Multilevel regression modelling to investigate variation in disease prevalence across locations

In this article, we show how to investigate the role of individual (personal) risk factors in outcome prevalence in multicentre studies with multilevel modelling. The variation in outcome prevalence is modelled by introducing a random intercept. In the next step, the empty model is compared with the model containing the risk factor(s). Because the outcome is dichotomous, this comparison can only be carried out after having rescaled the models’ parameter values to the variance of an underlying continuous variable. We illustrate this approach with data from Phase Two of the International Study of Asthma and Allergies in Childhood (ISAAC) and provide a corresponding Stata do-file

Pattern of paresis in ALS is consistent with the physiology of the corticomotoneuronal projections to different muscle groups

OBJECTIVE: A recent neuroanatomical staging scheme of amyotrophic lateral sclerosis (ALS) indicates that a cortical lesion may spread, as a network disorder, both at the cortical level and via corticofugal tracts, including corticospinal projections providing direct monosynaptic input to α-motoneurons. These projections are involved preferentially and early in ALS. If these findings are clinically relevant, the pattern of paresis in ALS should primarily involve those muscle groups that receive the strongest direct corticomotoneuronal (CM) innervation. METHODS: In a large cohort (N=436), we analysed retrospectively the pattern of muscle paresis in patients with ALS using the UK Medical Research Council (MRC) scoring system; we subsequently carried out two independent prospective studies in two smaller groups (N=92 and N=54). RESULTS: The results indicated that a characteristic pattern of paresis exists. When pairs of muscle groups were compared within patients, the group known to receive the more pronounced CM connections was significantly weaker. Within patients, there was greater relative weakness (lower MRC score) in thumb abductors versus elbow extensors, for hand extensors versus hand flexors and for elbow flexors versus elbow extensors. In the lower limb, knee flexors were relatively weaker than extensors, and plantar extensors were weaker than plantar flexors. CONCLUSIONS: These findings were mostly significant (p<0.01) for all six pairs of muscles tested and provide indirect support for the concept that ALS may specifically affect muscle groups with strong CM connections. This specific pattern could help to refine clinical and electrophysiological ALS diagnostic criteria and complement prospective clinicopathological correlation studies

Dental and Maxillofacial Cone Beam CT-High Number of Incidental Findings and Their Impact on Follow-Up and Therapy Management.

Cone beam computed tomography (CBCT) is increasingly used for dental and maxillofacial imaging. The occurrence of incidental findings has been reported, but clinical implications of these findings remain unclear. The study's aim was to identify the frequency and clinical impact of incidental findings in CBCT. A total of 374 consecutive CBCT examinations of a 3 year period were retrospectively evaluated for the presence, kind, and clinical relevance of incidental findings. In a subgroup of 54 patients, therapeutic consequences of CBCT incidental findings were queried from the referring physicians. A total of 974 incidental findings were detected, involving 78.6% of all CBCT, hence 2.6 incidental findings per CBCT. Of these, 38.6% were classified to require treatment, with an additional 25.2% requiring follow-up. Incidental findings included dental pathologies in 55.3%, pathologies of the paranasal sinuses and airways in 29.2%, osseous pathologies in 14.9% of all CBCT, and findings in the soft tissue or TMJ in few cases. Clinically relevant dental incidental findings were detected significantly more frequently in CBCT for implant planning compared to other indications (60.7% vs. 43.2%, p &lt; 0.01), and in CBCT with an FOV ≥ 100 mm compared to an FOV &lt; 100 mm (54.7% vs. 40.0%, p &lt; 0.01). Similar results were obtained for paranasal incidental findings. In a subgroup analysis, 29 of 54 patients showed incidental findings which were previously unknown, and the findings changed therapeutical management in 19 patients (35%). The results of our study highlighted the importance of a meticulous analysis of the entire FOV of CBCT for incidental findings, which showed clinical relevance in more than one in three patients. Due to a high number of clinically relevant incidental findings especially in CBCT for implant planning, an FOV of 100 × 100 mm covering both the mandible and the maxilla was concluded to be recommendable for this indication

