Quality of life in a randomized trial comparing two neoadjuvant regimens for locally advanced rectal cancer-INCAGI004.

BACKGROUND: Neoadjuvant chemoradiotherapy (neoCRT) followed by surgery is the standard of care for locally advanced rectal cancer (LARC), but the emergence of different drug regimens may result in different response rates. Good clinical response translates into greater sphincter preservation, but quality of life (QOL) may be impaired after treatment due to chemoradiotherapy and surgical side effects. OBJECTIVE: To prospectively evaluate the impact of clinical response and surgical resection on QOL in a randomized trial comparing two different neoCRT regimens. METHODS: Stage II and III rectal cancer patients were randomized to receive neoCRT with either capecitabine (group 1) or 5-Fu and leucovorin (group 2) concomitant to long-course radiotherapy. Clinical downstaging was accessed using MRI 6-8 weeks after treatment. EORTCs QLQ-C30 and CR38 were applied before treatment (T0), after neoCRT (T1), after rectal resection (T2), early after adjuvant chemotherapy (T3), and 1 year after the end of treatment or stoma closure (T4). The Wexner scale was used for fecal incontinence evaluation at T4. A C30SummaryScore (Geisinger and cols.) was calculated to compare QOL results. RESULTS: Thirty-two patients were assigned to group 1 and 31 to group 2. Clinical downstaging occurred in 70.0% of group 1 and 53.3% of group 2 (p = 0.288), and sphincter preservation was 83.3% in group 1 and 80.0% in group 2 (p = 0.111). No significant difference in QOL was detected when comparing the two treatment groups after neoCRT using QLQ-C30. However, the CR38 module detected differences in micturition problems (15.3 points), gastrointestinal problems (15.3 points), defecation problems (11.8 points), and sexual satisfaction (13.3 points) favoring the capecitabine group. C30SummaryScore detected significant improvement comparing T0 to T1 and deterioration comparing T1 to T2 (p = 0.025). The mean Wexner scale score was 9.2, and a high score correlated with symptoms of diarrhea and defecation problems at T4. CONCLUSIONS: QOL was equivalent between groups after neoCRT except for micturition problems, gastrointestinal problems, defecation problems, and sexual satisfaction favoring the capecitabine arm after. The overall QOL using the C30SummaryScore was improved after neoCRT, but decreased following rectal resection, returning to basal levels at late evaluation. Fecal incontinence was high after sphincter preservation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03428529.

One-Year Readmission Following Undifferentiated Acute Hypercapnic Respiratory Failure.

Patients with acute hypercapnic respiratory failure (AHRF) often require hospitalization and respiratory support. Early identification of patients at risk of readmission would be helpful. We evaluated 1-y readmission and mortality rates of patients admitted for undifferentiated AHRF and identified the impact of initial severity on clinically important outcomes. We retrospectively analyzed patients who presented with AHRF to the emergency department of St Michael's Hospital in 2017. We collected data about patients' characteristics, hospital admission, readmission and mortality one year after the index admission. We analyzed predictors of readmission and mortality and conducted a survival analysis comparing patients who did and did not receive ventilatory support. A cohort of 212 patients with AHRF who survived their hospital admission were analyzed. At one year, 150 patients (70.8%) were readmitted and 19 (9%) had died. Main diagnoses included chronic obstructive pulmonary disease (60%), congestive heart failure (36%), asthma (22%) and obesity (19%), and these categories of patients had similar 1 y readmission rates. One third had more than one coexisting chronic illness. Although comorbidities were more frequent in readmitted patients, only a history of previous hospital admissions remained associated with 1 y readmission and mortality in multivariate analysis. Need for ventilatory support at admission was not associated with higher 1 y probability of readmission or death. Undifferentiated AHRF is the presentation of multiple chronic illnesses. Patients who survive one episode of AHRF and with previous history of admission have the highest risk of readmission and death regardless of whether they receive ventilatory support during index admission.

