Population Pharmacokinetics of Oral Migalastat in Adolescents and Adults With and Without Renal Impairment.

Migalastat is approved for the treatment of Fabry disease (FD) with amenable variants. Objectives were to characterize effects of estimated glomerular filtration rate (eGFR) on oral clearance (CL), predict doses in mild to moderate renal impairment and in pediatric patients with FD, and to improve designs of FD studies. A 2-compartment model was fit to data from 260 subjects with/without FD and iteratively refined with evolving data. FD, eGFR, and weight affected CL, while weight and FD affected volume. Optimal sampling theory was used to choose pharmacokinetic sampling times for pediatric studies. Doses in patients with renal impairment and in pediatrics were determined by targeting exposure in adults receiving migalastat 123 mg every other day. A clinical study was conducted in 20 adolescent patients with FD ≥45 kg. eGFR had the largest effect on CL. Simulations showed that exposures in moderate renal impairment were within phase 2-3 exposures; patients aged 2-17 years require weight-based dosing; and predicted exposures in adolescent patients ≥45 kg receiving migalastat 123 mg every other day were similar to adults (data confirmed in a clinical study). Model-informed drug development optimized dosing and design of clinical studies and supported that no dose adjustments were needed in patients with mild to moderate renal impairment or in adolescent patients ≥45 kg.

Perioperative Continuous Positive Airway Pressure Therapy: A Review With the Emphasis on Randomized Controlled Trials and Obstructive Sleep Apnea.

The perioperative use of continuous positive airway pressure (CPAP) therapy has increased substantially in recent years, particularly in relationship to the treatment of patients with known or suspected obstructive sleep apnea (OSA). OSA is common in the surgical population and is reported as an independent risk factor for postoperative complications, intensive care unit admission, and increased length of hospital stay. A large proportion of OSA patients are undiagnosed at the time of surgery and can therefore not be optimized preoperatively. Nowadays, golden standard treatment of moderate to severe OSA is nightly CPAP at home, often with an autotitration mode. Unfortunately, there are only a handful of randomized clinical trials investigating the effect of preoperative and/or postoperative CPAP treatment in OSA patients, so the perioperative guidelines are based on a combination of randomized clinical trials, observational studies, case studies, and expert opinions. In this review, we have summarized the current evidence regarding the use of perioperative CPAP therapy with an emphasis on patients with OSA. We identified 21 randomized, controlled trials that investigated the effect of CPAP on postoperative physiology and complications in surgical patients. Our review reveals evidence, suggesting that CPAP after surgery improves oxygenation and reduces the need for reintubation and mechanical ventilation after surgery. It is also evident that CPAP reduces apnea and hypopnea frequency and related hypoxemia after surgery. Poor adherence to CPAP in the perioperative setting is a limiting factor in assessing its potential to optimize postoperative cardiorespiratory outcomes. Studies of postoperative outcomes in patients who have previously been prescribed CPAP for OSA and are therefore familiar with its use could help to address this shortcoming, but they are unfortunately lacking. This shortcoming should be addressed in future studies. Furthermore, many of the studies of the postoperative effect of CPAP in OSA patents are small, and therefore, single-center studies and larger randomized, controlled multicenter studies are warranted.

Migalastat Tissue Distribution: Extrapolation From Mice to Humans Using Pharmacokinetic Modeling and Comparison With Agalsidase Beta Tissue Distribution in Mice.

Approved therapies for Fabry disease (FD) include migalastat, an oral pharmacological chaperone, and agalsidase beta and agalsidase alfa, 2 forms of enzyme replacement therapy. Broad tissue distribution may be beneficial for clinical efficacy in FD, which has severe manifestations in multiple organs. Here, migalastat and agalsidase beta biodistribution were assessed in mice and modeled using physiologically based pharmacokinetic (PBPK) analysis, and migalastat biodistribution was subsequently extrapolated to humans. In mice, migalastat concentration was highest in kidneys and the small intestine, 2 FD-relevant organs. Agalsidase beta was predominantly sequestered in the liver and spleen (organs unaffected in FD). PBPK modeling predicted that migalastat 123 mg every other day resulted in concentrations exceeding the in vitro half-maximal effective concentration in kidneys, small intestine, skin, heart, and liver in human subjects. However, extrapolation of mouse agalsidase beta concentrations to humans was unsuccessful. In conclusion, migalastat may distribute to tissues that are inaccessible to intravenous agalsidase beta in mice, and extrapolation of mouse migalastat concentrations to humans showed adequate tissue penetration, particularly in FD-relevant organs.

