Influence of temperature on the calcium sensitivity of the myofilaments of skinned ventricular muscle from the rabbit.

The steady-state myofilament Ca sensitivity was determined in skinned cardiac trabeculae from the rabbit right ventricle (diameter, 0.13-0.34 mm) at 36, 29, 22, 15, 8, and 1 degree C. Muscles were stimulated to 0.5 Hz and stretched to a length at which maximum twitch tension was generated. The preparation was then skinned with 1% vol/vol Triton X-100 in a relaxing medium (10 mM EGTA, pCa 9.0). Each preparation was exposed to a series of Ca-containing solutions (pCa 6.3-4.0) at two of the six temperatures studied (temperature was regulated to +/- 0.1 degree C). The pCa values (mean +/- SD, n = 6) corresponding to half maximal tension at 36, 29, 22, 15, 8, and 1 degree C were 5.47 +/- 0.07, 5.49 +/- 0.07, 5.34 +/- 0.05, 5.26 +/- 0.09, 4.93 +/- 0.06, and 4.73 +/- 0.04, respectively. Mean (+/- SD) maximum tension (Cmax) developed by the preparation as a percentage of that at 22 degrees C was 118 +/- 10, 108 +/- 5, 74 +/- 6, 57 +/- 7, and 29 +/- 5% at 36, 29, 15, 8, and 1 degree C, respectively. As cooling led to a shift of Ca sensitivity towards higher [Ca2+] and a reduction of Cmax, the Ca sensitivity curves over this range of temperatures do not cross over as has been described for canine Purkinje fibers (Fabiato 1985). Since tension is decreased by cooling at all levels of [Ca2+] it is unlikely that changes in myofilament Ca sensitivity play a role in the large hypothermic inotropy seen in rabbit ventricular muscle. The increase in sensitivity of the myofilaments to Ca on warming from 1 to 29 degrees C might be related to the increase in force seen on rewarming from a rapid cooling contracture in intact rabbit ventricular muscle

Formal Analysis of Linear Control Systems using Theorem Proving

Control systems are an integral part of almost every engineering and physical system and thus their accurate analysis is of utmost importance. Traditionally, control systems are analyzed using paper-and-pencil proof and computer simulation methods, however, both of these methods cannot provide accurate analysis due to their inherent limitations. Model checking has been widely used to analyze control systems but the continuous nature of their environment and physical components cannot be truly captured by a state-transition system in this technique. To overcome these limitations, we propose to use higher-order-logic theorem proving for analyzing linear control systems based on a formalized theory of the Laplace transform method. For this purpose, we have formalized the foundations of linear control system analysis in higher-order logic so that a linear control system can be readily modeled and analyzed. The paper presents a new formalization of the Laplace transform and the formal verification of its properties that are frequently used in the transfer function based analysis to judge the frequency response, gain margin and phase margin, and stability of a linear control system. We also formalize the active realizations of various controllers, like Proportional-Integral-Derivative (PID), Proportional-Integral (PI), Proportional-Derivative (PD), and various active and passive compensators, like lead, lag and lag-lead. For illustration, we present a formal analysis of an unmanned free-swimming submersible vehicle using the HOL Light theorem prover.Comment: International Conference on Formal Engineering Method

Establishing a children’s orthopaedic hospital for Malawi: A review after 10 years

BackgroundBEIT CURE International Hospital (BCIH) opened in 2002 providingorthopaedic surgical services to children in Malawi. This study reviews thehospital’s progress 10 years after establishment of operational services. Inaddition we assess the impact of the hospital’s Malawi national clubfootprogramme (MNCP) and influence on orthopaedic training.MethodsAll operative paediatric procedures performed by BCIH services in the10th operative year were included. Data on clubfoot clinic locations andnumber of patients treated were obtained from the MNCP. BCIH recordswere reviewed to identify the number of healthcare professionals whohave received training at the BCIH.Results609 new patients were operated on in the 10th year of hospital service.Patients were treated from all regions; however 60% came fromSouthern regions compared with the 48% in the 5th year. Clubfoot,burn contracture and angular lower limb deformities were the three mostcommon pathologies treated surgically. In total BCIH managed 9,842patients surgically over a 10-year period. BCIH helped to establish andco-ordinate the MNCP since 2007. At present the program has a totalof 29 clinics, which have treated 5748 patients. Furthermore, BCIH hasoverseen the full or partial training of 5 orthopaedic surgeons and 82orthopaedic clinical officers in Malawi.ConclusionThe BCIH has improved the care of paediatric patients in a country thatprior to its establishment had no dedicated paediatric orthopaedic service,treating almost 10,000 patients surgically and 6,000 patients in the MNCP.This service has remained consistent over a 10-year period despite times of global austerity. Whilst the type of training placement offered at BCIH has changed in the last 10 years, the priority placed on training has remained paramount. The strategic impact of long-term training  commitments are now being realised, in particular by the addition of Orthopaedic surgeons serving the nation

