as population stratification and a subject-specific prognosis. In the work presented here, mixed effects modeling is used to derive global and individual marker trajectories for a training population. Test subject (new patient) specific models are then instantiated using a stratified "marker signature" that defines a subpopulation of similar cases within the training database. From this subpopulation, personalized models of the expected trajectory of several markers are subsequently estimated for unseen patients. These patient specific models of markers are shown to provide better predictions of time-to-conversion to Alzheimer's disease than population based models.

Long-term Oncologic Outcome After Transanal Endoscopic Microsurgery for Rectal Carcinoma.

BACKGROUND: Transanal endoscopic microsurgery is superior to other methods of local excision of rectal cancer, but few studies report long-term follow-up data. OBJECTIVE: This study investigated the use of transanal endoscopic microsurgery alone as curative and compromise therapy based on long-term disease recurrence and mortality. DESIGN: This was a retrospective review of prospectively collected data. SETTINGS: The study was conducted at a tertiary care university medical center. PATIENTS: The study included 133 patients treated between 1985 and 2007. There were 3 groups, including transanal endoscopic microsurgery in curative intent (low-risk rectal carcinoma, including pT1, G1/2, L0, and LX with clear margins and a minimal distance between tumor and resection margin of >1 mm (N = 64) or clear margins only (N = 18 ))) and as compromise therapy (high-risk or incompletely resected rectal carcinoma; N = 51). MAIN OUTCOME MEASURES: Log-rank tests were used to compare overall and cancer-specific survival. RESULTS: The median follow-up time was 8.6 years (range, 0.2-25.1 years), and a total of 131 of 133 patients (98.5%) were followed >5 years or until death. The preoperative diagnosis of carcinoma was not associated with belonging into 1 of the 3 categories. In patients with low-risk completely (>1 mm) resected carcinoma, the 5- and 10-year local recurrence rates were 6.6% and 11.6%. In patients with high-risk or incompletely resected carcinoma, the rates were 32.5% and 35.0% (p = 0.006). The 5- and 10-year cancer-specific survival rates for low-risk patients were 98.0% and 91.0% and 84.3% and 74.3% for high-risk patients (p = 0.05). LIMITATIONS: The study was limited by its retrospective design and small subgroups. CONCLUSIONS: The high cancer-specific survival justifies transanal endoscopic microsurgery alone as curative treatment in low-risk rectal carcinoma. Complete resection is essential to lower the risk of local recurrence. The high local recurrence rate in patients with high-risk rectal carcinoma restricts the use of TEM alone as compromise therapy.

Silver-Russell syndrome in Hong Kong.

OBJECTIVES: To examine the molecular pathogenetic mechanisms, (epi)genotype-phenotype correlation, and the performance of the three clinical scoring systems-namely Netchine et al, Bartholdi et al, and Birmingham scores-for patients with Silver-Russell syndrome in Hong Kong. METHODS: This retrospective case series was conducted at two tertiary genetic clinics, the Clinical Genetic Service, Department of Health, and clinical genetic clinic in Queen Mary Hospital in Hong Kong. All records of patients with suspected Silver-Russell syndrome under the care of the two genetic clinics between January 2010 and September 2015 were retrieved from the computer database. RESULTS: Of the 28 live-birth patients with Silver-Russell syndrome, 35.7% had H19 loss of DNA methylation, 21.4% had maternal uniparental disomy of chromosome 7, 3.6% had mosaic maternal uniparental disomy of chromosome 11, and the remaining 39.3% were Silver-Russell syndrome of unexplained molecular origin. No significant correlation between (epi)genotype and phenotype could be identified between H19 loss of DNA methylation and maternal uniparental disomy of chromosome 7. Comparison of molecularly confirmed patients and patients with Silver-Russell syndrome of unexplained origin revealed that postnatal microcephaly and café-au-lait spots were more common in the latter group, and body and limb asymmetry was more common in the former group. Performance analysis showed the Netchine et al and Birmingham scoring systems had similar sensitivity in identifying Hong Kong Chinese subjects with Silver-Russell syndrome. CONCLUSION: This is the first territory-wide study of Silver-Russell syndrome in Hong Kong. The clinical features and the spectrum of underlying epigenetic defects were comparable to those reported in western populations.

A novel cis-acting element from the 3'UTR of DNA damage-binding protein 2 mRNA links transcriptional and post-transcriptional regulation of gene expression.

