Risk characterization of N-nitrosodimethylamine in pharmaceuticals.

Since 2018, N-nitrosodimethylamine (NDMA) has been a reported contaminant in numerous pharmaceutical products. To guide the pharmaceutical industry, FDA identified an acceptable intake (AI) of 96 ng/day NDMA. The approach assumed a linear extrapolation from the Carcinogenic Potency Database (CPDB) harmonic-mean TD50 identified in chronic studies in rats. Although NDMA has been thought to act as a mutagenic carcinogen in experimental animals, it has not been classified as a known human carcinogen by any regulatory agency. Humans are exposed to high daily exogenous and endogenous doses of NDMA. Due to the likelihood of a threshold dose for NDMA-related tumors in animals, we believe that there is ample scientific basis to utilize the threshold-based benchmark dose or point-of-departure (POD) approach when estimating a Permissible Daily Exposure limit (PDE) for NDMA. We estimated that 29,000 ng/kg/day was an appropriate POD for calculating a PDE. Assuming an average bodyweight of 50 kg, we expect that human exposures to NDMA at doses below 5800 ng/day in pharmaceuticals would not result in an increased risk of liver cancer, and that there is little, if any, risk for any other type of cancer, when accounting for the mode-of-action in humans.

Symptomatic unilateral idiopathic giant bullous emphysema : a case report.

BACKGROUND: Idiopathic Giant Bullous Emphysema (or Vanishing Lung Syndrome) is a rare condition which is usually associated with male gender, active smoking and underlying emphysematous disease. We present an unusual case of a giant bulla occurring in the absence of these risk factors. CASE PRESENTATION: A 54-year-old woman presented to the respiratory outpatient clinic with gradually worsening left sided chest discomfort, which was most marked during a recent flight. She had no significant dyspnoea or other symptoms. She had a remote 5-pack-year smoking history. Chest X-Ray revealed a large hyperlucent area in the left upper lobe. CT Thorax found this to be an isolated bulla occupying more than one-third of the hemithorax. The remaining lung parenchyma was normal. A diagnosis of Idiopathic Giant Bullous Emphysema was made. The patient was referred for VATS (Video-assisted thoracoscopic surgery) bullectomy which was carried out without complication. Her symptoms resolved completely following the operation. CONCLUSIONS: This is an unusual case of a solitary giant bulla occurring without major risk factors or underlying lung disease. VATS bullectomy was shown to be an effective therapeutic option, allowing re-expansion of compressed lung tissue and complete resolution of symptoms.

UK 2022 Consensus on Normal Tissue Dose-Volume Constraints for Oligometastatic, Primary Lung and Hepatocellular Carcinoma Stereotactic Ablative Radiotherapy.

The use of stereotactic ablative radiotherapy (SABR) in the UK has expanded over the past decade, in part as the result of several UK clinical trials and a recent NHS England Commissioning through Evaluation programme. A UK SABR Consortium consensus for normal tissue constraints for SABR was published in 2017, based on the existing literature at the time. The published literature regarding SABR has increased in volume over the past 5 years and multiple UK centres are currently working to develop new SABR services. A review and update of the previous consensus is therefore appropriate and timely. It is hoped that this document will provide a useful resource to facilitate safe and consistent SABR practice.

Complications of an uncovered metallic tracheal stent managed by veno-venous extracorporeal membrane oxygenation: a case report.

Airway stents are primarily inserted for the management of airway obstruction associated with an inoperable malignancy and are rarely indicated in benign disease. We outline the complications associated with tracheal stents and describe the use of veno-venous extracorporeal membrane oxygenation (V-V ECMO) to facilitate open tracheal surgery in an apnoeic patient who had an uncovered metallic tracheal stent left in place for an inappropriately long period. Computerised tomography imaging of the neck and thorax provided information for operative planning and described of the stent in addition to the extensive granulation tissue at the distal end of the stent. Veno-venous extracorporeal membrane oxygenation was used to facilitate open tracheal surgery, removal of the tracheal stent and formation of a surgical tracheostomy. Prolonged use of an uncovered metallic airway stent in younger patients with benign disease may lead to the stent being difficult to remove. There may be an accumulation of granulation tissue with the risk of airway obstruction.

Endobronchial valve use in COVID-19 related pneumothorax and persistent air leak.

