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Fucoidans from brown macroalgae have beneficial biomedical properties but their use as pharma products requires homogenous oligomeric products. In this study, the action of five recombinant microbial fucoidan degrading enzymes were evaluated on fucoidans from brown macroalgae: Sargassum mcclurei, Fucus evanescens, Fucus vesiculosus, Turbinaria ornata, Saccharina cichorioides, and Undaria pinnatifida. The enzymes included three endo-fucoidanases (EC 3.2.1.-GH 107), FcnA2, Fda1, and Fda2, and two unclassified endo-fucoglucuronomannan lyases, FdlA and FdlB. The oligosaccharide product profiles were assessed by carbohydrate-polyacrylamide gel electrophoresis and size exclusion chromatography. The recombinant enzymes FcnA2, Fda1, and Fda2 were unstable but were stabilised by truncation of the C-terminal end (removing up to 40% of the enzyme sequence). All five enzymes catalysed degradation of fucoidans containing α(1→4)-linked l-fucosyls. Fda2 also degraded S. cichorioides and U. pinnatifida fucoidans that have α(1→3)-linked l-fucosyls in their backbone. In the stabilised form, Fda1 also cleaved α(1→3) bonds. For the first time, we also show that several enzymes catalyse degradation of S. mcclurei galactofucan-fucoidan, known to contain α(1→4) and α(1→3) linked l-fucosyls and galactosyl-β(1→3) bonds in the backbone. These data enhance our understanding of fucoidan degrading enzymes and their substrate preferences and may assist development of enzyme-assisted production of defined fuco-oligosaccharides from fucoidan substrates. [ABSTRACT FROM AUTHOR]

Summary Left atrial thrombus in neonates is uncommon. We describe a newborn with coarctation of the aorta, in whom a thrombus confined to the left appendage was discovered on the first day of life and was thought to be a myxoma. [ABSTRACT FROM AUTHOR]

Purpose: Delays to access to radiotherapy are long in our context. The purpose of this study was to analyze the effect of neoadjuvant chemotherapy to concomitant chemoradiotherapy in locally advanced cervical cancers. Patients and Methods: We conducted a retrospective study from April 2014 to April 2016 at the radiotherapy center of "Hopital du Mali" in Bamako, Mali. Patients were allocated according to age, histological type, tumor size and the 2002 classification of the FIGO. Experimental protocol was the administration of a neoadjuvante chemotherapy with association of Paclitaxel 175mg/m² + Carboplatine AUC 5 every 3 weeks and radiothérapy cure with avec linac 6 MV at 70 Gy due to 5 sessions of 2 Gy per week associated with a concomitant chemotherapy with cisplatin at 40 mg/m²/week. The clinical response was assessed at the end of neoadjuvant chemotherapy and of concomitant chemoradiotherapy. Results: Thirty patients were included in the study. The mean age was 53.63 ± 8.9 years. The mean size of the tumor was 5.17 cm (2 to 7 cm). According to the 2002 classification of the FIGO stages IIB were 33% (n = 10); IIIB were 57% (n = 17) and IVA were 10% (n = 3). Clinical evaluation at the end of neoadjuvant chemotherapy found: complete response 17 % (n = 5), partial response 10% (n = 3) and stable disease 73 % (n = 22). Evaluation at the end of the concomitant chemoradiotherapy had found the complete response in 90% (n = 27) and stable disease in 10% (n = 3). Conclusion: Neoadjuvant chemotherapy to concomitant chemoradiotherapy in locally advanced cervical cancer allows stabilization of the tumor and improves local control. Due to long delays to access to radiotherapy treatment in our context; neoadjuvant chemotherapy is an alternative to stabilize the disease and prevent distant metastasis from locally advanced cervical cancers. [ABSTRACT FROM AUTHOR]

Community-based real-world outcomes on effectiveness of antiviral therapies for chronic hepatitis B virus ( CHB) in Asians are limited. Whether hepatitis B surface antigen ( HBsAg) loss correlates with undetectable virus and alanine aminotransferase ( ALT) normalization on treatment or what predicts risk of seroreversion or detectable virus after stopping therapy is unclear. We aim to evaluate rates and predictors of HBsAg loss, seroconversion, ALT normalization and undetectable HBV DNA, including HBsAg seroreversion or re-emergence of HBV DNA among Asian CHB patients. We retrospectively evaluated 1072 CHB adults on antiviral therapy at two community gastroenterology clinics from 1997 to 2015. Rates of HBsAg loss, ALT normalization, achieving undetectable HBV DNA and developing surface antibody (anti- HBs) were stratified by HBeAg status. Following HBsAg loss, HBsAg seroreversion or re-emergence of detectable HBV DNA was analysed. With median treatment of 76.7 months, the overall rate of HBsAg loss was 4.58%, with similar HBsAg loss rates between HBeAg-positive and HBeAg-negative patients (4.44% vs 4.71%, P=.85) in a predominantly Asian population (98.1%). Among HBsAg loss patients, 33.3% developed anti- HBs, 95.8% achieved undetectable virus and 66.0% normalized ALT. No significant baseline or on-treatment predictors of HBsAg loss were observed. While six patients who achieved HBsAg loss had seroreversion with re-emergence of HBsAg positivity, viral load remained undetectable, demonstrating the sustainability of viral suppression. Among a large community-based real-world cohort of Asian CHB patients treated with antiviral therapy, rate of HBsAg loss was 4.58%. Despite only 33.3% of HBsAg loss patients achieving anti- HBs, nearly all patients achieved sustained undetectable virus. [ABSTRACT FROM AUTHOR]