The DNA damage-binding protein 2 (DDB2) is an adapter protein that can direct a modular Cul4-DDB1-RING E3 Ligase complex to sites of ultraviolet light-induced DNA damage to ubiquitinate substrates during nucleotide excision repair. The DDB2 transcript is ultraviolet-inducible; therefore, its regulation is likely important for its function. Curiously, the DDB2 mRNA is reportedly short-lived, but the transcript does not contain any previously characterized cis-acting determinants of mRNA stability in its 3' untranslated region (3'UTR). Here, we used a tetracycline regulated d2EGFP reporter construct containing specific 3'UTR sequences from DDB2 to identify novel cis-acting elements that regulate mRNA stability. Synthetic 3'UTRs corresponding to sequences as short as 25 nucleotides from the central region of the 3'UTR of DDB2 were sufficient to accelerate decay of the heterologous reporter mRNA. Conversely, these same 3'UTRs led to more rapid induction of the reporter mRNA, export of the message to the cytoplasm and the subsequent accumulation of the encoded reporter protein, indicating that this newly identified cis-acting element affects transcriptional and post-transciptional processes. These results provide clear evidence that nuclear and cytoplasmic processing of the DDB2 mRNA is inextricably linked.

Impact of exercise intensity on cardiac function in adolescent runners.

BACKGROUND: Prolonged exercise may induce a transient reduction in the left ventricular (LV) function (exercise-induced cardiac fatigue) in adults. However, data related to the cardiovascular consequences of prolonged exercise in adolescents are extremely limited. This study examined the impact of exercise intensity adopted in routine long-distance run training on LV function in trained adolescent runners in a laboratory-based setting. METHODS: Twelve male adolescent runners (14.5 ± 1.5 years) performed two 90-min treadmill runs with intensity set at the running speeds that corresponded to either 80% (T1) or 100% (T2) ventilatory threshold. LV function was examined echocardiographically pre- and post-exercise. RESULTS: The two-factor repeated-measures ANOVA revealed no significant (P>0.05) main effects for the intensity and the interaction of intensityÍ pre- and postexercise in ejection fraction (EF), systolic blood pressure/end systolic volume ratio (SBP/ESV) and early to atrial diastolic flow velocity ratio (E:A). Nevertheless, the main effect for time course in EF was significant (P<0.05). Pre-exercise EF in T1 (74 ± 5 vs. 70 ± 5%, P<0.05), but not in T2 (75 ± 4 vs. 72 ± 7%, P>0.05), decreased significantly post-exercise, yet this did not reach clinical levels. Further, no difference (P>0.05) was found between pre- and post-exercise in SBP/ESV (T1: 3.9 ± 0.9 vs. 3.7 ± 1.1; T2: 4.0 ± 0.7 vs. 4.6 ± 1.9 mmHg·ml⁻¹) and E:A (T1: 1.87 ± 0.11 vs. 1.87 ± 0.11; T2: 1.83 ± 0.11 vs. 1.87 ± 0.09) in both trials. CONCLUSION: These findings suggest that the training intensities adopted in routine long-distance run training in the adolescent runners do not seem to induce cardiac fatigue. Adolescent hearts appear to cope well with prolonged run performed on training.

Quality of Life Analysis of Patients Treated with Percutaneous Hepatic Perfusion for Uveal Melanoma Liver Metastases.

PURPOSE: Percutaneous hepatic perfusion with melphalan (M-PHP) is a minimally invasive therapy with proven efficacy in patients with uveal melanoma (UM) liver metastases. M-PHP is associated with a short hospital admission time and limited systemic side effects. In this study, we assessed quality of life (QoL) in UM patients treated with M-PHP. MATERIALS AND METHODS: A prospective, single-center study including 24 patients treated with M-PHP for UM metastases to the liver. QoL questionnaires were collected at baseline, on day 2/3 after M-PHP, and on day 7 and day 21 after M-PHP, according to study protocol. The results were scored according to EORTC-QLQ C30 global health status (GHS), functional scales, and symptom scales. The difference in scores at baseline and subsequent time points was analyzed with the Wilcoxon signed-rank test and multiple testing Bonferroni correction. Adverse events (AE) were registered up to 30 days after M-PHP according to CTCAE v5.0. RESULTS: Twenty-four patients (14 males; median age 63.0 years) completed 96 questionnaires. Most scores on all scales declined on day 2/3 after M-PHP. On day 21 after M-PHP, 12 out of 15 scores returned to baseline, including median GHS scores. Three variables were significantly worse on day 21 compared to baseline: fatigue (6-33; p = 0.002), physical functioning (100 vs 86.7; p = 0.003), and role functioning (100 vs 66.7; p = 0.001). Grade 3/4 AEs consisted mainly of hematological complications, such as leukopenia and thrombopenia. CONCLUSION: M-PHP causes fatigue and a decline in physical and role functioning in the 1st weeks after treatment, but GHS returns to baseline levels within 21 days. LEVEL OF EVIDENCE 3: Cohort study.