Primary Neurons and Differentiated NSC-34 Cells Are More Susceptible to Arginine-Rich ALS Dipeptide Repeat Protein-Associated Toxicity than Non-Differentiated NSC-34 and CHO Cells.

A repeat expansion mutation in the C9orf72 gene is the most common known genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In this study, using multiple cell-based assay systems, we reveal both increased dipeptide repeat protein (DRP) toxicity in primary neurons and in differentiated neuronal cell lines. Using flow cytometry and confocal laser scanning microscopy of cells treated with fluorescein isothiocyanate (FITC)-labeled DRPs, we confirm that poly-glycine-arginine (GR) and poly-proline-arginine (PR) DRPs entered cells more readily than poly-glycine-proline (GP) and poly-proline-alanine (PA) DRPs. Our findings suggest that the toxicity of C9-DRPs may be influenced by properties associated with differentiated and aging motor neurons. Further, our findings provide sensitive cell-based assay systems to test phenotypic rescue ability of potential interventions.

Role of APOE Gene in Bone Mineral Density and Incidence of Bone Fractures in Brazilian Postmenopausal Women.

Osteoporosis is one of the major diseases that affects mostly postmenopausal women. Despite being a multifactorial disease, some genes have been shown to play an important role in osteoporosis. Bone mineral density (BMD) is still largely used to diagnose it, although many other biomarkers are used to better follow the disease onset. It has been shown that the apolipoprotein E (APOE) gene could be a biomarker for risk of fractures as well as to predict lower BMD in patients with osteoporosis. The human APOE gene encodes 3 protein isoforms called ApoE2, ApoE3, and ApoE4, resulting in 4 possible genotypes, because they are a product of a single nucleotide polymorphism found in this gene. So far, the APOE4 allele has been associated with low BMD in postmenopausal women and to incidence of bone breaking in older women. This study aimed to investigate the role of ApoE isoforms in a cohort of 413 postmenopausal Brazilian women. These patients were randomly recruited, clinically examined, and subjected to dual-energy X-ray absorptiometry to measure their BMD. Patients were further grouped as normal BMD (T-score < 0.5) or low BMD (T-score > 1.0, osteopenic or osteoporotic). Patients with osteopenia or osteoporosis were further genotyped for APOE alleles as well as tested for many serum bone turnover biomarkers. Our data showed that presence of the APOE3 allele was associated with both higher BMDs and higher serum concentrations of osteocalcin and alkaline phosphatase, biomarkers for bone formation. On the other hand, the APOE2 and APOE4 alleles were associated with lower BMD as well as higher levels of serum C-terminus collagen peptide and urinary deoxipyridinolines, biomarkers for bone resorption. However, these effects on lower BMD and bone resorption biomarkers observed in either APOE2 or APOE4 alleles were eliminated when patients' genotype carried the APOE3 allele. Codominance of the APOE3 allele was also associated with lesser cases of bone fractures in these patients within a 5-year follow-up. In conclusion, our data show that APOE4 may be associated with lower bone formation as well as increased risk of osteoporosis and bone fractures, whereas APOE3 seems to decrease lowering BMD in postmenopausal women, and its presence seemed to lower the incidence of bone breaking in patients with osteoporosis.

Toxoplasma gondii: prevalence and characterization of new genotypes in free-range chickens from south Brazil.

