Maternal and perinatal health research during emerging and ongoing epidemic threats: a landscape analysis and expert consultation.

INTRODUCTION: Pregnant women and their offspring are often at increased direct and indirect risks of adverse outcomes during epidemics and pandemics. A coordinated research response is paramount to ensure that this group is offered at least the same level of disease prevention, diagnosis, and care as the general population. We conducted a landscape analysis and held expert consultations to identify research efforts relevant to pregnant women affected by disease outbreaks, highlight gaps and challenges, and propose solutions to addressing them in a coordinated manner. METHODS: Literature searches were conducted from 1 January 2015 to 22 March 2022 using Web of Science, Google Scholar and PubMed augmented by key informant interviews. Findings were reviewed and Quid analysis was performed to identify clusters and connectors across research networks followed by two expert consultations. These formed the basis for the development of an operational framework for maternal and perinatal research during epidemics. RESULTS: Ninety-four relevant research efforts were identified. Although well suited to generating epidemiological data, the entire infrastructure to support a robust research response remains insufficient, particularly for use of medical products in pregnancy. Limitations in global governance, coordination, funding and data-gathering systems have slowed down research responses. CONCLUSION: Leveraging current research efforts while engaging multinational and regional networks may be the most effective way to scale up maternal and perinatal research preparedness and response. The findings of this landscape analysis and proposed operational framework will pave the way for developing a roadmap to guide coordination efforts, facilitate collaboration and ultimately promote rapid access to countermeasures and clinical care for pregnant women and their offspring in future epidemics.

Audience segmentation of New Zealand cat owners: Understanding the barriers and drivers of cat containment behavior.

Free-roaming companion cats have a detrimental impact on the environment and are at risk of harm. Despite these negative impacts, it is the norm in New Zealand (NZ) to allow companion cats to roam freely and only a minority of cat owners practice cat containment. This study firstly sought to identify what factors act as barriers and drivers of NZ owners' participation in cat containment, and secondly whether NZ owners could be segmented into unique audiences based on the factors predicting their cat containment behavior. It was hypothesized that cat owners with greater capability, opportunity, and motivation to perform cat containment would have greater cat containment intentions and behavior. Furthermore, it was expected that at least three segments of cat owners would exist in NZ which differed significantly in the set of capability, opportunity and motivational factors predicting their cat containment behavior. A quantitative online cross-sectional survey of 395 NZ cat owners was conducted, measuring containment intentions and behavior, and capability, opportunity, and motivation to perform cat containment. Results from bivariate correlations and multiple regression demonstrated that capability, opportunity, and motivational factors predicted increased cat containment intentions and behavior. Latent profile analysis identified four distinct segments of cat owners with unique COM profiles; engaged (6%), receptive (17%), ambivalent (48%), and opposed (30%). Validation analysis demonstrated that these groups all differed significantly in their cat containment intentions and behaviors. From these findings theoretically grounded behavior change interventions can be developed to target the causes of non-participation in cat containment for each of the identified cat owner segments, thereby improving the management of free-roaming cats in NZ.

Fitting high-resolution electron density maps from atomic models to solution scattering data.

Solution scattering techniques, such as small- and wide-angle X-ray scattering (SWAXS), provide valuable insights into the structure and dynamics of biological macromolecules in solution. In this study, we present an approach to accurately predict solution X-ray scattering profiles at wide angles from atomic models by generating high-resolution electron density maps. Our method accounts for the excluded volume of bulk solvent by calculating unique adjusted atomic volumes directly from the atomic coordinates. This approach eliminates the need for one of the free fitting parameters commonly used in existing algorithms, resulting in improved accuracy of the calculated SWAXS profile. An implicit model of the hydration shell is generated that uses the form factor of water. Two parameters, namely the bulk solvent density and the mean hydration shell contrast, are adjusted to best fit the data. Results using eight publicly available SWAXS profiles show high-quality fits to the data. In each case, the optimized parameter values show small adjustments demonstrating that the default values are close to the true solution. Disabling parameter optimization produces significantly more accurate predicted scattering profiles compared to the leading software. The algorithm is computationally efficient, comparable to the leading software and up to 10 times faster for large molecules. The algorithm is encoded in a command line script called denss.pdb2mrc.py and is available open source as part of the DENSS v1.7.0 software package. In addition to improving the ability to compare atomic models to experimental SWAXS data, these developments pave the way for increasing the accuracy of modeling algorithms using SWAXS data and decreasing the risk of overfitting.

