Efficacy of botulinum toxin injection before pneumatic dilatation in patients with idiopathic achalasia

Graded pneumatic dilatation (PD) is an appropriate long-term therapy and botulinum toxin injection (BT) is a relatively short-term therapy in idiopathic achalasia. Their combination has not been previously scrutinized. This study aimed to evaluate the role of BT in enhancing the efficacy of PD with 30 mm balloons. Patients who underwent PD with 30 mm balloons after botulinum toxin injections and a group of age- and sex-matched controls who were treated only with PD were enrolled in the study. Symptom scores were taken before, 1 month after and then every 3 months after PD. There were no significant differences between the two groups in gender, duration or severity of symptoms. One of the 12 patients in the case group relapsed 30 months after PD but the others were in remission for an average of 25.6 months. In the control group, all the patients relapsed after a mean of 12.6 months and needed a 35-mm PD. The cumulative remission rate was significantly higher in the case group compared with the control group (P < 0.01). The mean symptom score decreased by 76% in the case group (P < 0.001) and 53% in the controls (P < 0.01) at the end of the first month. Neither age, sex, nor duration or severity of symptoms were predictive of patients' responses to treatment. It seems that BT may be a meaningful enhancing factor in long-term efficacy of PD. PD with a 30 mm balloon after a BT session may resolve the need for the future higher grade PD.     

Low back pain education and short term quality of life: a randomized trial

Background  

Different interventions can reduce the burden of the chronic low back pain. One example is the use of a 'Back School Programme'. This is a brief therapy that uses a health education method to empower participants through a procedure of assessment, education and skill development. This study aimed to evaluate to what extent the programme could improve quality of life in those who suffer from the condition.     

Molecular dynamics simulation on the low sensitivity of mutants of NEDD-8 activating enzyme for MLN4924 inhibitor as a cancer drug

MLN4924 is an experimental cancer drug known as inhibitor of NEDD8-activating enzyme (NAE). This anti-tumor candidate is a selective small-molecule inhibitor of NAE which is conjugated to cullin protein on Cullin-RING ligases (CRLs). This covalent modification actives cullin complex to recruit an ubiquitin-charged E2 and leads to downstream target protein polyubiquitination and proteasomal degradation. MLN4924, which can form a covalent adduct with NEDD8, and block NAE at the first step in this pathway, has shown anti-tumor activity in many kinds of cancer cell lines and also xenograft models, including lung cancer, colon cancer, melanoma and lymphoma. The anti-tumor activity of MLN4924 results from inactivation of CLRs, which causes DNA re-replication and inhibition of nuclear factor (NF)-κB signaling, thus leading to cancer cell death. A mutation can reduce the enzyme’s sensitivity to MLN4924. Verma et al. in 2013 studied on molecular dynamics simulation of a mutant A171T and consequently found out that this mutation reduce MLN4924 interaction with DNA Binding site of enzyme as a result of reduction of enzyme affinity to ATP. One year later, in 2014, Wei Xu et al. carried out a research on inhibitor resistant cell lines and revealed that a couple of mutations so called Y352H and I310N leads to enzyme resistance to MLN4924 inhibitor, interestingly, the cause reported was the increase of enzyme affinity to ATP. As in Wei Xu et al. experiment the molecular dynamics simulation was not considered, present study is conducted to identify enzyme mutation mechanism by molecular dynamics approach using advantages of Gromacs software version 4.5.6.     

GWAS with longitudinal phenotypes: performance of approximate procedures

Analysis of genome-wide association studies with longitudinal data using standard procedures, such as linear mixed model (LMM) fitting, leads to discouragingly long computation times. There is a need to speed up the computations significantly. In our previous work (Sikorska et al: Fast linear mixed model computations for genome-wide association studies with longitudinal data. Stat Med 2012; 32.1: 165–180), we proposed the conditional two-step (CTS) approach as a fast method providing an approximation to the P-value for the longitudinal single-nucleotide polymorphism (SNP) effect. In the first step a reduced conditional LMM is fit, omitting all the SNP terms. In the second step, the estimated random slopes are regressed on SNPs. The CTS has been applied to the bone mineral density data from the Rotterdam Study and proved to work very well even in unbalanced situations. In another article (Sikorska et al: GWAS on your notebook: fast semi-parallel linear and logistic regression for genome-wide association studies. BMC Bioinformatics 2013; 14: 166), we suggested semi-parallel computations, greatly speeding up fitting many linear regressions. Combining CTS with fast linear regression reduces the computation time from several weeks to a few minutes on a single computer. Here, we explore further the properties of the CTS both analytically and by simulations. We investigate the performance of our proposal in comparison with a related but different approach, the two-step procedure. It is analytically shown that for the balanced case, under mild assumptions, the P-value provided by the CTS is the same as from the LMM. For unbalanced data and in realistic situations, simulations show that the CTS method does not inflate the type I error rate and implies only a minimal loss of power.     