Toxoplasma gondii is an intracellular parasite that can infect all warm-blooded animals including humans. Recent studies showed that T. gondii strains from South America are genetically diverse. The present work aimed to determine T. gondii prevalence in free-ranging chicken in northwest Parana state in Brazil by two serological tests, to isolate the parasites from seropositive chickens and to genotype the isolates. Antibodies to T. gondii in 386 serum samples from 24 farms were investigated by immunofluorescence antibody assay (IFA) and modified agglutination test (MAT). Samples having titers ≥ 16 were considered positive for both tests. Among the 386 serum samples, 102 (26.4%) were positive for IFA, 64 (16.6%) were positive for MAT, 47 (12.2%) were positive in both tests, and 119 (30.8%) were positive in at least one of the two tests. Brain and pool of heart, lung, and liver from the 119 seropositive chickens were used for mouse bioassay to isolate the parasites. Thirty eight (31.9%) of these seropositive chickens were considered positives in mouse bioassay and 18 isolates were obtained. The isolates were characterized by 10 PCR-RFLP genetic markers including SAG1, SAG2 (5'-3'SAG2, alt.SAG2), SAG3, BTUB, GRA6, c22-8, c29-2, L358, PK1, and Apico. Results of genotyping were compared with the genotypes in ToxoDB database. It revealed ten genotypes, including ToxoDB PCR-RFLP genotypes #6 (n = 2), #19 (n = 1), #21 (n = 2), #111 (n = 2), #152 (n = 1), and #175 (n = 1) and four new types not described before. Our results confirmed a high genetic diversity of this parasite in southern Brazil and also showed that the use of two serological tests in combination can improve the chance of T. gondii isolation. More studies should be taken to determine the zoonotic potential of chickens in the transmission of T. gondii.

Phase IIa trial of fingolimod for amyotrophic lateral sclerosis demonstrates acceptable acute safety and tolerability.

INTRODUCTION: Immune activation has been implicated in progression of amytrophic lateral sclerosis (ALS). Oral fingolimod reduces circulating lymphocytes. The objective of this phase IIa, randomized, controlled trial was to test the short-term safety, tolerability, and target engagement of fingolimod in ALS. METHODS: Randomization was 2:1 (fingolimod:placebo). Treatment duration was 4 weeks. Primary outcomes were safety and tolerability. Secondary outcomes included circulating lymphocytes and whole-blood gene expression. RESULTS: Thirty participants were randomized; 28 were administered a drug (fingolimod 18, placebo 10). No serious adverse events occurred. Adverse events were similar by treatment arm, as was study discontinuation (2 fingolimod vs. 0 placebo, with no statistical difference). Forced expiratory volume in 1 second (FEV1 ) and FEV1 /slow vital capacity changes were similar in the fingolimod and placebo arms. Circulating lymphocytes decreased significantly in the fingolimod arm (P < 0.001). Nine immune-related genes were significantly downregulated in the fingolimod arm, including forkhead box P3 (P < 0.001) and CD40 ligand (P = 0.003). DISCUSSION: Fingolimod is safe and well-tolerated and can reduce circulating lymphocytes in ALS patients. Muscle Nerve 56: 1077-1084, 2017.

KRAS mutations: variable incidences in a Brazilian cohort of 8,234 metastatic colorectal cancer patients.

BACKGROUND: KRAS mutations are frequently found in colorectal cancer (CRC) indicating the importance of its genotyping in the study of the molecular mechanisms behind this disease. Although major advances have occurred over the past decade, there are still important gaps in our understanding of CRC carcinogenesis, particularly whether sex-linked factors play any role. METHODS: The profile of KRAS mutations in the Brazilian population was analyzed by conducting direct sequencing of KRAS codons 12 and 13 belonging to 8,234 metastatic CRC patient samples. DNA was extracted from paraffin-embedded tissue, exon 1 was amplified by PCR and submitted to direct sequencing. The data obtained was analysed comparing different geographical regions, gender and age. RESULTS: The median age was 59 years and the overall percentage of wild-type and mutated KRAS was 62.8% and 31.9%, respectively. Interestingly, different percentages of mutated KRAS patients were observed between male and female patients (32.5% versus 34.8%, respectively; p = 0.03). KRAS Gly12Asp mutation was the most prevalent for both genders and for most regions, with the exception of the North where Gly12Val was the most frequent mutation found. CONCLUSIONS: To the best of our knowledge this is one of the largest cohorts of KRAS genotyping in CRC patients and the largest to indicate a higher incidence of KRAS mutation in females compared to males in Brazil. Nevertheless, further research is required to better address the impact of gender differences in colorectal cancer.