Sofosbuvir/ledipasvir ( SOF/ LDV) is the first all-oral ribavirin-free treatment approved for chronic hepatitis C virus ( HCV) genotype 6, offering a safe and highly efficacious treatment option. Large studies evaluating real-world outcomes of this regimen are lacking. We aim to evaluate real-world treatment outcomes for HCV genotype 6. A retrospective cohort study evaluated 65 adults (age ≥18) with chronic HCV genotype 6 treated with SOF/ LDV without ribavirin at a community gastroenterology clinic in the United States from November 2014 to May 2016. Rates of undetectable virus at week 4 on treatment, at end of treatment ( EOT) and SVR12 were stratified by the presence of cirrhosis and prior treatment (treatment naïve vs treatment experienced). Among 65 patients with chronic HCV genotype 6 treated with SOF/ LDV (52.3% male, mean age 66.3 years [ SD 9.7], 41.5% cirrhosis and 15.4% treatment experienced), 97.3% had undetectable virus at week 4 on treatment, 96.9% had undetectable virus at EOT and 95.3% achieved SVR12. SVR12 was 100% in females vs 91.2% in males, P=.096, and 92.3% in patients with cirrhosis vs 97.4% in those without cirrhosis, P=.347. Resistance testing of treatment failures was attempted but unsuccessful due to lack of conforming primers to define the possible resistance mutations. Among the largest U.S. community-based real-world cohort of Asian chronic HCV genotype 6 patients treated with all-oral SOF/ LDV without ribavirin, SVR12 was similar to SVR12 reported in clinical trials, confirming the safety and effectiveness of this regimen and validating current HCV genotype 6 treatment guideline recommendations. [ABSTRACT FROM AUTHOR]

Purpose/objective(s): Current treatment for patients with newly diagnosed glioblastoma includes concurrent chemoradiation and maintenance temozolomide with Tumor Treating Fields (TTFields, 200 kHz). Preclinical studies suggest TTFields and radiation treatment have synergistic effects. We report our clinical trial evaluating feasibility and tolerability of scalp-sparing radiation with concurrent temozolomide and TTFields.Materials/methods: This is a single arm pilot study. Adult patients (age ≥ 18 years) with newly diagnosed glioblastoma with a KPS of ≥ 60 were eligible. All patients received concurrent scalp-sparing radiation (60 Gy in 30 fractions) with temozolomide (75 mg/m2 daily) and TTFields (200 kHz). Maintenance therapy included temozolomide and continuation of TTFields. Radiation treatment was delivered through TTFields arrays. Total scalp was defined as 5 mm thickness from skin surface above the level of the foramen magnum. The scalp was used as an avoidance structure for planning, with the following dose constraints: mean < 20 Gy, 20 cc < 50 Gy, and 30 cc < 40 Gy. The primary endpoint was safety and toxicity of tri-modality treatment within 30 days of completion of chemoradiation treatment.Results: A total of 30 patients were enrolled in the trial. Twenty were male and ten were female, with a median age of 58 years (range 19 to 77 years). Median KPS was 90 (range 70 to 100). Median follow-up was 8.9 months (range 1.6 to 21.4 months). Twenty (66.7%) patients had unmethylated MGMT promotor status and ten (33.3%) patients had methylated promoter status. Median time from surgery to radiation was 34 days (26 to 49 days). Scalp dose constraints were achieved for all patients, with the mean dose having a median value of 8.3 Gy (range 4.3 to 14.8 Gy), the D20cc median was 26.1 Gy (range 17.7 to 42.8 Gy), and the D30cc median was 23.5 Gy (range 14.8 to 35.4 Gy). Skin adverse events (AEs; erythema, dermatitis, irritation, folliculitis) were noted in 83.3% of patients, however, these were limited to Grade 1 or 2 events, which resolved spontaneously or with topical medications. No patient had radiation treatment interruption due to skin AEs. Other Grade 1 events included pruritus (33.3%), fatigue (30%), nausea (13.3%), headache (10%), dizziness (6.7%), and cognitive impairment (3.3%). Other Grade 2 events included headache (3.3%). Nineteen patients (63.3%) had progression, with a median PFS of 7.6 months (range 1.6 to 12.7 months). Overall survival was not reached.Conclusion: Concurrent TTFields (200 kHz) with scalp-sparing chemoradiation is feasible treatment option with limited toxicity. Future randomized prospective trials are warranted to define therapeutic advantages of concurrent TTFields with chemoradiation.Author Disclosure: R.C. Miller: None. A.J. Song: None. A. Ali: None. V. Bar-Ad: None. N. Martinez: None. J. Glass: None. I. Alnahhas: None. D.W. Andrews: None. K. Judy: None. J. Evans: None. C. Farrell: None. M. Werner-Wasik: Advisory Board; ASTRA Zeneca. Stock; Illumina. leading operations of the committee; NRG Oncology. I. Chervoneva: None. M. Ly: None. J.D. Palmer: Research Grant; Varian Medical Systems, The Kroger Company. Consultant; Huron Consulting. Speaker's Bureau; Varian Medical Systems, Depuy Synthes. Advisory Board; Novocure. Member of panel; NCCN.H. Liu: None. W. Shi: Independent Contractor; Wenyin Shi. Research Grant; Novocure, BrainLab, Regeneron. Consultant; Varian, BrainLab, Zai lab. [ABSTRACT FROM AUTHOR]