Pneumothoraces may occur rarely in coronavirus (COVID-19) patients, often resulting from a combination of fibrotic parenchymal changes and prolonged high-pressure ventilation. Very few studies have been published describing the management of pneumothorax in the novel COVID-19 pneumonia patients. Although chest drain insertion represents the first line of treatment, a persistent pneumothorax and air leak requiring intervention could be managed by a thoracoscopic procedure or, as is the case here, by endobronchial valve insertion. Endobronchial valve insertion is a minimally invasive technique that provides a treatment option in patients with severe parenchymal COVID-19 related lung disease. As far as the authors are aware this is the first report of the use of endobronchial valves in a COVID-19 patient.

Inter-Observer Variability in Target Volume Delineations of Benign and Metastatic Brain Tumours for Stereotactic Radiosurgery: Results of a National Quality Assurance Programme.

AIMS: To quantify inter-observer variation between all the intracranial stereotactic radiosurgery (SRS) providers in England in delineating the target volumes of four brain tumour cases. MATERIALS AND METHODS: Twenty-two, cross-platform SRS providers in England were instructed during a national commissioning assessment to contour the gross tumour volume (GTV) of six brain metastases, one cavernous sinus meningioma, one vestibular schwannoma and one pituitary adenoma. An expert reference group provided feedback if submitted contours were considered to be outliers and those centres were instructed to resubmit their contours. All contours were analysed in Python. The target volume contour (observed volume; VOBS), encompassing volume, 50% agreement volume (AV50), 100% agreement volume (AV100), concordance index (CCI) and discordance index (DCI) were calculated. RESULTS: Twenty-one centres participated using five different treatment platforms (CyberKnife, Gamma Knife, Varian Linac, Elekta Linac, Tomotherapy) and seven different treatment planning systems (GammaPlan, iPlan, Multiplan, Pinnacle, Eclipse, CMS Focal). The greatest variability was observed in the smallest brain metastases (GTV5 AV50 0.0 cm3, CCI 0.28-0.84, DCI 0.00-0.70) and pituitary case (AV50 1.1 cm3, CCI 0.42-0.82, DCI 0.01-0.40). The greatest agreement was observed with the vestibular schwannoma (AV50 2.8 cm3, CCI 0.77-0.94, DCI 0.00-0.17). There were four resubmissions for the cavernous sinus meningioma and three resubmissions for the pituitary adenoma. CONCLUSIONS: Inter-observer variability was most evident with the smallest brain metastases and pituitary case. Several additional outliers and one acceptable contour were suggested using the metric-based analysis of AV50, CCI and DCI. Comparing contours using these metrics is an effective way to identify whether individual contours are similar to the 'true' target and to flag potentially significant deviations.

Provision of Organ at Risk Contouring Guidance in UK Radiotherapy Clinical Trials.

AIMS: Accurate delineation of organs at risk (OAR) is vital to the radiotherapy planning process. Inaccuracies in OAR delineation arising from imprecise anatomical definitions may affect plan optimisation and risk inappropriate dose delivery to normal tissues. The aim of this study was to review the provision of OAR contouring guidance in National Institute of Health Research Clinical Research Network (NIHR CRN) portfolio clinical trials. MATERIALS AND METHODS: The National Radiotherapy Quality Trials Assurance (RTTQA) Group carried out a two-round Delphi assessment to determine which OAR descriptions provided optimal guidance. RESULTS: Eighty-four clinical trials involving radiotherapy quality assurance were identified as either in recruitment or in setup within the NIHR CRN portfolio. Fifty-nine trials mandated OAR contouring. In total there were 412 OAR; 171 were uniquely named; 159 OAR had more than one name associated with a single structure, with the greatest nomenclature variation seen for the femoral head ± neck, the parotid gland, and bowel. The two-round Delphi assessment determined 42 OAR descriptions as providing optimal contouring guidance. CONCLUSIONS: This study identified the need for OAR nomenclature and contouring guidance consistency across clinical trials. In response to this study and in conjunction with the Global Quality Assurance of Radiation Therapy Clinical Trials Harmonisation Group, the RTTQA Group is in collaboration with international partners to provide consensus recommendations for OAR delineation in clinical trials.

Influence of machine-based puffing parameters on aerosol and smoke emissions from next generation nicotine inhalation products.