[Factors associated to the length of time on mechanical ventilation in the postoperative period of cardiac surgery]. / Fatores associados ao tempo de ventilação mecânica no pós-operatório de cirurgia cardíaca.

Our objective was to identify factors associated with the duration of mechanical ventilation (MV) postoperative to cardiac surgery and assess the association between duration of endotracheal intubation, length of stay in the Intensive Care Unit (ICU) and hospital. Longitudinal, retrospective study of medical records of 116 adults undergoing cardiac surgery from March 2012 to May 2013. The mean age was 57 +/- 14 years, predominantly male and coronary artery bypass grafting surgery (52.6%). The MV time was 15.25 (7.66 to 23.68) hours. Associated with longer MV was the age (r = 0.5, p < 0.001), comorbidities (r = 0.344, p < 0.001), cardiopulmonary bypass time (r = 0.244, p = 0.008), duration of continuous sedation (r = 0.607, p < 0.001), sedative doses (r = 0.4, p < 0.001), time of vasoconstrictors and vasodilators (r = 0.711, p < 0.001, r = 0.368, p < 0.001), drainage of the 1st time (r = 0.201, p < 0.031), presence of drains (r = 0.445, p < 0.001), postoperative complications (r=0.524, p< 0.001) and hospital stay. Our data confirms that both preoperative, transoperative and postoperative variables prolong the VM and therefore the hospital stay.

Airway opening pressure maneuver to detect airway closure in mechanically ventilated pediatric patients.

Background: Airway closure, which refers to the complete collapse of the airway, has been described under mechanical ventilation during anesthesia and more recently in adult patients with acute respiratory distress syndrome (ARDS). A ventilator maneuver can be used to identify airway closure and measure the pressure required for the airway to reopen, known as the airway opening pressure (AOP). Without that maneuver, AOP is unknown to clinicians. Objective: This study aims to demonstrate the technical adaptation of the adult maneuver for children and illustrate its application in two cases of pediatric ARDS (p-ARDS). Methods: A bench study was performed to adapt the maneuver for 3-50 kg patients. Four maneuvers were performed for each simulated patient, with 1, 2, 3, and 4 s of insufflation time to deliver a tidal volume (Vt) of 6 ml/kg by a continuous flow. Results: Airway closure was simulated, and AOP was visible at 15 cmH2O with a clear inflection point, except for the 3 kg simulated patient. Regarding insufflation time, a 4 s maneuver exhibited a better performance in 30 and 50 kg simulated patients since shorter insufflation times had excessive flowrates (>10 L/min). Below 20 kg, the difference in resistive pressure between a 3 s and a 4 sec maneuver was negligible; therefore, prolonging the maneuver beyond 3 s was not useful. Airway closure was identified in two p-ARDS patients, with the pediatric maneuver being employed in the 28 kg patient. Conclusions: We propose a pediatric AOP maneuver delivering 6 ml/kg of Vt at a continuous low-flow inflation for 3 s for patients weighing up to 20 kg and for 4 s for patients weighing beyond 20 kg.

PERK modulation, with GSK2606414, Sephin1 or salubrinal, failed to produce therapeutic benefits in the SOD1G93A mouse model of ALS.