Purpose: Indwelling central venous catheters (CVCs) have been increasingly used to enable delivery of intravenous chemotherapy. We aimed to compare the safety and cost of two commonly used CVCs, peripherally inserted central venous catheter (PICCs) and ports, in the delivery of chemotherapy in patients with non-haematological malignancies. Methods: Seventy patients were randomly assigned to receive either a PICC or a port. The primary endpoint was occurrence of major complications, which required removal of the CVC and secondary endpoints included occurrence of any complications. Results: Port devices were associated with fewer complications compared with PICC lines (hazard ratio of 0.25, CI, 0.09–0.86, P = 0.038). Major complication rate was lower in the port arm compared to the PICC arm (0.047 versus 0.193 major complications/100 catheter days, P = 0.034) with 6 versus 20 % of patients experiencing major complications, respectively. Thrombosis, the most common complication, was significantly higher in the PICC arm compared to the port arm (25 versus 0 %, P = 0.013). Quality of life and cost estimates did not differ significantly between the two arms. Conclusions: Port devices are associated with a lower risk of complications, with no difference in cost, compared to PICC lines in patients with non-haematological malignancies receiving intravenous chemotherapy. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate clinicopathologic and molecular features of patients with metastatic colorectal cancer (mCRC) and their outcomes in early-phase trials using pathway-targeting agents. Patients and Methods: We analyzed characteristics of 238 patients with mCRC referred to the phase 1 trials unit at MD Anderson Cancer Center. KRAS, PIK3CA and BRAF status were tested using PCR-based DNA sequencing. Results: Fifty-one percent of patients harbored KRAS mutations; 15% had PIK3CA mutations. In the multivariate regression model for clinical characteristics KRAS mutations were associated with an increased incidence of lung and bone metastases and decreased incidence of adrenal metastases; PIK3CA mutations were marginally correlated with mucinous tumors (p = 0.05). In the univariate analysis, KRAS and PIK3CA mutations were strongly associated. Advanced Duke's stage (p<0.0001) and KRAS mutations (p = 0.01) were the only significant independent predictors of poor survival (Cox proportional hazards model). Patients with PIK3CA mutations had a trend toward shorter progression-free survival when treated with anti-EGFR therapies (p = 0.07). Eighteen of 78 assessable patients (23%) treated with PI3K/Akt/mTOR axis inhibitors achieved stable disease [SD] ⩾6 months or complete response/partial response (CR/PR), only one of whom were in the subgroup (N = 15) with PIK3CA mutations, perhaps because 10 of these 15 patients (67%) had coexisting KRAS mutations. No SD ⩾6 months/CR/PR was observed in the 10 patients treated with mitogen-activating protein kinase (MAPK) pathway targeting drugs. Conclusions: KRAS and PIK3CA mutations frequently coexist in patients with colorectal cancer, and are associated with clinical characteristics and outcome. Overcoming resistance may require targeting both pathways. [ABSTRACT FROM AUTHOR]

Abstract: Amyloid-β peptide species accumulating in the brain of patients with Alzheimer''s disease are assumed to have a neurotoxic action and hence to be key actors in the physiopathology of this neurodegenerative disease. We have studied a new mouse mutant (APPxPS1-Ki) line developing both early-onset brain amyloid-β deposition and, in contrast to most of transgenic models, subsequent neuronal loss. In 6-month-old mice, we observed cell layer atrophies in the hippocampus, together with a dramatic decrease in neurogenesis and a reduced brain blood perfusion as measured in vivo by magnetic resonance imaging. In these mice, neurological impairments and spatial hippocampal dependant memory deficits were also substantiated and worsened with aging. We described here a phenotype of APPxPS1-Ki mice that summarizes several neuroanatomical alterations and functional deficits evocative of the human pathology. Such a transgenic model that displays strong face validity might be highly beneficial to future research on AD physiopathogeny and therapeutics. [Copyright &y& Elsevier]

The purpose of this study was to examine the mental health needs of individuals at risk for adult onset hereditary disorder (AOHD) from the perspective of their genetic service providers, as it is unknown to what extent psychosocial services are required and being met. A mail-out survey was sent to 281 providers on the membership lists of the Canadian Association of Genetic Counsellors and the Canadian College of Medical Geneticists. The survey assessed psychosocial issues that were most commonly observed by geneticists, genetic counsellors (GCs), and nurses as well as availability and types of psychosocial services offered. Of the 129 respondents, half of genetic service providers reported observing signs of depression and anxiety, while 44% noted patients' concerns regarding relationships with family and friends. In terms of providing counselling to patients, as the level of psychological risk increased, confidence in dealing with these issues decreased. In addition, significantly more GCs reported that further training in psychosocial issues would be most beneficial to them if resources were available. As a feature of patient care, it is recommended that gene-based predictive testing include an integrative model of psychosocial services as well as training for genetic service providers in specific areas of AOHD mental health. [ABSTRACT FROM AUTHOR]

In 2007, we published a paper in the Journal of Exposure Science and Environmental Epidemiology describing PCDD/F and dioxin-like PCB serum concentration data collected for the 2001–2002 National Health and Nutrition Examination Survey. Since publication of this paper, several of the 1998 World Health Organization Toxic Equivalency Factors (TEFs), which were used to calculate the summary statistics we presented, have been changed. In this addendum, we publish new reference statistics using the WHO2006 TEFs in addition to assessing the effect of these new TEFs on total TEQ concentrations for the general US population. We also examined the effect of the limits of detection (LODs) on the calculated TEQ summary statistics for the top seven contributing congeners and completed a missing data analysis to determine whether our estimates were biased by excluding individuals without complete congener profiles. Similar to our previous results, 2, 3, 7, 8-TCDD; 1, 2, 3, 7, 8-PeCDD; 1, 2, 3, 6, 7, 8-HxCDD; 2, 3, 4, 7, 8-PeCDF; and PCB 126 contributed the most to total TEQ. However, both PCB 156 and 157 were no longer significant contributors, instead being displaced by 1, 2, 3, 4, 7, 8-HxCDF, and PCB 169. In general, the decrease in TEFs for the mono-ortho-substituted PCBs decreased their contribution to total TEQ appreciably, causing TEQ17-9 to approximately equal TEQ17-3. The effect of LODs for five of the top seven contributing congeners was negligible; however, the LODs for 2, 3, 7, 8-TCDD and 1, 2, 3, 7, 8-PeCDD were noticeably higher and may impact TEQ estimates primarily for individuals aged 20–29 years. Results from the missing data analysis provide compelling evidence that the summary statistics we reported previously, as well as those described here, were not greatly influenced due to censoring data.Journal of Exposure Science and Environmental Epidemiology (2008) 18, 524–532; doi:10.1038/jes.2008.10; published online 26 March 2008 [ABSTRACT FROM AUTHOR]