Fitting high-resolution electron density maps from atomic models to solution scattering data.

Solution scattering techniques, such as small and wide-angle X-ray scattering (SWAXS), provide valuable insights into the structure and dynamics of biological macromolecules in solution. In this study, we present an approach to accurately predict solution X-ray scattering profiles at wide angles from atomic models by generating high-resolution electron density maps. Our method accounts for the excluded volume of bulk solvent by calculating unique adjusted atomic volumes directly from the atomic coordinates. This approach eliminates the need for a free fitting parameter commonly used in existing algorithms, resulting in improved accuracy of the calculated SWAXS profile. An implicit model of the hydration shell is generated which uses the form factor of water. Two parameters, namely the bulk solvent density and the mean hydration shell contrast, are adjusted to best fit the data. Results using eight publicly available SWAXS profiles show high quality fits to the data. In each case, the optimized parameter values show small adjustments demonstrating that the default values are close to the true solution. Disabling parameter optimization results in a significant improvement of the calculated scattering profiles compared to the leading software. The algorithm is computationally efficient, showing more than tenfold reduction in execution time compared to the leading software. The algorithm is encoded in a command line script called denss.pdb2mrc.py and is available open source as part of the DENSS v1.7.0 software package (https://github.com/tdgrant1/denss). In addition to improving the ability to compare atomic models to experimental SWAXS data, these developments pave the way for increasing the accuracy of modeling algorithms utilizing SWAXS data while decreasing the risk of overfitting.

KDM1A inhibition increases UVA toxicity and enhances photodynamic therapy efficacy.

BACKGROUND: Lysine-specific histone demethylase 1 (KDM1A/LSD1) regulates multiple cellular functions, including cellular proliferation, differentiation, and DNA repair. KDM1A is overexpressed in squamous cell carcinoma of the skin and inhibition of KDM1A can suppress cutaneous carcinogenesis. Despite the role of KDM1A in skin and DNA repair, the effect of KDM1A inhibition on cellular ultraviolet (UV) response has not been studied. METHODS: The ability of KDM1A inhibitor bizine to modify cell death after UVA and UVB exposure was tested in normal human keratinocytes and melanocytes, HaCaT, and FaDu cell lines. KDM1A was also downregulated using shRNA and inhibited by phenelzine in HaCaT and FaDu cells to confirm the role of KDM1A in UVA response. In addition, cellular reactive oxygen species (ROS) changes were assessed by a lipid-soluble fluorescent indicator of lipid oxidation, and ROS-related gene regulation using qPCR. During photodynamic therapy (PDT) studies HaCaT and FaDu cells were treated with aminolaevulinic acid (5-ALA) or HPPH (2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a) sodium and irradiated with 0-8 J/cm2 red LED light. RESULTS: KDM1A inhibition sensitized cells to UVA radiation-induced cell death but not to UVB. KDM1A inhibition increased ROS generation as detected by increased lipid peroxidation and the upregulation of ROS-responsive genes. The effectiveness of both ALA and HPPH PDT significantly improved in vitro in HaCaT and FaDu cells after KDM1A inhibition. CONCLUSION: KDM1A is a regulator of cellular UV response and KDM1A inhibition can improve PDT efficacy.

In Vivo Models for Studying Interstitial Photodynamic Therapy of Locally Advanced Cancer.

Interstitial photodynamic therapy (I-PDT) is a promising therapy considered for patients with locally advanced cancer. In I-PDT, laser fibers are inserted into the tumor for effective illumination and activation of the photosensitizer in a large tumor. The intratumoral light irradiance and fluence are critical parameters that affect the response to I-PDT. In vivo animal models are required to conduct light dose studies, to define optimal irradiance and fluence for I-PDT. Here we describe two animal models with locally advanced tumors that can be used to evaluate the response to I-PDT. One model is the C3H mouse bearing large subcutaneous SCCVII carcinoma (400-600 mm3). Using this murine model, multiple light regimens with one or two optical fibers with cylindrical diffuser ends (cylindrical diffuser fiber, CDF) can be used to study tumor response to I-PDT. However, tissue heating may occur when 630 nm therapeutic light is delivered through CDF at an intensity ≥60 mW/cm and energy ≥100 J/cm. These thermal effects can impact tumor response while treating locally advanced mice tumors. Magnetic resonance imaging and thermometry can be used to study these thermal effects. A larger animal model, New Zealand White rabbit with VX2 carcinoma (~5000 mm3) implanted in either the sternomastoid (neck implantation model) or the biceps femoris muscle (thigh implantation model), can be used to study I-PDT with image-based pretreatment planning using computed tomography. In the VX2 model, the light delivery can include the use of multiple laser fibers to test light dosimetry and delivery that are relevant for clinical use of I-PDT.