Hypoxic ventilatory response after rocuronium-induced partial neuromuscular blockade in men with obstructive sleep apnoea.

Obstructive sleep apnoea and residual neuromuscular blockade are, independently, known to be risk factors for respiratory complications after major surgery. Residual effects of neuromuscular blocking agents are known to reduce the hypoxic ventilatory response in healthy volunteers. Patients with obstructive sleep apnoea have impaired control of breathing, but it is not known to what extent neuromuscular blocking agents interfere with the regulation of breathing in such patients. In a physiological study in 10 unsedated men with untreated obstructive sleep apnoea, we wished to examine if partial neuromuscular blockade had an effect on hypoxic ventilatory response (isocapnic hypoxia to oxygen saturation of 80%) and hypercapnic ventilatory response (normoxic inspired carbon dioxide 5%). The hypoxic ventilatory response was reduced by 32% (p = 0.016) during residual neuromuscular block (rocuronium to train-of-four ratio 0.7), but the hypercapnic ventilatory response was unaffected. We conclude that neuromuscular blockade specifically depresses peripheral chemosensitivity, and not respiratory muscle function since the hypercapnic ventilatory response was unaffected.

The Role of MRI in Children With Congenital Limb Deficiencies With Associated Scoliosis.

BACKGROUND: The association of scoliosis and congenital limb deficiency has been well described. However, the incidence of neural axis abnormalities in this population is not known. The ability to assess the neural axis by physical examination may be limited in patients with a limb deficiency. Although mobility of the spine is important for all children, it can be especially so in children with a limb deficiency. As spinal fusion in children with limb deficiency potentially has more functional impact, detecting reversible forms of scoliosis seems particularly important. METHODS: Retrospective review of children treated at 1 institution between 1990 and 2017 with both a diagnosis of a congenital limb deficiency, upper or lower, and scoliosis. Children were excluded if they had any neurological difference on history or physical examination, if they had sacral agenesis or spina bifida, or if their limb deficiency was related to trauma or early amniotic rupture sequence. RESULTS: Twenty-four children were identified, 11 with lower extremity deficiency, 14 with upper extremity deficiency with 1 having both. Fifteen children demonstrated neural axis abnormalities, 6 (40%) required neurosurgery. Five (45%) of 11 lower extremity deficiency children had MRI findings, 3 of these needing neurosurgery. Of the 14 upper extremity deficiency children, 10 had MRI changes, and 3 required neurosurgery. Eight children with congenital scoliosis, 5 had MRI findings, with 4 children requiring neurosurgery. The other 16 children had scoliosis without vertebral abnormalities, 10 had MRI findings, and 2 required neurosurgery. CONCLUSIONS: There is a high incidence of neural axis abnormalities (63%) in children with congenital limb deficiencies and scoliosis. A large portion of these require neurosurgical intervention. MRI should be considered soon after presentation in this population of children. LEVEL OF EVIDENCE: Level IV. DESIGN: Retrospective cohort.

Evaluation and use of an anti-cynomolgus monkey CD79b surrogate antibody-drug conjugate to enable clinical development of polatuzumab vedotin.