There is increasing diversity of nicotine inhalation products worldwide. Next Generation Products (NGP) such as e-cigarettes, have gained mass popularity, and there is increasing use of electrical and carbon-based Tobacco-Heating Products (e-THP and c-THP respectively). Recently, emission levels from these products have been compared to conventional cigarettes (CC); however, few formal laboratory testing standards exist, and inconsistent puffing parameters have been used. We investigated the impact of how a number of NGPs, including two e-cigarettes, a carbon-heated THP, and both pulse- and continuously-heated e-THPs, are puffed on the magnitude of their emissions, examining the influence of puff profile, volume, frequency and duration, in comparison to standard CCs. Our findings demonstrated that for each NGP choice of puffing parameters has a substantial impact on the magnitude of aerosol and smoke emissions, and that significant differences exist between different types of NGP. With e-cigarettes and pulse-heated e-THPs puff duration is the most important puffing parameter influencing yields. In contrast, for CCs, c-THPs and continuously-heated e-THPs, puff volume and puff frequency were the critical parameters. For e-cigarettes, there was no significant difference in emissions between rectangular and bell-shaped profiles. Our study has also shown that these different behaviours are a result of how heat-management within different NGPs, from heat-source to the nicotine- and aerosol-releasing substrates, is a vital mechanistic factor impacting aerosol generation. These findings point the need for detailed real-world e-cigarette and THP puffing topography data in order to identify the most appropriate puffing parameters for laboratory testing; our findings will help focus these studies on the most important parameters and can thereby support the future development of robust standardised NGP testing regimes.

Hydraulic fracturing volume is associated with induced earthquake productivity in the Duvernay play.

A sharp increase in the frequency of earthquakes near Fox Creek, Alberta, began in December 2013 in response to hydraulic fracturing. Using a hydraulic fracturing database, we explore relationships between injection parameters and seismicity response. We show that induced earthquakes are associated with completions that used larger injection volumes (104 to 105 cubic meters) and that seismic productivity scales linearly with injection volume. Injection pressure and rate have an insignificant association with seismic response. Further findings suggest that geological factors play a prominent role in seismic productivity, as evidenced by spatial correlations. Together, volume and geological factors account for ~96% of the variability in the induced earthquake rate near Fox Creek. This result is quantified by a seismogenic index-modified frequency-magnitude distribution, providing a framework to forecast induced seismicity.

UK Consensus on Normal Tissue Dose Constraints for Stereotactic Radiotherapy.

Six UK studies investigating stereotactic ablative radiotherapy (SABR) are currently open. Many of these involve the treatment of oligometastatic disease at different locations in the body. Members of all the trial management groups collaborated to generate a consensus document on appropriate organ at risk dose constraints. Values from existing but older reviews were updated using data from current studies. It is hoped that this unified approach will facilitate standardised implementation of SABR across the UK and will allow meaningful toxicity comparisons between SABR studies and internationally.

A multicentre audit of HDR/PDR brachytherapy absolute dosimetry in association with the INTERLACE trial (NCT015662405).

A UK multicentre audit to evaluate HDR and PDR brachytherapy has been performed using alanine absolute dosimetry. This is the first national UK audit performing an absolute dose measurement at a clinically relevant distance (20 mm) from the source. It was performed in both INTERLACE (a phase III multicentre trial in cervical cancer) and non-INTERLACE brachytherapy centres treating gynaecological tumours. Forty-seven UK centres (including the National Physical Laboratory) were visited. A simulated line source was generated within each centre's treatment planning system and dwell times calculated to deliver 10 Gy at 20 mm from the midpoint of the central dwell (representative of Point A of the Manchester system). The line source was delivered in a water-equivalent plastic phantom (Barts Solid Water) encased in blocks of PMMA (polymethyl methacrylate) and charge measured with an ion chamber at 3 positions (120° apart, 20 mm from the source). Absorbed dose was then measured with alanine at the same positions and averaged to reduce source positional uncertainties. Charge was also measured at 50 mm from the source (representative of Point B of the Manchester system). Source types included 46 HDR and PDR 192Ir sources, (7 Flexisource, 24 mHDR-v2, 12 GammaMed HDR Plus, 2 GammaMed PDR Plus, 1 VS2000) and 1 HDR 60Co source, (Co0.A86). Alanine measurements when compared to the centres' calculated dose showed a mean difference (±SD) of +1.1% (±1.4%) at 20 mm. Differences were also observed between source types and dose calculation algorithm. Ion chamber measurements demonstrated significant discrepancies between the three holes mainly due to positional variation of the source within the catheter (0.4%-4.9% maximum difference between two holes). This comprehensive audit of absolute dose to water from a simulated line source showed all centres could deliver the prescribed dose to within 5% maximum difference between measurement and calculation.