TLD1433-Mediated Photodynamic Therapy with an Optical Surface Applicator in the Treatment of Lung Cancer Cells In Vitro.

Intra-operative photodynamic therapy (IO-PDT) in combination with surgery for the treatment of non-small cell lung cancer and malignant pleural mesothelioma has shown promise in improving overall survival in patients. Here, we developed a PDT platform consisting of a ruthenium-based photosensitizer (TLD1433) activated by an optical surface applicator (OSA) for the management of residual disease. Human lung adenocarcinoma (A549) cell viability was assessed after treatment with TLD1433-mediated PDT illuminated with either 532- or 630-nm light with a micro-lens laser fiber. This TLD1433-mediated PDT induced an EC50 of 1.98 µM (J/cm2) and 4807 µM (J/cm2) for green and red light, respectively. Cells were then treated with 10 µM TLD1433 in a 96-well plate with the OSA using two 2-cm radial diffusers, each transmitted 532 nm light at 50 mW/cm for 278 s. Monte Carlo simulations of the surface light propagation from the OSA computed light fluence (J/cm2) and irradiance (mW/cm2) distribution. In regions where 100% loss in cell viability was measured, the simulations suggest that >20 J/cm2 of 532 nm was delivered. Our studies indicate that TLD1433-mediated PDT with the OSA and light simulations have the potential to become a platform for treatment planning for IO-PDT.

An Optical Surface Applicator for Intraoperative Photodynamic Therapy.

BACKGROUND AND OBJECTIVES: Intraoperative photodynamic therapy (IO-PDT) is typically administered by a handheld light source. This can result in uncontrolled distribution of light irradiance that impacts tissue and tumor response to photodynamic therapy. The objective of this work was to characterize a novel optical surface applicator (OSA) designed to administer controlled light irradiance in IO-PDT. STUDY DESIGN/MATERIALS AND METHODS: An OSA was constructed from a flexible silicone mesh applicator with multiple cylindrically diffusing optical fibers (CDF) placed into channels of the silicone. Light irradiance distribution, at 665 nm, was evaluated on the OSA surface and after passage through solid tissue-mimicking optical phantoms by measurements from a multi-channel dosimetry system. As a proof of concept, the light administration of the OSA was tested in a pilot study by conducting a feasibility and performance test with 665-nm laser light to activate 2-(1'-hexyloxyethyl) pyropheophorbide-a (HPPH) in the thoracic cavity of adult swine. RESULTS: At the OSA surface, the irradiance distribution was non-uniform, ranging from 128 to 346 mW/cm2 . However, in the tissue-mimicking phantoms, beam uniformity improved markedly, with irradiance ranges of 39-153, 33-87, and 12-28 mW/cm2 measured at phantom thicknesses of 3, 5, and 10 mm, respectively. The OSA safely delivered the prescribed light dose to the thoracic cavities of four swine. CONCLUSIONS: The OSA can provide predictable light irradiances for administering a well-defined and potentially effective therapeutic light in IO-PDT. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.

Case report of oxalate nephropathy in a patient with pancreatic metastases from renal carcinoma.

BACKGROUND: Patients with metastatic renal carcinoma frequently have pre-existing renal impairment and not infrequently develop worsening renal function as a complication of their treatment. The presence of pancreatic metastases in patients with metastatic renal carcinoma, often confers a more favourable prognosis and as a consequence this patient group may be exposed to such treatments for more prolonged periods of time. However, the development of renal failure may also be a consequence of the cancer itself rather than its treatment. CASE PRESENTATION: We present an 84-year-old patient receiving the tyrosine kinase inhibitor (TKI) pazopanib for metastatic renal carcinoma who developed oxalate nephropathy as a consequence of pancreatic exocrine insufficiency resulting from pancreatic metastases. CONCLUSIONS: This case demonstrates the importance of investigating unexpected toxicities and highlights the potential consequences of pancreatic insufficiency and its sequelae in patients with pancreatic metastases.