Diffraction-limited ultrabroadband terahertz spectroscopy

Diffraction is the ultimate limit at which details of objects can be resolved in conventional optical spectroscopy and imaging systems. In the THz spectral range, spectroscopy systems increasingly rely on ultra-broadband radiation (extending over more 5 octaves) making a great challenge to reach resolution limited by diffraction. Here, we propose an original easy-to-implement wavefront manipulation concept to achieve ultrabroadband THz spectroscopy system with diffraction-limited resolution. Applying this concept to a large-area photoconductive emitter, we demonstrate diffraction-limited ultra-broadband spectroscopy system up to 14.5 THz with a dynamic range of 103. The strong focusing of ultrabroadband THz radiation provided by our approach is essential for investigating single micrometer-scale objects such as graphene flakes or living cells, and besides for achieving intense ultra-broadband THz electric fields

CFH, C3 and ARMS2 Are Significant Risk Loci for Susceptibility but Not for Disease Progression of Geographic Atrophy Due to AMD

Age-related macular degeneration (AMD) is a prevalent cause of blindness in Western societies. Variants in the genes encoding complement factor H (CFH), complement component 3 (C3) and age-related maculopathy susceptibility 2 (ARMS2) have repeatedly been shown to confer significant risks for AMD; however, their role in disease progression and thus their potential relevance for interventional therapeutic approaches remains unknown. Here, we analyzed association between variants in CFH, C3 and ARMS2 and disease progression of geographic atrophy (GA) due to AMD. A quantitative phenotype of disease progression was computed based on longitudinal observations by fundus autofluorescence imaging. In a subset of 99 cases with pure bilateral GA, variants in CFH (Y402H), C3 (R102G), and ARMS2 (A69S) are associated with disease (P = 1.6x10(-9), 3.2x10(-3), and P = 2.6x10(-12), respectively) when compared to 612 unrelated healthy control individuals. In cases, median progression rate of GA over a mean follow-up period of 3.0 years was 1.61 mm(2)/year with high concordance between fellow eyes. No association between the progression rate and any of the genetic risk variants at the three loci was observed (P>0.13). This study confirms that variants at CFH, C3, and ARMS2 confer significant risks for GA due to AMD. In contrast, our data indicate no association of these variants with disease progression which may have important implications for future treatment strategies. Other, as yet unknown susceptibilities may influence disease progression

Integrated injection seeded terahertz source and amplifier for time-domain spectroscopy.

We used a terahertz (THz) quantum cascade laser (QCL) as an integrated injection seeded source and amplifier for THz time-domain spectroscopy. A THz input pulse is generated inside a QCL by illuminating the laser facet with a near-IR pulse from a femtosecond laser and amplified using gain switching. The THz output from the QCL is found to saturate upon increasing the amplitude of the THz input power, which indicates that the QCL is operating in an injection seeded regime

A Randomized, Double Blind, Placebo-Controlled Trial of Pioglitazone in Combination with Riluzole in Amyotrophic Lateral Sclerosis

BACKGROUND: Pioglitazone, an oral anti-diabetic that stimulates the PPAR-gamma transcription factor, increased survival of mice with amyotrophic lateral sclerosis (ALS). METHODS/PRINCIPAL FINDINGS: We performed a phase II, double blind, multicentre, placebo controlled trial of pioglitazone in ALS patients under riluzole. 219 patients were randomly assigned to receive 45 mg/day of pioglitazone or placebo (one: one allocation ratio). The primary endpoint was survival. Secondary endpoints included incidence of non-invasive ventilation and tracheotomy, and slopes of ALS-FRS, slow vital capacity, and quality of life as assessed using EUROQoL EQ-5D. The study was conducted under a two-stage group sequential test, allowing to stop for futility or superiority after interim analysis. Shortly after interim analysis, 30 patients under pioglitazone and 24 patients under placebo had died. The trial was stopped for futility; the hazard ratio for primary endpoint was 1.21 (95% CI: 0.71-2.07, p = 0.48). Secondary endpoints were not modified by pioglitazone treatment. Pioglitazone was well tolerated. CONCLUSION/SIGNIFICANCE: Pioglitazone has no beneficial effects on the survival of ALS patients as add-on therapy to riluzole. TRIAL REGISTRATION: Clinicaltrials.gov NCT00690118