Amyotrophic lateral sclerosis (ALS) has been linked to overactivity of the protein kinase RNA-like ER kinase (PERK) branch of the unfolded protein response (UPR) pathway, both in ALS patients and mouse models. However, attempts to pharmacologically modulate PERK for therapeutic benefit have yielded inconsistent and often conflicting results. This study sought to address these discrepancies by comprehensively evaluating three commonly used, CNS-penetrant, PERK modulators (GSK2606414, salubrinal, and Sephin1) in the same experimental models, with the goal of assessing the viability of targeting the PERK pathway as a therapeutic strategy for ALS. To achieve this goal, a tunicamycin-challenge assay was developed using wild-type mice to monitor changes in liver UPR gene expression in response to PERK pathway modulation. Subsequently, multiple dosing regimens of each PERK modulator were tested in standardized, well-powered, gender-matched, and litter-matched survival efficacy studies using the SOD1G93A mouse model of ALS. The alpha-2-adrenergic receptor agonist clonidine was also tested to elucidate the results obtained from the Sephin1, and of the previously reported guanabenz studies, by comparing the effects of presence or absence of α-2 agonism. The results revealed that targeting PERK may not be an ideal approach for ALS treatment. Inhibiting PERK with GSK2606414 or activating it with salubrinal did not confer therapeutic benefits. While Sephin1 showed some promising therapeutic effects, it appears that these outcomes were mediated through PERK-independent mechanisms. Clonidine also produced some favorable therapeutic effects, which were unexpected and not linked to the UPR. In conclusion, this study highlights the challenges of pharmacologically targeting PERK for therapeutic purposes in the SOD1G93A mouse model and suggests that exploring other targets within, and outside, the UPR may be more promising avenues for ALS treatment.

Exergames as an Effective Alternative to Real Environmental Tennis Training for Adolescents.

(1) Background: The popularity of motion-sensing computer-based games, like virtual reality (VR) exergames, is increasing among adolescents. However, their efficacy compared to conventional physical training methods remains unclear. This study investigated whether VR exergames produce effects on reaction time (RT) comparable to traditional tennis training in school-aged adolescents. (2) Methods: In total, 130 adolescents (mean age: 15.6 ± 2.0 years; 67 boys: 15.5 ± 2.2 years; 63 girls: 15.7 ± 1.8 years) were recruited in schools and assigned to one of three groups: VR exergame (G1, n = 39), tennis training (G2, n = 25), or control (G3, n = 66). Participants' RTs were evaluated before and after the interventions. G1 engaged in VR exergames for 8 min, G2 underwent traditional tennis training for 30 min, and G3 did not participate in any physical activity. (3) Results: Our results indicated that in G3, girls exhibited slower RTs compared to boys (p < 0.0). No differences were observed in RTs when comparing G1 and G2. (4) Conclusions: Sex appeared to influence RT, with girls showing slower RTs than boys in G3. The findings suggest that VR exergames and traditional tennis training have similar impacts on RT. This indicates the potential of VR exergames as an alternative to conventional physical training for improving RT in adolescents.

Peripheral inflammatory hyperalgesia is exacerbated in rats with metabolic disorders induced by a fructose diet.

This study explored the effects of fructose-induced obesity and metabolic disorders on peripheral inflammatory hyperalgesia, employing quantitative sensory testing with the von Frey test and measuring paw edema to assess inflammatory responses. Wistar rats were administered water or 10% fructose solution ad libitum over a period of 5 weeks. After intraplantar administration of inflammatory agents such as carrageenan (1 mg/paw), lipopolysaccharide (LPS; 100 µg/paw), or prostaglandin E2 (PGE2, 100 ng/paw), we conducted mechanical hyperalgesia tests and paw edema evaluations. The fructose diet resulted in dyslipidemia, elevated insulin and leptin plasma levels, insulin resistance, and increased epididymal and retroperitoneal adiposity compared to control animals. In response to inflammatory agents, the fructose group displayed significantly enhanced peripheral hyperalgesia and more pronounced paw edema. Our results demonstrate that fructose not only contributes to the development of obesity and metabolic disorder but also exacerbates peripheral inflammatory pain responses by enhancing prostaglandin sensitivity.

An Individual Barrier Enclosure Actively Removing Aerosols for Airborne Isolation: A Vacuum Tent.