The effectiveness of the cough reflex in patients who aspirated following radiation for head and neck cancer was evaluated in 89 patients (49 chemoradiation, 33 postoperative radiation, and 7 radiation alone). All patients had modified barium swallow because of dysphagia. The cough reflex was graded as present and effective, ineffective, intermittently effective, or absent. All patients were cancer-free at the time of the swallowing study. The cough reflex was present and effective in 46 patients (52%), ineffective in 17 patients (19%), and absent in 26 patients (29%) on initial investigation. Among the 43 patients who had ineffective or absent cough reflex, their treatment was chemoradiation (26), postoperative radiation (13), and radiation alone (4). In 30 patients who had sequential modified barium swallow, the cough reflex was constantly effective, ineffective, or intermittently effective in 12 (40%), 13 (43%), and 5 (17%) patients, respectively. The cough reflex was frequently ineffective or absent in patients who aspirated following radiation for head and neck cancer. Cough may also be intermittently ineffective to protect the airways following radiation. [ABSTRACT FROM AUTHOR]

Summary: This study examines the efficacy of swallowing therapy in cancer-free patients who developed aspiration following treatment for locally advanced head and neck cancer. The records of 41 patients who underwent swallowing therapy for aspiration were reviewed. All patients were cancer free at a median follow-up of 25 months (6–150 months). Their treatment were respectively chemoradiation (24), and postoperative radiation (17). All patients had two or more modified barium swallow (MBS). Dysphagia severity was graded from 1 to 7. Dysphagia grade was compared before and following swallowing therapy. Before swallowing therapy, there were 16 grade 5 (trace aspiration), and 25 grade 6–7 (severe aspiration). In the chemoradiation group, there were nine grade 5, five grade 6, and 10 grade 7. Corresponding numbers for the postoperative group were: seven grade 5, seven grade 6, and three grade 7. Following swallowing therapy, there were six grade 3, seven grade 4, 10 grade 5, six grade 6, and 12 grade 7. In the chemoradiation group, there were four grade 3, three grade 4, four grade 5, five grade 6, and eight grade 7. In the postoperative group, there were two grade 3, four grade 4, six grade 5, one grade 6, and four grade 7. Overall, 13 patients (32%) had improvement of their dysphagia severity. Seven of them were in the chemoradiation group (29%), and six (35%) were in the postoperative group. Among 25 patients who presented with grade 6–7 aspiration, only nine (36%) improved to grade 5 or less. Four of them (27%) were in the chemoradiation group, and five (29%) were in the postoperative group. Swallowing therapy is effective to improve dysphagia severity and reduce the need for tube feedings. However, a significant number of patients still suffered from chronic severe aspiration. New strategies must be devised to improve their outcome. [Copyright &y& Elsevier]

Summary: Background: We would like to assess the safety and effectiveness of prophylactic percutaneous endoscopic gastrostomy (PEG) tube feedings during concurrent chemoradiation for head and neck cancer. Methods: Patients who underwent chemotherapy and radiation for head and neck malignancies were evaluated for their ability to resume oral feeding following treatment. All patients underwent PEG tube placement prior to the treatment because of the expected mucositis. Gastrostomy tubes were removed following treatment when the patients were able to resume oral feedings without aspiration. Results: Between March 1999 and 2006, 104 patients with locally advanced head and neck cancer underwent concurrent chemotherapy and radiation. One patient declined placement of gastrostomy tube. Ninety patients (86%) developed grade 3–4 mucositis during chemoradiation. Five patients died during treatment from aspiration pneumonia and sepsis. One hundred two patients lost weight during treatment. The mean and median weight loss during concurrent therapy was, respectively, 8.5 and 8kg (1–23.5kg). Following treatment, tube feedings were continued 1–41 months (mean: 8 months; median: 5 months) because of continued weight loss, chronic dysphagia, or aspiration. At a median follow-up of 19 months (1–62 months), no patient developed serious complications from tube feedings. Conclusion: Dysphagia resulting from the severe mucositis produced severe weight loss, despite tube feedings. Gastrostomy tube feedings are safe. Gastrostomy tubes should be placed prophylactically for patients undergoing chemoradiation for head and neck cancer. [Copyright &y& Elsevier]

Abstract: Background and purpose: We would like to assess the prevalence of aspiration before and following chemoradiation for head and neck cancer. Patients and methods: We reviewed retrospectively the Modified Barium Swallow (MBS) in 63 patients who underwent concurrent chemotherapy and radiation for head and neck cancer. MBS was performed prior to treatment to determine the need for immediate gastrostomy tube placement. MBS was repeated following treatment to assess the safety of oral feeding prior to removal of tube feeding. All patients were cancer free at the time of the swallowing study. No patient had surgery. Dysphagia severity was graded on a scale of 1–7. Tube feedings were continued if patients were diagnosed to have severe aspiration (grade 6–7) or continued weight loss. Patients with abnormal swallow (grade 3–7) received swallowing therapy following MBS. Results: Before treatment, there were 18 grade 1, 18 grade 2, 9 grade 3, 8 grade 4, 3 grade 5, 3 grade 6, and 4 grade 7. Following chemoradiation, at a median follow-up of 2 months (1–10 months), one patient had grade 1, eight patients had grade 2, nine patients had grade 3, eight patients had grade 4, 13 patients had grade 5, seven patients had grade 6, and 11 patients had grade 7. Six patients died from aspiration pneumonia (one before, three during, and two post-treatment), and did not have the second MBS. Overall, 37/63 (59%) patients developed aspiration, six of them (9%) fatal. If we excluded the 10 patients who had severe aspiration at diagnosis and the six patients who died from pneumonia, the prevalence of severe aspiration was 33% (21/63). Conclusions: Aspiration remained a significant morbidity following chemoradiation for head and neck cancer. Its prevalence is underreported in the literature because of its often silent nature. Diagnostic studies such as MBS should be part of future head and neck cancer prospective studies to assess the prevalence of aspiration, and for rehabilitation. [Copyright &y& Elsevier]