BACKGROUND AND PURPOSE: Polatuzumab vedotin is an antibody-drug conjugate (ADC) being developed for non-Hodgkin's lymphoma. It contains a humanized anti-CD79b IgG1 monoclonal antibody linked to monomethyl auristatin E (MMAE), an anti-mitotic agent. Polatuzumab vedotin binds to human CD79b only. Therefore, a surrogate ADC that binds to cynomolgus monkey CD79b was used to determine CD79b-mediated pharmacological effects in the monkey and to enable first-in-human clinical trials. EXPERIMENTAL APPROACH: Polatuzumab vedotin, the surrogate ADC, and the corresponding antibodies were evaluated in different assays in vitro and in animals. In vitro assessments included binding to peripheral blood mononuclear cells from different species, binding to a human and monkey CD79b-expressing cell line, binding to human Fcγ receptors, and stability in plasma across species. In vivo, ADCs were assessed for anti-tumour activity in mice, pharmacokinetics/pharmacodynamics in monkeys, and toxicity in rats and monkeys. KEY RESULTS: Polatuzumab vedotin and surrogate ADC bind with similar affinity to human and cynomolgus monkey B cells, respectively. Comparable in vitro plasma stability, in vivo anti-tumour activity, and mouse pharmacokinetics were also observed between the surrogate ADC and polatuzumab vedotin. In monkeys, only the surrogate ADC showed B-cell depletion and B-cell-mediated drug disposition, but both ADCs showed similar MMAE-driven myelotoxicity, as expected. CONCLUSIONS AND IMPLICATIONS: The suitability of the surrogate ADC for evaluation of CD79b-dependent pharmacology was demonstrated, and anti-tumour activity, pharmacokinetics/pharmacodynamics, and toxicity data with both ADCs supported the entry of polatuzumab vedotin into clinical trials.

Regulatory strategies for rare diseases under current global regulatory statutes: a discussion with stakeholders.

Rare or orphan diseases often are inherited and overwhelmingly affect children. Many of these diseases have no treatments, are incurable, and have a devastating impact on patients and their families. Regulatory standards for drug approval for rare diseases must ensure that patients receive safe and efficacious treatments. However, regulatory bodies have shown flexibility in applying these standards to drug development in rare diseases, given the unique challenges that hinder efficient and effective traditional clinical trials, including low patient numbers, limited understanding of disease pathology and progression, variability in disease presentation, and a lack of established endpoints.To take steps toward improving rare disease clinical development strategies under current global regulatory statutes, Amicus Therapeutics, Inc. and BioNJ convened a 1-day meeting that included representatives from the Food and Drug Administration (FDA), biopharmaceutical industry, and not-for-profit agencies. The meeting focused on orphan diseases in pediatric and adult patients and was intended to identify potential strategies to overcome regulatory hurdles through open collaboration.During this meeting, several strategies were identified to minimize the limitations associated with low patient numbers in rare diseases, including the use of natural history to generate historical control data in comparisons, simulations, and identifying inclusion/exclusion criteria and appropriate endpoints. Novel approaches to clinical trial design were discussed to minimize patient exposure to placebo and to reduce the numbers of patients and clinical trials needed for providing substantial evidence. Novel statistical analysis approaches were also discussed to address the inherent challenges of small patient numbers. Areas of urgent unmet need were identified, including the need to develop registries that protect patient identities, to establish close collaboration and communication between the sponsor and regulatory bodies to address methodological and statistical challenges, to collaborate in pre-competitive opportunities within multiple sponsors and in conjunction with academia and disease-specific patient advocacy groups for optimal data sharing, and to develop harmonized guidelines for data extrapolation from source to target pediatric populations. Ultimately, these innovations will help in solving many regulatory challenges in rare disease drug development and encourage the availability of new treatments for patients with rare diseases.

Duvoglustat HCl Increases Systemic and Tissue Exposure of Active Acid α-Glucosidase in Pompe Patients Co-administered with Alglucosidase α.