Performance Characteristics of Photoacoustic Imaging Probes with Varying Frequencies and Light-delivery Schemes.

Photoacoustic imaging (PAI) is an emerging biomedical imaging technique that utilizes a combination of light and ultrasound to detect photoabsorbers embedded within tissues. While the clinical utility of PAI has been widely explored for several applications, limitations in light penetration and detector sensitivity have restricted these studies to mostly superficial sites. Given the importance of PA signal generation and detection on light delivery and ultrasound detector frequency, there is an ongoing effort to optimize these parameters to enhance photoabsorber detection at increased depths. With this in mind, in this study we examined performance benchmarks of a commercially available PAI/ultrasound linear array system when using different imaging frequencies and light delivery schemes. A modified light fiber jacket providing focused light delivery (FLD) at the center of the probe was compared with the built-in fiber optics lining the length of the probe. Studies were performed in vitro to compare performance characteristics such as imaging resolution, maximum imaging depth, and sensitivity to varying hematocrit concentration for each frequency and light delivery method. Monte Carlo simulations of each light delivery method revealed increased light penetration with FLD. In tissue-mimicking phantoms, vascular channels used to simulate blood vessels could be visualized at a depth of 2.4 cm when lowering imaging frequency and utilizing FLD. Imaging at lower frequencies with FLD also enabled enhanced detection of varying hematocrit concentration levels at increased depths, although lateral imaging resolution was reduced. Finally, a proof of concept in vivo probe comparison study in a mouse tumor model provided supportive evidence of our in vitro results. Collectively, our findings show that adjusting imaging frequency and applying FLD can be a straightforward approach for improving PAI performance.

The Gulfwatch contaminants monitoring program in the Gulf of Maine: Are its data being used for ocean protection, with special reference to Nova Scotia, Canada?

The Gulfwatch Contaminants Monitoring Program is part of the Canada-US, Gulf of Maine Council on the Marine Environment (GOMC). Programs monitoring legacy toxic substances, i.e., chemical contaminants, such as Gulfwatch, collect and analyse environmental samples (e.g., blue mussels), interpret the data, and report on chemical levels and trends (spatial and temporal) in coastal waters. This study explored the extent to which its extensive information (data, reports, papers) has been used broadly and by Nova Scotia, a GOMC member. A mixed-methods study was conducted, using quantitative and qualitative metrics. Citations to some Gulfwatch papers and analysis of use of the Gulfwatch website showed that its data and information were accessed, mostly by government departments. However, interviews revealed that the departments were not using the data to inform Nova Scotia provincial coastal policy or practices. Recommendations are presented to improve the visibility and use of information provided by long-term, environmental monitoring programs.

Temporal validation of a simplified blastocyst grading system.

We have recently established the clinical effectiveness and credibility of a simplified blastocyst grading system by demonstrating its prognostic potential and the inter- and intra-observer variability associated with it. To be considered clinically useful, however, the grading system also needs to be accurate (i.e. well calibrated with good discriminative ability). This study prospectively evaluates the performance of the grading system on subsequent patients from the same IVF unit in an attempt to temporally validate the model. All day 5 single embryo transfers between 1st July 2012 and 30th June 2014 were included in the study. The observed implantation, clinical pregnancy and live birth rates according to grade of embryo transferred were compared to the expected rates as predicted by the development data set and the statistical significance of any differences between the two were calculated using the Chi-square test. A total of 435 single embryo transfers were included. For each grade of embryo transferred, there was generally no significant difference between the observed and expected frequencies of implantation, clinical pregnancy and live birth suggesting that the simplified blastocyst grading system is accurate and temporal validation has been satisfactorily demonstrated. It is now necessary to externally validate the grading system to prove generality before further dissemination.

A clinically useful simplified blastocyst grading system.