Abstract: Objective: The purpose of the study is to evaluate dysphagia severity following chemoradiation and postoperative radiation for head and neck cancer, and particularly the aspiration risk because of its potential life-threatening consequence. Materials and methods: We reviewed retrospectively the modified barium swallow (MBS) results in 110 patients who complained of dysphagia following chemoradiation (57) and postoperative radiation (53) of their head and neck cancer. Patients were selected if they were cancer free at the time of the swallowing study. Dysphagia severity was graded on a scale of 1–7. Patients were grouped according to the dysphagia severity: mild (grades 2–3), moderate (grades 4–5), and severe (grades 6–7). Results: Mean and median dysphagia grades were 4.84/5 and 4.12/4 for chemoradiation and postoperative radiation respectively. The mean difference between the two groups is statistically significant (p =0.02). Mild dysphagia occurred in 13 patients (22%) of the chemoradiation group and 17 (32%) of the postoperative group. Corresponding number for the moderate group was 25 (43%) and 25 (48%), respectively. Severe dysphagia was significant in the chemoradiation group (34%) compared to the postoperative group (19%). However, the difference was not statistically significant (p =0.29). There was a higher proportion of patients with large tumor (T3–T4) in the chemoradiation group who developed severe dysphagia. Conclusion: Dysphagia remained a significant morbidity of chemoradiation and postoperative radiation for head and neck cancer. Dysphagia may be more severe in the chemoradiation group because of the higher proportion of patients with large tumor, the high radiation dose, and a high number of oropharyngeal tumors. Aspiration occurred in both groups. Diagnostic studies such as MBS should be part of future head and neck cancer prospective studies to assess the prevalence of aspiration, as it may be silent. [Copyright &y& Elsevier]

Summary: We would like to assess the evolution of chronic dysphagia (1 year or more) following treatment for head and neck cancer. Modified barium swallow (MBS) examinations were performed in cancer-free patients who complained of dysphagia following treatment for head and neck cancer. The severity of the dysphagia was graded on a scale of 1–7. Each patient had at least 2 MBS. Severity of dysphagia was compared between the first and last MBS study to determine whether the swallowing dysfunction had returned to normal. Patients with complaint of dysphagia and normal MBS also underwent a regular barium swallow to assess the structural integrity of the pharynx and esophagus. Between 1996 and 2001, 25 patients with dysphagia underwent repeat MBS following treatment. Swallowing dysfunction did not return to normal in the majority of the patients. At a median time of 26 months following treatment (range 15–82 months), only two patient (8%) had normalization of the swallowing. The severity of dysphagia decreased in eight patients (32%), remained unchanged in 12 patients (48%), and worsened in five patients (20%). Eight patients (32%) still had aspiration problems at 12–83 months following treatment. Six patients (24%) required dilation because of pharyngeal stenosis. Three patients who required dilation had improvement of the dysphagia severity. Chronic dysphagia is a relentless process possibly due to excessive scarring. Patients with chronic dysphagia are at risk of malnutrition, and aspiration. Management of chronic dysphagia requires a team approach with nutritional support, psychological counseling, dilation, and tube feedings when indicated. [Copyright &y& Elsevier]

Introduction: Breast cancer is the most frequent cancer among women in sub-Saharan Africa with high mortality rates. As 60%–100% of the patients are diagnosed at late stages, downstaging strategies have been the focus of international discussions to improve survival. The aim of this study was to analyze the entire breast cancer patient´s pathway from first symptom recognition to begin of treatment and survival in Mali to advice on such strategies. Methods: The model of pathways to treatment was used as a framework to assess important time intervals during the patient´s pathway and to match results of the mixed-methods approach. For the quantitative part, N=64 breast cancer patients were interviewed, with a structured questionnaire at the only pathology department in Mali, about breast symptom recognition and first health care visit. Information on begin of treatment and survival were collected at 18-months follow up. Simple Cox regression analyses were performed. To discover additional barriers, three focus group discussions in the communities in Bamako were conducted (2). Results: Median time to first health care visit was 4.8 months, from first health care visit to diagnosis 0.9 months, and for the patients who started treatment (N=46) time from diagnosis to treatment was 1.3 months. Knowledge of breast-self-examination, and correct symptom interpretation increased the chance to visit health care earlier. Shorter duration to first health care visit, working women compared with housewives, and living within Bamako prolonged time to diagnosis. Living outside Bamako, and smaller tumor size (T1/T2) prolonged time to treatment. Visit of a traditional healer, and larger tumor size (T3/T4) shortened survival time, while time to first health visit, and subsequent time to diagnosis had no influence on survival. In the focus groups, low level of breast cancer knowledge, mistrust in the community health care centers, and economic hardship were reported as additional barriers to first health care visit. Low quality of health care services, and lack of social support were reported as barriers to diagnosis and high costs, and lack of specialized services for treatment begin. Discussion: Patients are diagnosed with late stage diseases, due to low knowledge of breast cancer. A weak health care system and out of pocket expenses discourage patients to seek health care, to have diagnostic services, and to start treatment. Conclusion: The continuum of care has to be warranted for the majority of patients to benefit from down-staging strategies. [ABSTRACT FROM AUTHOR]

