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.

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.

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.

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.

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.

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.

A randomized, controlled trial of acupuncture self-needling as maintenance therapy for cancer-related fatigue after therapist-delivered acupuncture.

BACKGROUND: Maintenance acupuncture is advocated by clinicians after successful clinic-based acupuncture. We aimed to assess the effectiveness of maintenance acupuncture in the management of cancer-related fatigue (CRF); treatment delivered by therapists or self-acupuncture/self-needling was compared with no maintenance treatment. METHODS: Breast cancer patients who participated in a randomized trial of acupuncture for CRF management (reported elsewhere) were re-randomized to receive an additional four acupuncturist-delivered weekly sessions; four self-administered weekly acupuncture sessions (self-needling); or no acupuncture. Primary outcome was general fatigue (Multidimensional Fatigue Inventory). Mood, quality of life and safety were also assessed. RESULTS: In total, 197 patients were re-randomized, with 65 to therapist-delivered sessions, 67 to self-acupuncture/self-needling and 65 to no further acupuncture. Primary outcome scores were equivalent between the therapist-delivered acupuncture and self-acupuncture (P > 0.05). A non-significant trend in improving fatigue was observed at the end of 4 weeks in the combined acupuncture arms (P = 0.07). There was no impact on mood or quality of life of the further acupuncture sessions at 18 weeks beyond the improvement observed in initial trial. CONCLUSION: Self-acupuncture is an acceptable, feasible and safe maintenance treatment for patients with CRF. However, overall, maintenance acupuncture did not yield important improvements beyond those observed after an initial clinic-based course of acupuncture. TRIAL REGISTRATION NUMBER: NCT00957112.

Quality assurance and independent dosimetry for an intraoperative x-ray device.

PURPOSE: Quality assurance is an essential component of accurate and safe radiotherapy delivery, and should include measurements which are independent of manufacturer-provided calibration. However, the physical and dosimetric properties of the INTRABEAM compact mobile 50 kV x-ray source are different from conventional kilovoltage therapy units and few reports describe methods for independent checks, frequencies, or tolerances for quality assurance tests. METHODS: Based on the available evidence and local experience, methods are described for determination of the key dosimetric parameters: beam quality, output, isotropy, and depth doses. Internal system checks are also described, along with measurements of long-term stability. RESULTS: A small volume parallel plate ionization chamber in a liquid water tank is the gold standard for measurements with this unit, but solid water-equivalent materials, thermoluminescent dosimeters and radiochromic film can all be used as practical alternatives with an accuracy of 5%-10%. The main cause of measurement uncertainty is positioning of the detector in the steep dose gradient, but energy dependence should also be considered. CONCLUSIONS: A quality assurance schedule with suggested tolerances is proposed, which includes both internal tests, before each treatment and on a monthly basis, and independent tests every year or after servicing or recalibration.

Profiling undergraduates' generic learning skills on entry to medical school; an international study.

BACKGROUND: Medical education faces challenges posed by widening access to training, a demand for globally competent healthcare workers and progress towards harmonisation of standards. AIM: To explore potential challenges arising from variation in diversity and educational background of medical school entrants. METHOD: This study investigated the reported experience and confidence, in a range of 31 generic skills underpinning learning, of 2606 medical undergraduates entering 14 medical schools in England and South Africa, using a validated questionnaire. RESULTS: Responses suggest that there is considerable similarity in prior educational experience and confidence skills profiles on entry to South African and English medical schools. South African entrants reported significantly more experience in 'Technical skills', 'Managing their own Learning', and 'Presentation', while English students reported increased experience in 'IT' skills. South African undergraduates reported more confidence in 'Information Handling', while English students were more confident in 'IT' skills. The most noticeable difference, in 'IT' skills, is probably due to documented differences in access to computer facilities at high school level. Differences between individual schools within each country are noticeable. CONCLUSIONS: Educators need to acquire a good understanding of their incoming cohorts, and ensure necessary tailored support for skills development.

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.

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.

Physiological regulation of early and late stages of megakaryocytopoiesis by thrombopoietin.

Thrombopoietin (TPO) has recently been cloned and shown to regulate megakaryocyte and platelet production by activating the cytokine receptor c-mpl. To determine whether TPO is the only ligand for c-mpl and the major regulator of megakaryocytopoiesis, TPO deficient mice were generated by gene targeting. TPO-/- mice have a >80% decrease in their platelets and megakaryocytes but have normal levels of all the other hematopoietic cell types. A gene dosage effect observed in heterozygous mice suggests that the TPO gene is constitutively expressed and that the circulating TPO level is directly regulated by the platelet mass. Bone marrow from TPO-/- mice have decreased numbers of megakaryocyte-committed progenitors as well as lower ploidy in the megakaryocytes that are present. These results demonstrate that TPO alone is the major physiological regulator of both proliferation and differentiation of hematopoietic progenitor cells into mature megakaryocytes but that TPO is not critical to the final step of platelet production.