Duvoglustat HCl (AT2220, 1-deoxynojirimycin) is an investigational pharmacological chaperone for the treatment of acid α-glucosidase (GAA) deficiency, which leads to the lysosomal storage disorder Pompe disease, which is characterized by progressive accumulation of lysosomal glycogen primarily in heart and skeletal muscles. The current standard of care is enzyme replacement therapy with recombinant human GAA (alglucosidase alfa [AA], Genzyme). Based on preclinical data, oral co-administration of duvoglustat HCl with AA increases exposure of active levels in plasma and skeletal muscles, leading to greater substrate reduction in muscle. This phase 2a study consisted of an open-label, fixed-treatment sequence that evaluated the effect of single oral doses of 50 mg, 100 mg, 250 mg, or 600 mg duvoglustat HCl on the pharmacokinetics and tissue levels of intravenously infused AA (20 mg/kg) in Pompe patients. AA alone resulted in increases in total GAA activity and protein in plasma compared to baseline. Following co-administration with duvoglustat HCl, total GAA activity and protein in plasma were further increased 1.2- to 2.8-fold compared to AA alone in all 25 Pompe patients; importantly, muscle GAA activity was increased for all co-administration treatments from day 3 biopsy specimens. No duvoglustat-related adverse events or drug-related tolerability issues were identified.

Clinical markers of asthma and IgE assessed in parents before conception predict asthma and hayfever in the offspring.

BACKGROUND: Mice models suggest epigenetic inheritance induced by parental allergic disease activity. However, we know little of how parental disease activity before conception influences offspring's asthma and allergy in humans. OBJECTIVE: We aimed to assess the associations of parental asthma severity, bronchial hyperresponsiveness (BHR), and total and specific IgEs, measured before conception vs. after birth, with offspring asthma and hayfever. METHODS: The study included 4293 participants (mean age 34, 47% men) from the European Community Respiratory Health Survey (ECRHS) with information on asthma symptom severity, BHR, total and specific IgEs from 1991 to 1993, and data on 9100 offspring born 1972-2012. Adjusted relative risk ratios (aRRR) for associations of parental clinical outcome with offspring allergic disease were estimated with multinomial logistic regressions. RESULTS: Offspring asthma with hayfever was more strongly associated with parental BHR and specific IgE measured before conception than after birth [BHR: aRRR = 2.96 (95% CI: 1.92, 4.57) and 1.40 (1.03, 1.91), respectively; specific IgEs: 3.08 (2.13, 4.45) and 1.83 (1.45, 2.31), respectively]. This was confirmed in a sensitivity analysis of a subgroup of offspring aged 11-22 years with information on parental disease activity both before and after birth. CONCLUSION & CLINICAL RELEVANCE: Parental BHR and specific IgE were associated with offspring asthma and hayfever, with the strongest associations observed with clinical assessment before conception as compared to after birth of the child. If the hypothesis is confirmed in other studies, parental disease activity assessed before conception may prove useful for identifying children at risk for developing asthma with hayfever.

Anti-CD22 and anti-CD79b antibody-drug conjugates preferentially target proliferating B cells.

BACKGROUND AND PURPOSE: CD22 and CD79b are cell-surface receptors expressed on B-cell-derived malignancies such as non-Hodgkin's lymphoma (NHL). An anti-mitotic agent, monomethyl auristatin E, was conjugated to anti-CD22 and anti-CD79b antibodies to develop target-specific therapies for NHL. The mechanism of action (MOA) and pharmacological and pharmacokinetic (PK) profiles of these antibody-drug conjugates (ADCs) were investigated in cynomolgus monkeys. EXPERIMENTAL APPROACH: Animals were administered anti-CD22 or anti-CD79b ADCs, respective unconjugated antibodies or vehicle. Pharmacodynamic effects on total and proliferating B cells and serum PK were then assessed. Antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) of the ADCs were evaluated in vitro. KEY RESULTS: Depletion of B cells was observed after administration of either ADC or the respective unconjugated antibodies. An extended duration of depletion was observed in animals administered ADCs. Similarly, preferential depletion of proliferating B cells in blood and germinal centre B cells in spleen were only observed in animals administered ADCs. Serum PK profiles of ADCs and respective unconjugated antibodies were comparable. In vitro, anti-human CD22 and anti-human CD79b antibodies showed no or only moderate ADCC activity, respectively; neither antibody had CDC activity. CONCLUSIONS AND IMPLICATIONS: The findings support the proposed MOA: initial depletion of total B cells by antibody-mediated opsonization, followed by preferential, sustained depletion of proliferating B cells by the auristatin conjugate due to its anti-mitotic action. Delivering potent anti-mitotic agents to B cells via the specificity of monoclonal antibodies provides a means to eliminate pathogenic B cells in NHL with improved risk-benefit profiles over traditional chemotherapeutics.