Objectifs Une bonne fonction respiratoire est essentielle pour une palliation univentriculaire. Une paralysie diaphragmatique, par lésion du nerf phrénique, peut nécessiter une ventilation mécanique prolongée et grever le pronostic de ces patients. Le but était de comparer les résultats des plicatures diaphragmatiques après réparation biventriculaire ou palliation univentriculaire. Matériels et méthodes Il s’agit d’une analyse rétrospective de 2005–2015. Résultats Vingt-cinq patients sur les 27 cas recensés de paralysie ont bénéficié d’une plicature soit 0,3 % des 8120 patients opérés, dont 11 après palliation univentriculaire. L’âge moyen à la plicature est de 10 mois pour le groupe univentriculaire contre 2,1 mois pour le groupe biventriculaire ( p = 0,65), avec un délai médian chirurgie-plicature de 16 contre 14 jours. Il n’y a pas de différence en termes de durée de ventilation, réanimation et hospitalisation après plicature (24 h, 3j, 10 j groupe univentriculaire contre 24,5 h, 3j et 11j) ou de survie entre les groupes. Conclusion L’incidence des paralysies diaphragmatiques est très faible dans notre unité. La plicature est sure et efficace, pour les réparations biventriculaires comme les palliations univentriculaires. Une réalisation précoce évite une ventilation prolongée. [ABSTRACT FROM AUTHOR]

Objective: To quantitatively assess the impact of early versus late surgical intervention on midfacial growth using a mouse model., Methods: A full-thickness mucoperiosteal flap surgery was performed on newborn (P17) mice and on neonatal (P30) mice. High-resolution micro-computed tomographic imaging coupled with histomorphometric analyses was used to assess craniomaxillofacial growth. Histology and immunohistochemical analyses were used to assess cellular and molecular responses postsurgery., Results: Early surgical intervention at P17 resulted in significant midfacial growth arrest, with pronounced maxillary hypoplasia. Histomorphometric analyses revealed significant (P < 0.05) growth disruptions in the mid-palatal suture complex, including premature removal of the cartilaginous growth plate and its replacement by bone. In the suture itself, cell proliferation was significantly reduced (P < 0.05) compared with controls. The same surgical intervention performed in mice at P30 did not lead to significant midfacial growth arrest., Conclusions: Early surgical intervention in a mouse model mirrors the adverse growth outcomes in children undergoing early cleft repair. Molecular and cellular observations accompanying this midfacial growth arrest may inform therapeutic strategies to mitigate midfacial growth disturbances in patients and highlight the need for refined surgical techniques to minimize adverse growth outcomes., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of Mutaz B. Habal, MD.)

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Introduction: Brain age is a machine learning-derived estimate that captures lower brain volume. Previous studies have found that brain age is significantly higher in mild cognitive impairment and Alzheimer's disease (AD) compared to healthy controls. Few studies have investigated changes in brain age longitudinally in MCI and AD. We hypothesized that individuals with MCI and AD would show heightened brain age over time and across the lifespan. We also hypothesized that both MCI and AD would show faster rates of brain aging (higher slopes) over time compared to healthy controls., Methods: We utilized data from an archival dataset, mainly Alzheimer's disease Neuroimaging Initiative (ADNI) 1 with 3Tesla (3 T) data which totaled 677 scans from 183 participants. This constitutes a secondary data analysis on existing data. We included control participants (healthy controls or HC), individuals with MCI, and individuals with AD. We predicted brain age using a pre-trained model and tested for accuracy. We investigated cross-sectional differences in brain age by group [healthy controls or HC, mild cognitive impairment (MCI), and AD]. We conducted longitudinal modeling of age and brain age by group using time from baseline in one model and chronological age in another model., Results: We predicted brain age with a mean absolute error (MAE) < 5 years. Brain age was associated with age across the study and individuals with MCI and AD had greater brain age on average. We found that the MCI group had significantly higher rates of change in brain age over time compared to the HC group regardless of individual chronologic age, while the AD group did not differ in rate of brain age change., Discussion: We replicated past studies that showed that MCI and AD had greater brain age than HC. We additionally found that this was true over time, both groups showed higher brain age longitudinally. Contrary to our hypothesis, we found that the MCI, but not the AD group, showed faster rates of brain aging. We essentially found that while the MCI group was actively experiencing faster rates of brain aging, the AD group may have already experienced this acceleration (as they show higher brain age). Individuals with MCI may experience higher rates of brain aging than AD and controls. AD may represent a homeostatic endpoint after significant neurodegeneration. Future work may focus on individuals with MCI as one potential therapeutic option is to alter rates of brain aging, which ultimately may slow cognitive decline in the long-term., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ly, Yu, Son, Pascoal, Karim and the Alzheimer’s disease Neuroimaging Initiative.)