Stereotactic Body Radiation Therapy Reirradiation for Locally Recurrent Rectal Cancer: Outcomes and Toxicity

PURPOSE: Stereotactic body radiation therapy (SBRT) has emerged as a potential therapeutic option for locally recurrent rectal cancer (LRRC) but contemporaneous clinical data are limited. We aimed to evaluate the local control, toxicity, and survival outcomes in a cohort of patients previously treated with neoadjuvant pelvic radiation therapy for nonmetastatic locally recurrent rectal cancer, now treated with SBRT. METHODS AND MATERIALS: Inoperable rectal cancer patients with ≤3 sites of pelvic recurrence and >6 months since prior pelvic radiation therapy were identified from a prospective registry over 4 years. SBRT dose was 30 Gy in 5 fractions, daily or alternate days, using cumulative organ at risk dose constraints. Primary outcome was local control (LC). Secondary outcomes were progression free survival, overall survival, toxicity, and patient reported quality of life scores using the EQ visual analog scale (EQ-VAS) tool. RESULTS: Thirty patients (35 targets) were included. Median gross tumor volume size was 14.3 cm3. In addition, 27 of 30 (90%) previously received 45 to 50.4 Gy in 25 of 28 fractions, with 10% receiving an alternative prescription. All patients received the planned reirradiation SBRT dose. The median follow-up was 24.5 months (interquartile range, 17.8-28.8). The 1-year LC was 84.9% (95% confidence interval [CI], 70.6-99) and a 2-year LC was 69% (95% CI, 51.8-91.9). The median progression free survival was 12.1 months (95% CI, 8.6-17.66), and median overall survival was 28.3 months (95% CI, 17.88-39.5 months). No patient experienced >G2 acute toxicity and only 1 patient experienced late G3 toxicity. Patient-reported QoL outcomes were improved at 3 months after SBRT (Δ EQ-VAS, +10 points, Wilcoxon signed-rank, P = .009). CONCLUSIONS: Thirty patients (35 targets) were included. Median gross tumor volume size was 14.3 cm3. In addition, 27 of 30 (90%) previously received 45 to 50.4 Gy in 25 of 28 fractions, with 10% receiving an alternative prescription. All patients received the planned reirradiation SBRT dose. The median follow-up was 24.5 months (interquartile range, 17.8-28.8). The 1-year LC was 84.9% (95% confidence interval [CI], 70.6-99) and a 2-year LC was 69% (95% CI, 51.8-91.9). The median progression free survival was 12.1 months (95% CI, 8.6-17.66), and median overall survival was 28.3 months (95% CI, 17.88-39.5 months). No patient experienced >G2 acute toxicity and only 1 patient experienced late G3 toxicity. Patient-reported QoL outcomes were improved at 3 months after SBRT (Δ EQ-VAS, +10 points, Wilcoxon signed-rank, P = .009)

A Chromosome 7 Pericentric Inversion Defined at Single-Nucleotide Resolution Using Diagnostic Whole Genome Sequencing in a Patient with Hand-Foot-Genital Syndrome.