The Aftermath of the Fukushima Daiichi Accident: a Perspective from the British Embassy in Tokyo.

The British Embassy in Tokyo was at the heart of providing information in the immediate aftermath of the Fukushima Daiichi accident. Richard Oppenheim, who was present at the time, and Keith Franklin, who joined the Embassy shortly afterwards, give their perspectives on communicating information on radiation to the public and what lessons can be learned. Richard Oppenheim was head of the Climate Change and Energy team at the British Embassy in Tokyo from 2011 to 2015 and part of the Embassy team responding to the crisis. He travelled to Sendai on 12 March 2011. Keith Franklin has been on secondment to the British Embassy in Tokyo from the National Nuclear Laboratory since the accident at Fukushima Daiichi.

Construction and experimental validation of a simple, compact, resealable, and reliable Vycor(®) superleak assembly for use at low temperatures.

A new method of constructing a superleak assembly for use in experiments involving (4)He or (3)He-(4)He mixtures at very low temperatures is described. Superleaks are made of a porous medium with very small pores and channels. Superleaks are often incorporated in thermomechanical pumps, superfluid magnetic pumps, dilution refrigerators, and superfluid helium transfer systems. We used several cylindrical pieces of Vycor, a permeable glass with average pore diameter of 40 Å and porosity of 28%, as a candidate to be used in our superleak assembly. Our design is simple and compact. Our superleak assembly can be disassembled and easily reassembled for reuse. We successfully tested and validated this device at temperatures between 1.4 K and 2.7 K. We experienced no superfluid leaks into the surrounding vacuum. We also report that thermal cycling caused no performance degradation. It is our goal to share the design and construction techniques of this new superleak assembly.

Oral Migalastat HCl Leads to Greater Systemic Exposure and Tissue Levels of Active α-Galactosidase A in Fabry Patients when Co-Administered with Infused Agalsidase.

UNLABELLED: Migalastat HCl (AT1001, 1-Deoxygalactonojirimycin) is an investigational pharmacological chaperone for the treatment of α-galactosidase A (α-Gal A) deficiency, which leads to Fabry disease, an X-linked, lysosomal storage disorder. The currently approved, biologics-based therapy for Fabry disease is enzyme replacement therapy (ERT) with either agalsidase alfa (Replagal) or agalsidase beta (Fabrazyme). Based on preclinical data, migalastat HCl in combination with agalsidase is expected to result in the pharmacokinetic (PK) enhancement of agalsidase in plasma by increasing the systemic exposure of active agalsidase, thereby leading to increased cellular levels in disease-relevant tissues. This Phase 2a study design consisted of an open-label, fixed-treatment sequence that evaluated the effects of single oral doses of 150 mg or 450 mg migalastat HCl on the PK and tissue levels of intravenously infused agalsidase (0.2, 0.5, or 1.0 mg/kg) in male Fabry patients. As expected, intravenous administration of agalsidase alone resulted in increased α-Gal A activity in plasma, skin, and peripheral blood mononuclear cells (PBMCs) compared to baseline. Following co-administration of migalastat HCl and agalsidase, α-Gal A activity in plasma was further significantly increased 1.2- to 5.1-fold compared to agalsidase administration alone, in 22 of 23 patients (95.6%). Importantly, similar increases in skin and PBMC α-Gal A activity were seen following co-administration of migalastat HCl and agalsidase. The effects were not related to the administered migalastat HCl dose, as the 150 mg dose of migalastat HCl increased α-Gal A activity to the same extent as the 450 mg dose. Conversely, agalsidase had no effect on the plasma PK of migalastat. No migalastat HCl-related adverse events or drug-related tolerability issues were identified. TRIAL REGISTRATION: ClinicalTrials.gov NCT01196871.