Background: Single ventricle palliation may be performed in patients with congenitally corrected transposition of the great arteries due to hypoplasia of 1 ventricle or anatomic complexity rendering biventricular repair unfeasible. There have been only a few small studies of the outcomes of single ventricle palliation in the setting of congenitally corrected transposition of the great arteries., Methods: A multicenter, international, retrospective cohort study of patients with congenitally corrected transposition of the great arteries undergoing single ventricle palliation was conducted in 29 tertiary hospitals in 6 countries from 1990 to 2018., Results: A total of 194 patients with congenitally corrected transposition of the great arteries underwent single ventricle palliation. A functionally univentricular heart was present in 62.4% (121/194). Patients with 2 good-sized ventricles had more laterality defects (50.7% vs 28.1%, P = .002). Fontan completion was achieved in 80.3% (155/194). A tricuspid valve surgery was performed in 9.3% (18/194). Survival was 97.4% (95% CI, 92.1-99.2) at 15 years in the univentricular cohort and 89.8% (95% CI, 78.0-95.5) at 15 years in those with 2 adequate ventricles (P = .05). At last follow-up, 11.5% of patients had heart failure, whereas 6.0% had moderate or greater systemic right ventricle dysfunction and 8.4% exhibited moderate or greater tricuspid regurgitation. In multivariable analysis, aortic coarctation or hypoplasia (hazard ratio, 7.7; P = .005) was associated with mortality., Conclusions: Single ventricle palliation in patients with congenitally corrected transposition of the great arteries is associated with excellent long-term survival and low rates of heart failure and atrioventricular valve failure. In patients who would require complex surgery to achieve a biventricular repair, single ventricle palliation appears to be a good alternative., Competing Interests: Conflict of Interest Statement The authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (Copyright © 2024 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Objectives: The Quality of Life-Aged Care Consumers (QOL-ACC) is an aged-care-specific preference-based instrument currently being rolled out in residential care across Australia as part of the aged care Quality Indicator program. This study aimed to provide a comprehensive assessment of the feasibility, reliability, and construct validity of the QOL-ACC in a large national sample of older adults receiving aged care services at home., Methods: Older adults receiving in-home aged care services completed a survey including the QOL-ACC, Quality of Care Experience-ACC, adult social care outcome tool, EQ-5D-5L, and 2 global single item measures of health and quality of life. Feasibility was assessed by missing responses (≤5%) and ceiling/floor effects (≤15%). Construct validity was assessed by exploring the relationship between the QOL-ACC and other instruments (convergent validity) and its ability to discriminate varying levels of self-rated health and quality of life (known-group validity)., Results: A total of 802 respondents (mean age, 74.5 ± 6.3 years; 56.0% females) completed the survey. The QOL-ACC had no missing responses, no floor effects, and very low ceiling effect (3.5%) and demonstrated moderate correlation with adult social care outcome tool (r = 0.59, P < .001), EQ-5D-5L (r = 0.65, P < .001), EQ-VAS (r = 0.53, P < .001), and a lower correlation with the QCE-ACC (r = 0.41, P < .001). Respondents with poor self-rated health and quality of life had significantly lower preference-weighted scores on the QOL-ACC., Conclusions: The QOL-ACC demonstrated adequate feasibility, reliability, and construct validity in a large population of older people accessing government-subsidized aged care services at home. Further studies will explore the responsiveness of the QOL-ACC to aged-care-specific interventions both in home and residential aged care settings., Competing Interests: Author Disclosures Author disclosure forms can be accessed below in the Supplemental Material section., (Copyright © 2024. Published by Elsevier Inc.)

Background: Normothermic machine perfusion (NMP) allows for the assessment and resuscitation of ex-vivo human livers prior to transplantation. Commercially available NMP systems are closed circuits that accumulate metabolic waste and cytokines over time, potentially limiting organ preservation times. Dialysis has been proposed as a method to remove waste and excess fluid from such systems. This study aimed to demonstrate the utility of integrating dialysis into a commercially available system by quantifying solute removal., Methods: A dialysis filter was attached in parallel to a commercially available liver perfusion system. Three livers declined for transplantation were split before undergoing long-term NMP with blood using the modified system. During perfusion, dialysate flow rates were set in the range of 100-600 mL/h for short periods of time. At each flow rate, perfusate and spent dialysate samples were collected and analyzed for solute clearance., Results: The addition of dialysis to a commercial NMP system removed water-soluble waste and helped regulate electrolyte concentrations. Interleukin-6 was successfully removed from the perfusate. Solute clearance was proportional to dialysate flow rate. A guide for our perfusion setup was created for the appropriate selection of dialysis flow rates and duration based on real-time perfusate composition., Conclusions: Dialysis circuits can efficiently remove waste and regulate perfusate composition, and can be easily incorporated to improve the performance of commercially available systems. Quantification of the effect of dialysis on perfusate composition enables refined dialysis control to optimize electrolyte profiles and avoid the over- or under-correction of key solutes., (© 2024 The Authors. Artificial Organs published by International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