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.

A phase I study of the nitroimidazole hypoxia marker SR4554 using 19F magnetic resonance spectroscopy.

BACKGROUND: SR4554 is a fluorine-containing 2-nitroimidazole, designed as a hypoxia marker detectable with 19F magnetic resonance spectroscopy (MRS). In an initial phase I study of SR4554, nausea/vomiting was found to be dose-limiting, and 1400 mg m(-2) was established as MTD. Preliminary MRS studies demonstrated some evidence of 19F retention in tumour. In this study we investigated higher doses of SR4554 and intratumoral localisation of the 19F MRS signal. METHODS: Patients had tumours > or = 3 cm in diameter and < or = 4 cm deep. Measurements were performed using 1H/19F surface coils and localised 19F MRS acquisition. SR4554 was administered at 1400 mg m(-2), with subsequent increase to 2600 mg m(-2) using prophylactic metoclopramide. Spectra were obtained immediately post infusion (MRS no. 1), at 16 h (MRS no. 2) and 20 h (MRS no. 3), based on the SR4554 half-life of 3.5 h determined from a previous study. 19Fluorine retention index (%) was defined as (MRS no. 2/MRS no. 1)*100. RESULTS: A total of 26 patients enrolled at: 1400 (n=16), 1800 (n=1), 2200 (n=1) and 2600 mg m(-2) (n=8). SR4554 was well tolerated and toxicities were all < or = grade 1; mean plasma elimination half-life was 3.7+/-0.9 h. SR4554 signal was seen on both unlocalised and localised MRS no. 1 in all patients. Localised 19F signals were detected at MRS no. 2 in 5 out of 9 patients and 4 out of 5 patients at MRS no. 3. The mean retention index in tumour was 13.6 (range 0.6-43.7) compared with 4.1 (range 0.6-7.3) for plasma samples taken at the same times (P=0.001) suggesting (19)F retention in tumour and, therefore, the presence of hypoxia. CONCLUSION: We have demonstrated the feasibility of using 19F MRS with SR4554 as a potential method of detecting hypoxia. Certain patients showed evidence of 19F retention in tumour, supporting further development of this technique for detection of tumour hypoxia.

Phorbol ester and mitogens stimulate human fibroblast secretions of plasmin-activatable plasminogen activator and protease nexin, an antiactivator/antiplasmin.

Tumor-promoting phorbol esters have been reported to greatly increase plasminogen activator (PA) activity produced in numerous cell types. Many of these studies have employed a widely used fibrinolysis assay for PA activity that involves large-scale dilution of cell lysates or conditioned medium (CM) into buffer containing plasminogen and the plasmin substrate 125I-fibrin. This assay indicates that phorbol ester and the mitogens epidermal growth factor (EGF) and thrombin all stimulate secretion of PA activity in our human foreskin fibroblast cultures. However, these effects are not observed in a modified fibrinolysis assay employing undiluted conditioned culture medium unless the medium is first treated at pH 3, which inactivates the secreted protease inhibitor, protease nexin (PN). Moreover, a direct assay for plasminogen activator activity based on cleavage of 125I-plasminogen indicates that conditioned culture medium contains little if any active plasminogen activator either before or after treatment of the cultures with phorbol ester or EGF. Phorbol ester and mitogens do stimulate secretion of (a) an inactive PA that can be activated by plasmin and (b) PN, which inhibits both the activated form of the PA and plasmin. Secretions of the inactive PA and PN are further correlated in that release of both is stimulated most by phorbol ester, somewhat less by EGF, and least by thrombin. Significantly, these effects are not accompanied by increases in total protein secretion. We propose that fibroblasts secrete PA in an inactive form in the presence of PN to confine PA activity to an as yet undefined location or event.

Nonlinear optical materials.

The current state of materials development in nonlinear optics is summarized, and the promise of these materials is critically evaluated. Properties and important materials constants of current commercial materials and of new, promising, inorganic and organic molecular and polymeric materials with potential in second- and third-order nonlinear optical applications are presented.

Sodium channel inactivation in squid axon is removed by high internal pH or tyrosine-specific reagents.

In squid axon, internal alkalinization from pH 7.1 to pH 10.2 results in a reversible decrease of the maximum inward current and the steady state sodium channel inactivation. Similar effects were observed after treatment of the axon with tetranitromethane or after iodination with lactoperoxidase. These results suggest that a tyrosine residue is an essential component of the inactivation process in this nerve.