Readiness to change for interprofessional collaboration in healthcare: Development and validation of a theory-based instrument

This paper presents a study that aimed to develop and validate a theory-based instrument for the assessment of readiness to change for interprofessional collaboration in healthcare (IPC-TTM). The instrument was developed in the Persian language and tested in the Iranian context. Healthcare professionals from medical and nursing professions participated in the assessment of validity and reliability of the instrument. We conducted this psychometric study in two phases: First, the questionnaire was developed based on the transtheoretical model (TTM) through literature review and expert panel. Then, in the validation phase, we held three modified Delphi rounds to assess the content and face validity of the questionnaire. We used confirmatory factor analysis (CFA) to evaluate the fit of the questionnaire as applied to modified TTM. Reliability of the final instrument was tested by assessing the test-retest reliability of instrument items with Kappa coefficient. We also calculated the intraclass correlation coefficient (ICC) and Cronbach’s alpha to assess the test-retest reliability and internal consistency of the instrument sub-scales. The initial item pool consisted of 30 items and three sub-scales (Attitude, Intention, and Action). The content validity of the questionnaire was confirmed with 17 items. Based on the CFA results two additional items were deleted to increase the fit of the model. The final instrument was confirmed with 15 items and three sub-scales. Reliability assessment on the 15-item instrument showed an acceptable test-retest reliability of the instrument items. ICC values for the Attitude, Intention, and Action sub-scales of the instrument were calculated as 0.82, 0.73, and 0.71, respectively. Moreover, Cronbach’s alpha for the Attitude, Intention, and Action sub-scales were 0.85, 0.73, and 0.77, respectively. This study offers a new theory-based instrument to measure readiness to change for interprofessional collaboration in healthcare in the Iranian context. The questionnaire can be used for ‘needs assessment’ in developing tailored educational interventions and self-assessments in interprofessional education studies.     

Erdafitinib for the treatment of metastatic bladder cancer

ABSTRACT

Introduction: Since the approval of immune checkpoint inhibitors (ICIs), there has been continuing and significant progress in urothelial cancer (UC) treatment. However, only about one fifth of UC patients respond to ICI. Recently, erdafitinib was developed for treating locally advanced or metastatic UC (mUC) with FGFR3 or FGFR2 alterations, accounting for 15–20% of patients. Erdafitinib is the first targeted therapy ever approved for mUC.

Areas covered: This review summarizes the preclinical and clinical data on erdafitinib for UC. PubMed search and relevant articles presented at international conferences were used for the literature search.

Expert opinion: The FDA approval of erdafitinib provided a new treatment option for FGFR-altered UC progressing on platinum-based chemotherapy. It is not clear whether FGFR inhibitor is a preferred second-line treatment choice to ICI. Compared to ICI, erdafitinib has a better response rate in patients with visceral metastases. However, a shorter duration of response and toxicity profile of erdafitinib, particularly ocular toxicity, is an important consideration. Regular eye exams are recommended by the FDA. Tumor profiling during upfront therapy may help identify those who benefit at the time of progression. In summary, a high unmet need remains for new drugs in chemotherapy- and ICI-refractory UC.     

Respiratory Flow–Sound Relationship During Both Wakefulness and Sleep and Its Variation in Relation to Sleep Apnea

Tracheal respiratory sound analysis is a simple and non-invasive way to study the pathophysiology of the upper airway and has recently been used for acoustic estimation of respiratory flow and sleep apnea diagnosis. However in none of the previous studies was the respiratory flow–sound relationship studied in people with obstructive sleep apnea (OSA), nor during sleep. In this study, we recorded tracheal sound, respiratory flow, and head position from eight non-OSA and 10 OSA individuals during sleep and wakefulness. We compared the flow–sound relationship and variations in model parameters from wakefulness to sleep within and between the two groups. The results show that during both wakefulness and sleep, flow–sound relationship follows a power law but with different parameters. Furthermore, the variations in model parameters may be representative of the OSA pathology. The other objective of this study was to examine the accuracy of respiratory flow estimation algorithms during sleep: we investigated two approaches for calibrating the model parameters using the known data recorded during either wakefulness or sleep. The results show that the acoustical respiratory flow estimation parameters change from wakefulness to sleep. Therefore, if the model is calibrated using wakefulness data, although the estimated respiratory flow follows the relative variations of the real flow, the quantitative flow estimation error would be high during sleep. On the other hand, when the calibration parameters are extracted from tracheal sound and respiratory flow recordings during sleep, the respiratory flow estimation error is less than 10%.