Coral hybridization or phenotypic variation? Genomic data reveal gene flow between Porites lobata and P. Compressa.

Major gaps remain in our understanding of the ecology, evolution, biodiversity, biogeography, extinction risk, and adaptive potential of reef building corals. One of the central challenges remains that there are few informative genetic markers for studying boundaries between species, and variation within species. Reduced representation sequencing approaches, such as RADseq (Restriction site Associated DNA sequencing) have great potential for resolving such relationships. However, it is necessary to identify loci in order to make inferences for endosymbiotic organisms such as corals. Here, we examined twenty-one coral holobiont ezRAD libraries from Hawai'i, focusing on P. lobata and P. compressa, two species with contrasting morphology and habitat preference that previous studies have not resolved. We used a combination of de novo assembly and reference mapping approaches to identify and compare loci: we used reference mapping to extract and compare nearly complete mitochondrial genomes, ribosomal arrays, and histone genes. We used de novo clustering and phylogenomic methods to compare the complete holobiont data set with coral and symbiont subsets that map to transcriptomic data. In addition, we used reference assemblies to examine genetic structure from SNPs (Single Nucleotide Polymorphisms). All approaches resolved outgroup taxa but failed to resolve P. lobata and P. compressa as distinct, with mito-nuclear discordance and shared mitochondrial haplotypes within the species complex. The holobiont and 'coral transcriptomic' datasets were highly concordant, revealing stronger genetic structure between sites than between coral morphospecies. These results suggest that either branching morphology is a polymorphic trait, or that these species frequently hybridize. This study provides examples of several approaches to acquire, identify, and compare loci across metagenomic samples such as the coral holobiont while providing insights into the nature of coral variability.

Left cardiac sympathetic denervation: case series and technical report.

BACKGROUND: Left cardiac sympathetic denervation (LCSD) is a surgical procedure that has been shown to have an antiarrhythmic and antifibrillatory effect. Evidence indicating its antiarrhythmic effect has been available for over 100 years. It involves the removal of the lower half of the stellate ganglion and T2-T4 of the sympathetic ganglia and is carried out as either a unilateral or bilateral procedure. With advancements in thoracic surgery, it can be safely performed via a minimally invasive Video-Assisted Thoracoscopic Surgery (VATS) approach resulting in significantly less morbidity and a shortened inpatient stay. LCSD provides a valuable treatment option for patients with life-threatening channelopathies and cardiomyopathies. AIMS AND METHODS: This case series reports the preliminary paediatric and adult experience in the Republic of Ireland with LCSD and describes five cases recently treated in addition to an outline of the operative procedure employed. Of the five cases included, two were paediatric cases and three were adult cases. RESULTS: One of the paediatric patients had a diagnosis of the rare catecholaminergic polymorphic ventricular tachycardia (CPVT) and the other a diagnosis of long-QT syndrome. Both paediatric patients experienced excellent outcomes. Of the three adult patients, two benefitted greatly and remain well at follow-up (one inappropriate sinus tachycardia and one CPVT). One patient with idiopathic ventricular fibrillation unfortunately passed away from intractable VF despite all attempts at resuscitation. CONCLUSION: In this case series, we highlight that LCSD provides a critical adjunct to existing medical therapies and should be considered for all patients with life-threatening refractory arrhythmias especially those patients on maximal medical therapy.

Isolated Unilateral Pulmonary Artery Agenesis complicated by Symptomatic Aspergilloma.

Isolated unilateral pulmonary artery agenesis is a rare diagnosis. Poor blood flow to the lung parenchyma renders the tissue susceptible to opportunistic infections. We present the unusual case of isolated unilateral pulmonary artery agenesis complicated by aspergilloma. Management options and considerations are discussed.

Liver and Kidney on Chips: Microphysiological Models to Understand Transporter Function.