BACKGROUND: Aerosol barrier enclosure systems have been designed to prevent airborne contamination, but their safety has been questioned. A vacuum tent was designed with active continuous suctioning to minimize risks of aerosol dispersion. We tested its efficacy, risk of rebreathing, and usability on a bench, in healthy volunteers, and in an ergonomic clinical assessment study. METHODS: First, a manikin with airway connected to a breathing simulator was placed inside the vacuum tent to generate active breathing, cough, and CO2 production; high-flow nasal cannula (HFNC) was applied in the manikin's nares. Negative pressure was applied in the vacuum tent's apex port using wall suction. Fluorescent microparticles were aerosolized in the vacuum tent for qualitative assessment. To quantify particles inside and around vacuum tent (aerosol retention), an airtight aerosol chamber with aerosolized latex microparticles was used. The vacuum tent was tested on healthy volunteers breathing with and without HFNC. Last, its usability was assessed in 5 subjects by 5 different anesthesiologists for delivery of full anesthesia, including intubation and extubation. RESULTS: The vacuum tent was adjusted until no leak was visualized using fluorescent particles. The efficacy in retaining microparticles was confirmed quantitatively. CO2 accumulation inside the vacuum tent showed an inverse correlation with the suction flow in all conditions (normal breathing and HFNC 30 or 60 L/min) in bench and healthy volunteers. Particle removal efficacy and safe breathing conditions (CO2, temperature) were reached when suctioning was at least 60 L/min or 20 L/min > HFNC flow. Five subjects were successfully intubated and anesthetized without ergonomic difficulties and with minimal interference with workflow and an excellent overall assessment by the anesthesiologists. CONCLUSIONS: The vacuum tent effectively minimized aerosol dispersion. Its continuous suction system set at a high suction flow was crucial to avoid the spread of aerosol particles and CO2 rebreathing.

Influence of maternal immune activation on autism-like symptoms and coping strategies in male offspring.

Maternal immune activation (MIA) caused by exposure to pathogens or inflammation during critical periods of gestation increased susceptibility to neurodevelopmental disorders, including autism, in the offspring. In the present work, we aimed to provide characterization of the long-term consequences on anxiety-like behavior and cardiovascular stress response of MIA in the offspring. This study aimed to evaluate the effect of MIA by lipopolysaccharide (LPS) in adult male offspring. In our study, the animals were subjected to a range of behavioral and physiological tests, including the elevated plus maze, social interaction, cat odor response, open field behavior, contextual fear conditioning, and cardiovascular responses during restraint stress. In the offspring of MIA, our study unveiled distinct anxious behaviors. This was evident by fewer entries into the open arms of the maze, diminished anti-thigmotaxis in the open field, and a decrease in social interaction time. Moreover, these rats showed heightened sensitivity to cat odor, exhibited prolonged freezing during fear conditioning, and presented elevated 22 Hz ultrasonic vocalizations. Notably, during restraint stress, these animals manifested an augmented blood pressure response, and this was associated with an increase in c-fos expression in the locus coeruleus compared to the control group. These findings collectively underline the extensive behavioral and physiological alterations stemming from MIA. This study deepens our understanding of the significance of maternal health in predisposing offspring to neurobehavioral deficits and psychiatric disorders.

Neuromodulator hydrogen sulfide attenuates sickness behavior induced by lipopolysaccharide.