We identify a population of Protogenin-positive (PRTG +ve ) MYC high NESTIN low stem cells in the four-week-old human embryonic hindbrain that subsequently localizes to the ventricular zone of the rhombic lip (RL VZ ). Oncogenic transformation of early Prtg +ve rhombic lip stem cells initiates group 3 medulloblastoma (Gr3-MB)-like tumors. PRTG +ve stem cells grow adjacent to a human-specific interposed vascular plexus in the RL VZ , a phenotype that is recapitulated in Gr3-MB but not in other types of medulloblastoma. Co-culture of Gr3-MB with endothelial cells promotes tumor stem cell growth, with the endothelial cells adopting an immature phenotype. Targeting the PRTG high compartment of Gr3-MB in vivo using either the diphtheria toxin system or chimeric antigen receptor T cells constitutes effective therapy. Human Gr3-MBs likely arise from early embryonic RL VZ PRTG +ve stem cells inhabiting a specific perivascular niche. Targeting the PRTG high compartment and/or the perivascular niche represents an approach to treat children with Gr3-MB., Competing Interests: Declaration of interests The authors declare no competing interests. A patent related to this work was submitted by University of Pittsburgh (University Docket No. 05700/F&R ref. 48881-0028P01), US 63/275,326, “Molecules that bind to Protogenin polypeptides.”, (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Obesity and excess adiposity at midlife are risk factors for Alzheimer disease (AD). Visceral fat is known to be associated with insulin resistance and a pro-inflammatory state, the two mechanisms involved in AD pathology. We assessed the association of obesity, MRI-determined abdominal adipose tissue volumes, and insulin resistance with PET-determined amyloid and tau uptake in default mode network areas, and MRI-determined brain volume and cortical thickness in AD cortical signature in the cognitively normal midlife population. Thirty-two middle-aged (age: 51.27±6.12 years, 15 males, body mass index (BMI): 32.28±6.39 kg/m2) cognitively normal participants, underwent bloodwork, brain and abdominal MRI, and amyloid and tau PET scan. Visceral and subcutaneous adipose tissue (VAT, SAT) were semi-automatically segmented using VOXel Analysis Suite (Voxa). FreeSurfer was used to automatically segment brain regions using a probabilistic atlas. PET scans were acquired using [11C]PiB and AV-1451 tracers and were analyzed using PET unified pipeline. The association of brain volumes, cortical thicknesses, and PiB and AV-1451 standardized uptake value ratios (SUVRs) with BMI, VAT/SAT ratio, and insulin resistance were assessed using Spearman's partial correlation. VAT/SAT ratio was associated significantly with PiB SUVRs in the right precuneus cortex (p=0.034) overall, controlling for sex. This association was significant only in males (p=0.044), not females (p=0.166). Higher VAT/SAT ratio and PiB SUVRs in the right precuneus cortex were associated with lower cortical thickness in AD-signature areas predominantly including bilateral temporal cortices, parahippocampal, medial orbitofrontal, and cingulate cortices, with age and sex as covariates. Also, higher BMI and insulin resistance were associated with lower cortical thickness in bilateral temporal poles. In midlife cognitively normal adults, we demonstrated higher amyloid pathology in the right precuneus cortex in individuals with a higher VAT/SAT ratio, a marker of visceral obesity, along with a lower cortical thickness in AD-signature areas associated with higher visceral obesity, insulin resistance, and amyloid pathology.

Fitz-Hugh-Curtis (FHCS) is characterized by an inflammation of the hepatic capsule concomitant or following pelvic infection due to Chlamydia trachomatis or Neisseria gonorrhea . It is a rare condition occurring most often in a woman of childbearing age and very rare in male patients. Splenic involvement is also a rare form of abdominal tuberculosis. The association of these two conditions is very uncommon. We report the exceptional case of a 58- year-old HIV-positive male patient, with whom abdominal ultrasound helped diagnose FHCS associated with abdominal tuberculosis invovlving the spleen., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Bile duct regeneration is hypothesized to prevent biliary strictures, a leading cause of morbidity after liver transplantation. Assessing the capacity for biliary regeneration may identify grafts as suitable for transplantation that are currently declined, but this has been unfeasible until now. This study used long-term ex situ normothermic machine perfusion (LT-NMP) to assess biliary regeneration. Human livers that were declined for transplantation were perfused at 36 °C for up to 13.5 days. Bile duct biopsies, bile, and perfusate were collected throughout perfusion, which were examined for features of injury and regeneration. Biliary regeneration was defined as new Ki-67-positive biliary epithelium following severe injury. Ten livers were perfused for a median duration of 7.5 days. Severe bile duct injury occurred in all grafts, and biliary regeneration occurred in 70% of grafts. Traditional biomarkers of biliary viability such as bile glucose improved during perfusion but this was not associated with biliary regeneration (P > .05). In contrast, the maintenance of interleukin-6 and vascular endothelial growth factor-A levels in bile was associated with biliary regeneration (P = .017 for both cytokines). This is the first study to demonstrate biliary regeneration during LT-NMP and identify a cytokine signature in bile as a novel biomarker for biliary regeneration during LT-NMP., Competing Interests: Declaration of competing interest The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation., (Copyright © 2024 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

Medical practitioners are entrusted with the pivotal task of making optimal decisions in healthcare delivery. Despite rigorous training, our confidence in reasoning can fail when faced with pressures, uncertainties, urgencies, difficulties, and occasional errors. Day-to-day decisions rely on swift, intuitive cognitive processes known as heuristic or type 1 decision-making, which, while efficient in most scenarios, harbor inherent vulnerabilities leading to systematic errors. Cognitive biases receive limited explicit discussion during our training as junior doctors in the domain of paediatric cardiology. As pediatric cardiologists, we frequently confront emergencies necessitating rapid decision-making, while contending with the pressures of stress, fatigue, an earnest interest in "doing the right thing" and the impact of parental involvement. This article aims to describe cognitive biases in pediatric cardiology, highlighting their influence on therapeutic interventions for congenital heart disease. Whether future pediatric cardiologists or experienced professionals, understanding and actively combating cognitive biases are essential components of our ongoing medical education. Furthermore, it is our responsibility to thoroughly examine our own practices in our unwavering commitment to providing high-quality care., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Padovani, Roy, Guerra, Cadeau, Ly, Vasile, Pass and Baruteau.)

The central nervous system coordinates peripheral cellular stress responses, including the unfolded protein response of the mitochondria (UPR MT ); however, the contexts for which this regulatory capability evolved are unknown. UPR MT is up-regulated upon pathogenic infection and in metabolic flux, and the olfactory nervous system has been shown to regulate pathogen resistance and peripheral metabolic activity. Therefore, we asked whether the olfactory nervous system in Caenorhabditis elegans controls the UPR MT cell nonautonomously. We found that silencing a single inhibitory olfactory neuron pair, AWC, led to robust induction of UPR MT and reduction of oxidative phosphorylation dependent on serotonin signaling and parkin -mediated mitophagy. Further, AWC ablation confers resistance to the pathogenic bacteria Pseudomonas aeruginosa partially dependent on the UPR MT transcription factor atfs-1 and fully dependent on mitophagy machinery. These data illustrate a role for the olfactory nervous system in regulating whole-organism mitochondrial dynamics, perhaps in preparation for postprandial metabolic stress or pathogenic infection.