Next generation sequencing methodologies are facilitating the rapid characterisation of novel structural variants at nucleotide resolution. These approaches are particularly applicable to variants initially identified using alternative molecular methods. We report a child born with bilateral postaxial syndactyly of the feet and bilateral fifth finger clinodactyly. This was presumed to be an autosomal recessive syndrome, due to the family history of consanguinity. Karyotype analysis revealed a homozygous pericentric inversion of chromosome 7 (46,XX,inv(7)(p15q21)x2) which was confirmed to be heterozygous in both unaffected parents. Since the resolution of the karyotype was insufficient to identify any putatively causative gene, we undertook medium-coverage whole genome sequencing using paired-end reads, in order to elucidate the molecular breakpoints. In a two-step analysis, we first narrowed down the region by identifying discordant read-pairs, and then determined the precise molecular breakpoint by analysing the mapping locations of "soft-clipped" breakpoint-spanning reads. PCR and Sanger sequencing confirmed the identified breakpoints, both of which were located in intergenic regions. Significantly, the 7p15 breakpoint was located 523 kb upstream of HOXA13, the locus for hand-foot-genital syndrome. By inference from studies of HOXA locus control in the mouse, we suggest that the inversion has delocalised a HOXA13 enhancer to produce the phenotype observed in our patient. This study demonstrates how modern genetic diagnostic approach can characterise structural variants at nucleotide resolution and provide potential insights into functional regulation

The Filter Detection Task for measurement of breathing-related interoception and metacognition

The study of the brain’s processing of sensory inputs from within the body (‘interoception’) has been gaining rapid popularity in neuroscience, where interoceptive disturbances are thought to exist across a wide range of chronic physiological and psychological conditions. Here we present a task and analysis procedure to quantify specific dimensions of breathing-related interoception, including interoceptive sensitivity, decision bias, metacognitive bias, and metacognitive performance. Two major developments address some of the challenges presented by low trial numbers in interoceptive experiments: (i) a novel adaptive algorithm to maintain task performance at 70–75% accuracy; (ii) an extended hierarchical metacognitive model to estimate regression parameters linking metacognitive performance to relevant (e.g. clinical) variables. We demonstrate the utility of the task and analysis developments, using both simulated data and three empirical datasets. This methodology represents an important step towards accurately quantifying interoceptive dimensions from a simple experimental procedure that is compatible with clinical settings

Superior outcomes of nodal metastases compared to visceral sites in oligometastatic colorectal cancer treated with stereotactic ablative radiotherapy

BACKGROUND: Stereotactic ablative radiotherapy (SBRT) is a radical option for oligometastatic colorectal cancer (CRC) patients, but most data relate to visceral metastases. METHODS: A prospective, multi-centre database of CRC patients treated with SBRT was interrogated. Inclusion criteria were ECOG PS 0-2, ≤ 3 sites of disease, a disease free interval of > 6 months unless synchronous liver metastases. Primary endpoints were local control (LC), progression free survival (PFS) and overall survival (OS). RESULTS: 163 patients (172 metastases) were analysed. The median FU was 16 months (IQR 12.2 - 22.85). The LC at 1 year was 83.8% (CI 76.4% - 91.9%) with a PFS of 55% (CI 47% - 64.7%) respectively. LC at 1 year was 90% (CI 83% - 99%) for nodal metastases (NM), 75% (63% - 90%) for visceral metastases (VM). NM had improved median PFS (9 vs 19 months) [HR 0.6, CI 0.38 - 0.94, p = 0.032] and median OS (32 months vs not reached) [HR 0.28, CI 0.18 - 0.7, p = 0.0062] than VM, regardless of whether the NM were located inside or outside the pelvis. On multivariate analysis, NM and ECOG PS 0 were significant good prognostic factors. An exploratory analysis suggests KRAS WT is also a good prognostic factor. CONCLUSION: Nodal site is an important prognostic determinant of SBRT that should incorporated into patient selection. We hypothesise this may have an immunoediting basis

Complete Genome Sequence of a Novel Avian Paramyxovirus (APMV-13) Isolated from a Wild Bird in Kazakhstan.

A novel avian paramyxovirus was identified during annual viral surveillance of wild bird populations in Kazakhstan in 2013. The virus was isolated from a white fronted goose (Anser albifrons) in northern Kazakhstan. Here, we report the complete genome sequence of the isolate, which we suggest should constitute a novel serotype