The aim of this study was to investigate whether a new simplified blastocyst grading system (A: fully expanded, clear inner cell mass, cohesive trophectoderm; B: not yet expanded, clear inner cell mass, cohesive trophectoderm; C: small inner cell mass ± irregular trophectoderm ± excluded/degenerate cells) was clinically useful. All day-5 single embryo transfers between 15 June 2009 and 29 June 2012 were reviewed. Implantation, clinical pregnancy and live birth rates were related to embryo quality. Five embryologists were asked to grade and decide the clinical fate of 80 images of day-5 embryos on two occasions 4-6 weeks apart. Implantation, clinical pregnancy and live birth rates decreased with deteriorating embryo quality. A highly significant (P < 0.01) difference was observed between the groups. Inter-observer agreement was substantial for grade allocation (K = 0.63) and clinical decision-making (K = 0.66). Intra-observer agreement ranged from substantial (K = 0.71) to almost perfect (K = 0.88) for grade allocation, and was almost perfect for clinical fate determination (K ≥ 0.84). This grading system is quick and easy to use, effectively predicts IVF outcome and has levels of agreement similar to, if not better than, those associated with more complex grading systems.

The impact of chronic cough: a cross-sectional European survey.

PURPOSE: Studies that investigate the impact of chronic cough have largely focused on patients attending secondary care. Our aim was to investigate the opinions of the wider general population across Europe. METHODS: An internet survey was made available in 12 languages on the European Lung Foundation website, between January 2012 and April 2013. RESULTS: Of 1120 respondents from 29 different European countries, 67 % were female, mean age 51 years (SD 15), median cough duration 2-5 years. The majority of respondents reported cough impacted their quality of life, mood and ability to undertake activities. Despite 72 % of respondents having visited their doctor ≥3 times, only 53 % had received a diagnosis. Asthma was the most common diagnosis (23 %). Most respondents reported limited or no effectiveness of medications. 88 % of respondents reported that they would like more information to be available on chronic cough. CONCLUSIONS: Chronic cough has a negative impact on quality of life. Further work is needed to raise awareness, promote management strategies, develop effective treatments and consider the educational and support needs of patients with chronic cough.

Massive surgical emphysema secondary to iatrogenic tracheal laceration.

A 78-year-old woman was admitted for a revision total hip replacement following a failed dynamic hip screw placed emergently 4 months earlier. Anaesthetic management consisted of general anaesthesia with endotracheal intubation and femoral nerve block. The patient's perioperative course was unremarkable except for a promptly recognised and corrected oesophageal intubation and a short period of breathing against a closed adjustable pressure limiting valve. In recovery, following a period of hypotension resistant to fluid therapy, she suddenly desaturated, developed severe facial and upper thoracic subcutaneous emphysema and type 2 respiratory failure. She was diagnosed with bilateral pneumothoraces, pneumomediastinum, pneumopericardium and surgical emphysema. This was treated emergently with supplemental oxygen and bilateral chest drains. A CT scan demonstrated a tracheal laceration, which was managed conservatively in the critical care unit. The patient had a tracheostomy on day 5 to treat an on-going air leak and later made a full recovery.

Nonpharmacological interventions for refractory chronic cough patients: systematic review.

BACKGROUND: For people with refractory chronic cough, nonpharmacological interventions are emerging as alternatives to antitussive medications. These treatments generally are delivered by physiotherapists and speech and language therapists and consist of education, breathing exercises, cough suppression techniques, and counselling. Although the number of studies investigating these treatment options has increased in recent years there has not been a systematic review of the efficacy of these treatment options. METHODS: Studies were searched for in EMBASE, AMED, Medline, CINAHL, and PsycINFO databases. Bibliographies of studies and reviews were searched by hand. Critical appraisal was carried out by one reviewer using the SIGN appraisal tools and Cochrane handbook for systematic reviews. RESULTS: From a total of 184 studies, 5 full-text English language articles were included in the review. Nonpharmacological interventions were found to significantly reduce cough reflex sensitivity, improve quality of life, and lead to reductions in cough severity and frequency. However, few studies used validated and reliable tools to measure cough severity and frequency thereby limiting the robustness of these findings. CONCLUSION: Present data support the use of two to four sessions of education, cough suppression techniques, breathing exercises, and counselling in order to achieve improvements in cough sensitivity and cough-related quality of life for people with chronic refractory cough. Due to the lack of validated outcome measures, results for other aspects of cough should be interpreted with caution. There is a need for additional larger-powered comparative studies investigating nonpharmacological interventions for refractory chronic cough.