Sickness behavior reflects a state of altered physiology and central nervous system function that occurs during systemic infection or inflammation, serving as an adaptive response to illness. This study aims to elucidate the role of hydrogen sulfide (H2S) in regulating sickness behavior and neuroinflammatory responses in a rat model of systemic inflammation. Adult male Wistar rats were treated with lipopolysaccharide (LPS) to induce sickness behavior. Intracerebroventricular (i.c.v.) pretreatments included aminooxyacetic acid (AOAA), an inhibitor of H2S synthesis, and sodium sulfide (NaHS), an H2S donor. Behavioral assays were conducted, along with the assessment of astrocyte activation, as indicated by GFAP expression in the hypothalamus. Pretreatment with NaHS mitigated LPS-induced behavioral changes, including hypophagia, social and exploratory deficits, without affecting peripheral cytokine levels, indicating a central modulatory effect. AOAA, conversely, accentuated certain behavioral responses, suggesting a complex role of endogenous H2S in sickness behavior. These findings were reinforced by a lack of effect on plasma interleukin levels but significant reduction in GFAP expression. Our findings support the central role of H2S in modulating neuroinflammation and sickness behavior, highlighting the therapeutic potential of targeting H2S signaling in neuroinflammatory conditions.

Digested galactoglucomannan mitigates oxidative stress in human cells, restores gut bacterial diversity, and provides chemopreventive protection against colon cancer in rats.

Galactoglucomannan (GGM) is the predominant hemicellulose in coniferous trees, such as Norway spruce, and has been used as a multipurpose emulsifier in the food industry. In vitro digestion with a cellular antioxidant activity assay was performed to determine the bioaccessibility and antioxidant activity of phenolic compounds, and the behaviour of GGM on in vivo experimental assay against induced colon cancer. The results showed that digestion decreased the bioaccessibility and antioxidant capacity of phenolic compounds. Cellular analysis did not support these findings once an antioxidant effect was observed in human cell lines. GGM attenuated the initiation and progression of colon cancer, by reducing the foci of aberrant crypts in rats, and modified the intestinal bacterial microbiota (disrupting the balance between Firmicutes and Bacteroidetes phyla). Thus, GGM provided chemopreventive protection against the development of colon cancer and acted as an intracellular antioxidant agent.

Phase 1 study of cetuximab in combination with 5-fluorouracil, cisplatin, and radiotherapy in patients with locally advanced anal canal carcinoma.

BACKGROUND: This study sought to determine the feasibility and recommended phase 2 dose (RP2D) of the combination of cetuximab with chemoradiotherapy based on 5-fluorouracil (5-FU) and cisplatin (CP) in locally advanced anal canal carcinoma. METHODS: Cetuximab was administered on days 1, 8, 15, 29, 36, 43, and 50 (400 mg/m(2) initial dose, then 250 mg/m(2) /week) concurrent with total dose radiation of 55 to 59 Gy, both starting on day 1. Escalating doses of 5-FU (96-hour infusion) and CP (2-hour infusion), both on days 1 and 29, were administered according to the following design: starting dose level (0) 5-FU/CP = 800/60 mg/m(2) /day and up to dose level (+2) 5-FU/CP = 1000/80 mg/m(2) /day. RESULTS: Dose-limiting toxicity (DLT) events (uncontrolled diarrhea or febrile neutropenia) occurred in 3 of 14 assessable patients receiving escalated dose of 5-FU/CP, with 1 in dose level (0) and 2 in dose level (+2). The RP2D was 5-FU/CP = 800/80 mg/m(2) /day. Because of unexpected non-DLT treatment-related grade 3 (G3) adverse events (AEs) such as thrombosis/embolism, syncope, and infection occurring in ≥ 20% of patients, a safety expansion cohort with an additional 9 patients was investigated with the RP2D. The most frequent G3/G4 AEs evaluated in 23 patients were radiation dermatitis (12 patients), diarrhea (10 patients), thrombosis/embolism (6 patients), and infection (5 patients). The study was closed due to these severe AEs, although no G5 AEs occurred. Twenty of 21 patients (95%) achieved pathological complete response at primary tumor. With a median follow-up of 43.4 months, the 3-year locoregional control rate was 64.2%. CONCLUSIONS: Cetuximab could not be integrated with chemoradiotherapy-cisplatin-based therapy due to the high toxicity rate. However, efficacy is encouraging and further investigation of an epidermal growth factor receptor-targeted agent (other than cetuximab) concurrent with chemoradiation should be pursued.