An open-label study to determine the pharmacokinetics and safety of migalastat HCl in subjects with impaired renal function and healthy subjects with normal renal function.

OBJECTIVES: Renal function may progressively decline in patients with Fabry disease. This study assessed pharmacokinetics, safety, and tolerability of a single oral dose of migalastat HCl 150 mg in subjects with normal or mildly, moderately, or severely impaired renal function. METHODS: Volunteers were enrolled into two cohorts stratified for renal function calculated using the Cockcroft-Gault equation for creatinine clearance. Pharmacokinetic parameters determined were: area under the concentration-time curve (AUC) from time zero to the last measurable concentration postdose (AUC0-t ) and extrapolated to infinity (AUC0-∞ ), maximum observed concentration (Cmax ), time to Cmax (tmax ), concentration at 48 hours postdose (C48h ), terminal elimination half-life (t1/2 ), oral clearance (CL/F), and apparent terminal elimination rate constant (λz) (ClinicalTrials.gov registration: NCT01730469). RESULTS: Thirty-two subjects enrolled and completed the study (Cohort 1: n = 24; Cohort 2: n = 8). Migalastat clearance decreased with increasing renal impairment, resulting in increases in migalastat HCl plasma t1/2 , AUC0-∞ , and C48h compared with subjects with normal renal function. Incidence of adverse events was comparable across all renal function groups. CONCLUSIONS: Plasma migalastat clearance decreased as degree of renal impairment increased. Data from the migalastat HCl clinical program will guide dosing and intervals for patients with Fabry disease with renal impairment.

Relative bioavailability and the effect of meal type and timing on the pharmacokinetics of migalastat in healthy volunteers.

Migalastat HCl is an investigational, pharmacological chaperone for mutant α-galactosidase A, which is responsible for Fabry disease, an X-linked, lysosomal storage disorder. Two Phase I studies evaluated relative bioavailability, effect of meal type and timing on pharmacokinetics, safety, and tolerability of migalastat HCl in healthy volunteers. Study 1 (N = 15, 19-55 years): single 100-mg doses of migalastat HCl capsule and solution formulations were bioequivalent. The ratios of LSM (90% CIs) for Cmax were 97.1% (86.8-109) and AUC0-inf 97.9% (88.8-108) under fasted conditions. Single 100-mg doses of migalastat HCl capsules administered with a high-fat meal decreased Cmax by 40% and AUC0-inf by 37%. A high-fat meal delayed tmax by approximately 1 hour. Study 2 (N = 20, 18-65 years): A high-fat or light meal up to 1 hour before or after administration of single 150 mg doses of migalastat HCl capsules decreased Cmax and AUC0-inf up to 40%, but had no apparent effect on tmax (range of medians with food: 1.5-3 hours, median fasted: 3 hours). A 50-g glucose drink co-administered with migalastat HCL did not result in clinically significant changes in migalastat absorption. No serious safety or tolerability issues were identified.

Stool submission data to help inform population-level incidence rates of enteric disease in a Canadian community.

Laboratory-based surveillance data is essential for monitoring trends in the incidence of enteric disease. Current Canadian human enteric surveillance systems report only confirmed cases of human enteric disease and are often unable to capture the number of negative test results. Data from 9116 hospital stool specimens from the Waterloo Region in Canada, with a mixed urban and rural population of about 500 000 were analysed to investigate the use of stool submission data and its role in reporting bias when determining the incidence of enteric disease. The proportion of stool specimens positive for Campylobacter spp. was highest in the 15-29 years age group, and in the 5-14 years age group for Salmonella spp. and E. coli O157:H7. By contrast, the age-specific incidence rates were highest for all three pathogens in the 0-4 years age group which also had the highest stool submission rate. This suggests that variations in age-specific stool submission rates are influencing current interpretation of surveillance data.

Complications of high-energy bicondylar tibial plateau fractures treated with dual plating through 2 incisions.