Because of complex cellular microenvironments of both the liver and kidneys, accurate modeling of transport function has remained a challenge, leaving a dire need for models that can faithfully recapitulate both the architecture and cell-cell interactions observed in vivo. The study of hepatic and renal transport function is a fundamental component of understanding the metabolic fate of drugs and xenobiotics; however, there are few in vitro systems conducive for these types of studies. For both the hepatic and renal systems, we provide an overview of the location and function of the most significant phase I/II/III (transporter) of enzymes, and then review current in vitro systems for the suitability of a transporter function study and provide details on microphysiological systems that lead the field in these investigations. Microphysiological modeling of the liver and kidneys using "organ-on-a-chip" technologies is rapidly advancing in transport function assessment and has emerged as a promising method to evaluate drug and xenobiotic metabolism. Future directions for the field are also discussed along with technical challenges encountered in complex multiple-organs-on-chips development.

Tracheo-oesophageal fistula in a patient with chronic sarcoidosis.

Sarcoidosis is a common multisystem granulomatous condition of unknown aetiology, predominantly involving the respiratory system. Tracheal stenosis has been described but we believe that we present the first case of a tracheo-oesophageal fistula secondary to chronic sarcoidosis. A 57-year-old woman with sarcoidosis, a known tracheal stricture and a Polyflex(®) stent in situ presented with stridor. Bronchoscopy confirmed in-stent stenosis, by exuberant granulation tissue. The stent was removed and the granulation tissue was resected accordingly. Postoperatively, the patient was noticed to have an incessant cough and video fluoroscopy raised the suspicion of a tracheo-oesophageal fistula. A repeat bronchoscopy demonstrated marked granulation tissue, accompanied by a fistulous connection with the oesophagus at the mid-lower [middle of the lower] third of the trachea. Three Polyflex(®) stents were sited across the entire length of the trachea. Sarcoidosis presents with varying clinical manifestations and disease progression. Tracheal involvement appears to be a rare phenomenon and usually results in stenosis. To date, there has been little or no documented literature describing the formation of a tracheo-oesophageal fistula resulting from sarcoidosis. Early reports documented the presence of sarcoidosis induced weakening in the tracheal wall, a process termed tracheal dystonia. Weaknesses are more apparent in the membranous aspect of the trachea. Despite the rare nature of such pathology, this case report highlights the need to consider the presence of a tracheo-oesophageal fistula in sarcoidosis patients presenting with repeat aspiration in the absence of an alternate pathology.

What impact does community service learning have on medical students' appreciation of population health?

OBJECTIVES: The Bar Ilan Faculty of Medicine places public health as a priority in its medical curriculum, emphasizing its importance by strategically placing the required course as first on entry into medical school. Students are introduced to the importance of population health and community engagement through participatory community learning experiences. This study aims to examine how participatory community teaching methods impact students' understanding and attitudes towards community health. STUDY DESIGN: Mixed quantitative and qualitative design. METHODS: 75 first year students completed the required public health course utilizing participatory community methods, including community visits, Team Based Learning, an ethnic forum, and lifestyle medicine. Evaluation comprised skills assessment through project work, analysis of reflective notes and comparison of assessment scores with students in the previous year who experienced a formal lecture-only based curriculum. RESULTS: Students acquired public health skills, including conducting a needs assessment, searching for research evidence and designing an evaluation framework. Reflective notes revealed in-depth understanding not only of course aims, but an appreciation of the social determinants of health and the local community. Test marks indicated public health knowledge reached a comparable standard (83 ± 7.3) to the previous year (85 ± 9.3; P = 0.431). CONCLUSIONS: Participatory community learning equips students with public health skills, knowledge, and enhanced understanding of communities. It offers a way to effectively teach public health, while emphasizing the extended role and societal responsibilities of doctors.

Electronic brachytherapy--current status and future directions.

In the past decade, electronic brachytherapy (EB) has emerged as an attractive modality for the treatment of skin lesions and intraoperative partial breast irradiation, as well as finding wider applications in intracavitary and interstitial sites. These miniature X-ray sources, which operate at low kilovoltage energies (<100 kV), have reduced shielding requirements and inherent portability, therefore can be used outside the traditional realms of the radiotherapy department. However, steep dose gradients and increased sensitivity to inhomogeneities challenge accurate dosimetry. Secondly, ease of use does not mitigate the need for close involvement by medical physics experts and consultant oncologists. Finally, further studies are needed to relate the more heterogeneous dose distributions to clinical outcomes. With these provisos, the practical convenience of EB strongly suggests that it will become an established option for selected patients, not only in radiotherapy departments but also in a range of operating theatres and clinics around the world.