[Short-course radiotherapy combined with CAPOX and PD-1 inhibitor for the total neoadjuvant therapy of locally advanced rectal cancer: the preliminary single-center findings of a prospective, multicentre, randomized phase II trial (TORCH)].

Objective: Total neoadjuvant therapy has been used to improve tumor responses and prevent distant metastases in patients with locally advanced rectal cancer (LARC). Patients with complete clinical responses (cCR) then have the option of choosing a watch and wait (W&W) strategy and organ preservation. It has recently been shown that hypofractionated radiotherapy has better synergistic effects with PD-1/PD-L1 inhibitors than does conventionally fractionated radiotherapy, increasing the sensitivity of microsatellite stable (MSS) colorectal cancer to immunotherapy. Thus, in this trial we aimed to determine whether total neoadjuvant therapy comprising short-course radiotherapy (SCRT) combined with a PD-1 inhibitor improves the degree of tumor regression in patients with LARC. Methods: TORCH is a prospective, multicenter, randomized, phase II trial (TORCH Registration No. NCT04518280). Patients with LARC (T3-4/N+M0, distance from anus ≤10 cm) are eligible and are randomly assigned to consolidation or induction arms. Those in the consolidation arm receive SCRT (25Gy/5 Fx), followed by six cycles of toripalimab plus capecitabine and oxaliplatin (ToriCAPOX). Those in the induction arm receive two cycles of ToriCAPOX, then undergo SCRT, followed by four cycles of ToriCAPOX. Patients in both groups undergo total mesorectal excision (TME) or can choose a W&W strategy if cCR has been achieved. The primary endpoint is the complete response rate (CR, pathological complete response [pCR] plus continuous cCR for more than 1 year). The secondary endpoints include rates of Grade 3-4 acute adverse effects (AEs) etc. Results: Up to 30 September 2022, 62 patients attending our center were enrolled (Consolidation arm: 34, Induction arm:28). Their median age was 53 (27-69) years. Fifty-nine of them had MSS/pMMR type cancer (95.2%), and only three MSI-H/dMMR. Additionally, 55 patients (88.7%) had Stage III disease. The following important characteristics were distributed as follows: lower location (≤5 cm from anus, 48/62, 77.4%), deeper invasion by primary lesion (cT4 7/62, 11.3%; mesorectal fascia involved 17/62, 27.4%), and high risk of distant metastasis (cN2 26/62, 41.9%; EMVI+ 11/62, 17.7%). All 62 patients completed the SCRT and at least five cycles of ToriCAPOX, 52/62 (83.9%) completing six cycles of ToriCAPOX. Finally, 29 patients achieved cCR (46.8%, 29/62), 18 of whom decided to adopt a W&W strategy. TME was performed on 32 patients. Pathological examination showed 18 had achieved pCR, four TRG 1, and 10 TRG 2-3. The three patients with MSI-H disease all achieved cCR. One of these patients was found to have pCR after surgery whereas the other two adopted a W&W strategy. Thus, the pCR and CR rates were 56.2% (18/32) and 58.1% (36/62), respectively. The TRG 0-1 rate was 68.8% (22/32). The most common non-hematologic AEs were poor appetite (49/60, 81.7%), numbness (49/60, 81.7%), nausea (47/60, 78.3%) and asthenia (43/60, 71.7%); two patients did not complete this survey. The most common hematologic AEs were thrombocytopenia (48/62, 77.4%), anemia (47/62, 75.8%), leukopenia/neutropenia (44/62, 71.0%) and high transaminase (39/62, 62.9%). The main Grade III-IV AE was thrombocytopenia (22/62, 35.5%), with three patients (3/62, 4.8%) having Grade IV thrombocytopenia. No Grade V AEs were noted. Conclusions: SCRT-based total neoadjuvant therapy combined with toripalimab can achieve a surprisingly good CR rate in patients with LARC and thus has the potential to offer new treatment options for organ preservation in patients with MSS and lower-location rectal cancer. Meanwhile, the preliminary findings of a single center show good tolerability, the main Grade III-IV AE being thrombocytopenia. The significant efficacy and long-term prognostic benefit need to be determined by further follow-up.