OBJECTIVES: To characterize the rate of complications after operative fixation of bicondylar (OTA/AO 41-C) tibial plateau fractures and to evaluate the contribution of common risk factors. DESIGN: Retrospective review. SETTING: Level 1 regional trauma center. PATIENTS/PARTICIPANTS: One hundred thirty-eight patients older than 18 years with 140 bicondylar tibial plateau fractures were participated in this study. INTERVENTION: Open reduction and internal fixation using medial and lateral plate construct through 2 incisions. MAIN OUTCOME MEASUREMENTS: Development of a deep infection or a nonunion. RESULTS: The overall major complication rate was 27.9%: 23.6% deep infection and 10.0% nonunion. Open fractures were associated with a higher rate of infection: 43.8% versus 21.0% for closed injuries (odds ratio = 2.96, P = 0.05). Fasciotomy closure before definitive fixation was associated with significantly fewer deep infections compared with internal fixation with open fasciotomy wounds: 11.8% versus 50.0% (odds ratio = 7.5, P = 0.05). The presence of compartment syndrome, tobacco use, diabetes, and timing of surgery had no statistically significant association on the rate of infection or nonunion. CONCLUSIONS: Nonunion and deep infections occur commonly after staged open reduction and internal fixation of high-energy tibial plateau fractures. Open fractures and open fasciotomy wounds at the time of internal fixation are associated with higher rates of infection. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Effect of an elastic girdle on lung function, intra-abdominal pressure, and pain after midline laparotomy: a randomized controlled trial.

PURPOSE: Girdles and abdominal binders may reduce pain and stabilize the abdominal wall after laparotomy, but a risk for increased intra-abdominal pressure and decreased lung function is also hypothesized. The aim of this study was to investigate the effect of an abdominal girdle after midline laparotomy in a randomized controlled trial. METHODS: Twenty-three patients undergoing laparotomy were randomized to wear an elastic girdle postoperatively and 25 were randomized to no girdle. Pulmonary function was evaluated with; forced vital capacity (FVC), forced expiratory volume during one second (FEV1), peak expiratory flow (PEF), and cough PEF. Pain was recorded using a visual analog scale (VAS). All patients completed the ventral hernia pain questionnaire (VHPQ) before surgery and at the end of the study. Intra-abdominal pressure was measured via an indwelling urinary catheter. Wound healing was assessed from photographs. RESULTS: FVC, FEV1, PEF, and cough PEF were reduced by about 30 % after surgery, but there were no differences between patients with or without a girdle (ANOVA). Intra-abdominal pressure and wound healing were the same in both groups. Pain was significantly lower on day 5 in the girdle group (p = 0.004). CONCLUSIONS: An individually fitted elastic girdle used after midline laparotomy was found to be safe, as this did not affect lung function, coughing, intra-abdominal pressure, or wound healing. The immediate decline in lung function after surgery is restrictive and due to anesthesia and the surgical procedure. Pain was significantly decreased in the girdle group. The study is registered at ClinicalTrials.gov, number NCT01517217.

Impact of plant shoot architecture on leaf cooling: a coupled heat and mass transfer model.

Plants display a range of striking architectural adaptations when grown at elevated temperatures. In the model plant Arabidopsis thaliana, these include elongation of petioles, and increased petiole and leaf angles from the soil surface. The potential physiological significance of these architectural changes remains speculative. We address this issue computationally by formulating a mathematical model and performing numerical simulations, testing the hypothesis that elongated and elevated plant configurations may reflect a leaf-cooling strategy. This sets in place a new basic model of plant water use and interaction with the surrounding air, which couples heat and mass transfer within a plant to water vapour diffusion in the air, using a transpiration term that depends on saturation, temperature and vapour concentration. A two-dimensional, multi-petiole shoot geometry is considered, with added leaf-blade shape detail. Our simulations show that increased petiole length and angle generally result in enhanced transpiration rates and reduced leaf temperatures in well-watered conditions. Furthermore, our computations also reveal plant configurations for which elongation may result in decreased transpiration rate owing to decreased leaf liquid saturation. We offer further qualitative and quantitative insights into the role of architectural parameters as key determinants of leaf-cooling capacity.