Alternative approach to calculate two-center overlap matrix through deformed exponential function.

In this work, we propose an alternative approach to evaluate two-center overlap integrals. It is computationally more efficient than the standard procedure and is based on the deformed exponential function. In the new procedure, the CPU time to calculate each element of the overlap matrix (Sµ,ν) is constant and independent of the number of Gaussian primitives (NG), whereas in the usual procedure this time increases, formally, with NG2. To evaluate the accuracy of the proposed methodology, we computed different molecular properties such as dipole moments, hardness values, atomic charges, multicenter bond indices, group indices, and some thermodynamic properties. In this work, all calculations were performed using a minimal STO-6G basis set and WTBS and the double-ζ Pople split-valence 6-31G basis set on the Hartree­Fock (HF) and post-HF approximations. The integrals were parametrized for the atoms of the first two rows of the periodic table. All calculations were performed in the general ab initio quantum chemistry package GAMESS, where the integrals were implemented.

Erosive and cariogenicity potential of pediatric drugs: study of physicochemical parameters.

BACKGROUND: Pediatric medications may possess a high erosive potential to dental tissues due to the existence of acid components in their formulations. The purpose was to determine the erosive and cariogenic potential of pediatric oral liquid medications through the analysis of their physicochemical properties in vitro. METHODS: A total of 59 substances were selected from the drug reference list of the National Health Surveillance Agency (ANVISA), which belong to 11 therapeutic classes, as follows: analgesics, non-steroidal anti-inflammatory, corticosteroids, antihistamines, antitussives, bronchodilators, antibacterials, antiparasitics, antiemetics, anticonvulsants and antipsychotics. Measurement of pH was performed by potentiometry, using a digital pH meter. For the Total Titratable Acidity (TTA) chemical assay, a 0.1 N NaOH standard solution was used, which was titrated until drug pH was neutralized. The Total Soluble Solids Contents (TSSC) quantification was carried out by refractometry using Brix scale and the analysis of Total Sugar Content was performed according to Fehling's method. In addition, it was analyzed the information contained in the drug inserts with regard to the presence of sucrose and type of acid and sweetener added to the formulations. RESULTS: All drug classes showed acidic pH, and the lowest mean was found for antipsychotics (2.61 ± 0.08). There was a large variation in the TTA (0.1% - 1.18%) and SST (10.44% - 57.08%) values. High total sugar contents were identified in the antitussives (53.25%) and anticonvulsants (51.75%). As described in the drug inserts, sucrose was added in 47.5% of the formulations, as well as citric acid (39.0%), sodium saccharin (36.4%) and sorbitol (34.8%). CONCLUSION: The drugs analyzed herein showed physicochemical characteristics indicative of a cariogenic and erosive potential on dental tissues. Competent bodies' strategies should be implemented in order to broaden the knowledge of health professionals, drug manufacturers and general consuming public about the risks from the consumption of medicines potentially harmful to dental tissues.

At-home wearables and machine learning sensitively capture disease progression in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis causes degeneration of motor neurons, resulting in progressive muscle weakness and impairment in motor function. Promising drug development efforts have accelerated in amyotrophic lateral sclerosis, but are constrained by a lack of objective, sensitive, and accessible outcome measures. Here we investigate the use of wearable sensors, worn on four limbs at home during natural behavior, to quantify motor function and disease progression in 376 individuals with amyotrophic lateral sclerosis. We use an analysis approach that automatically detects and characterizes submovements from passively collected accelerometer data and produces a machine-learned severity score for each limb that is independent of clinical ratings. We show that this approach produces scores that progress faster than the gold standard Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (-0.86 ± 0.70 SD/year versus -0.73 ± 0.74 SD/year), resulting in smaller clinical trial sample size estimates (N = 76 versus N = 121). This method offers an ecologically valid and scalable measure for potential use in amyotrophic lateral sclerosis trials and clinical care.