Dose to Organ at Risk and its Characteristic Variation with the Clinically Used Different Prescription Levels for Early-stage Left-sided Breast Cancer.

AIMS: To evaluate the organ at risk (OAR) dose and its characteristic variation with different clinically usable prescription doses (RxD) for breast and chest wall radiotherapy in patients with early-stage left-sided breast cancer. MATERIALS AND METHODS: In total, 145 patients with early-stage breast cancers (T1N0M0-T2N0M0) on the left side were treated with radiotherapy after a modified radical mastectomy or breast conservation surgery, with a mean age of 45.1 ± 21.6 years. The patient received 4050 cGy of field-in-field (three-dimensional conformal radiotherapy) treatment limited to the breast or chest wall, excluding the supraclavicular node, axillary node and internal mammary chain, over 15 fractions. Additional plans of 5000 cGy/25 fractions, 4500 cGy/20 fractions and 2600 cGy/5 fractions were created with no or minor changes to the original plan. Mathematical modelling was used to study the distinctive change in the dose-volume characteristics for various OARs as a function of the RxD. OAR dosages, both absolute and normalised, were expressed in terms of the RxD. The mathematical (functional) relationship between OAR doses and different prescription levels was deduced by the least squares fit method. RESULT: The left lung mean dose, V5Gy (%), V10Gy (%) and V20Gy (%) and the heart mean dose, V10Gy (%) and V20Gy (%) were evaluated. The dose-volume parameters showed a parabolic variation (x2) with the RxD. Prescription normalised OAR doses showed a linear relationship with the RxD; relative dose increased with diminishing RxD. Normalised lung and heart mean doses exhibited saturation (linear relationship) with RxD variation. Paired sample t-test results between RxD versus all evaluated parameters were found to be statistically significant (P = 0.004). The Pearson correlation coefficient between different prescription levels for left lung mean dose (range 0.942-1.0), heart mean dose (range 1.0-1.0), left lung V5Gy (%) (range 0.987-1.0), left lung V10Gy (%) (range 0.991-0.999), heart V10Gy (%) (range 0.998-1.0). CONCLUSION: The functional form of absolute OAR dose-volume parameters versus RxD is parabolic and the RxD normalised OAR dose-volume parameter versus RxD is a straight line with a negative slope as RxD increases. This indicates an increase in the relative OAR dose-volume parameters if the RxD is reduced. This study is the first of its kind to compare the OAR doses as a function of clinically used degenerate prescription levels. These data will help to comprehend the OAR doses while adopting a new dose fractionation regimen and reviewing the radiotherapy treatment plans.

Dark matter axion search using a Josephson Traveling wave parametric amplifier.

We describe the first implementation of a Josephson Traveling Wave Parametric Amplifier (JTWPA) in an axion dark matter search. The operation of the JTWPA for a period of about two weeks achieved sensitivity to axion-like particle dark matter with axion-photon couplings above 10-13 Ge V-1 over a narrow range of axion masses centered around 19.84 µeV by tuning the resonant frequency of the cavity over the frequency range of 4796.7-4799.5 MHz. The JTWPA was operated in the insert of the axion dark matter experiment as part of an independent receiver chain that was attached to a 0.56-l cavity. The ability of the JTWPA to deliver high gain over a wide (3 GHz) bandwidth has engendered interest from those aiming to perform broadband axion searches, a longstanding goal in this field.

Management of childhood MDR-TB in Europe and Central Asia: report of a Regional WHO meeting.

BACKGROUND: As the WHO European Region has the highest proportion of multidrug-resistant TB (MDR-TB) among total incident TB cases, many children and adolescents are at risk of MDR-TB infection and disease.METHODS: We performed an electronic survey of clinicians and TB programme personnel who attended the 2020 Regional Consultation on child and adolescent TB organised by the WHO Regional Office. We characterised access to diagnostics and drugs, and practices in the prevention and management of child and adolescent MDR-TB.RESULTS: Children and adolescents are inconsistently represented in national guidelines and budgets; child-friendly drug formulations for MDR-TB treatment are insufficiently available in 57% of countries, and 32% of countries reported paediatric drug stock-outs. The novel drugs, bedaquiline and delamanid, are accessible by respectively 80% and 60% of respondent countries. Respondents were asked how many children were diagnosed with MDR-TB in 2019, and a comparison of this number to modelled estimates of incidence (to identify the case detection gap) and WHO notifications (to identify the case reporting gap) showed substantial differences in both comparisons.CONCLUSIONS: Better representation of this patient group in guidelines and budgets, greater access to drugs and improved reporting are essential to reach TB elimination in this Region.

Barrier enclosure in tracheostomy: a protective box for healthcare workers during the coronavirus disease 2019 pandemic.

BACKGROUND: Tracheostomy, being a high aerosol-generating procedure, poses a great challenge to surgeons, especially during the coronavirus disease 2019 pandemic. It is important to preserve staff numbers as this fight may go on for a long time. Personal protective equipment plays a key role in the protection of healthcare workers. Barrier enclosure has been attempted in procedures such as intubation and tracheostomy. The use of boxes became popularised for intubation and they have been utilised in many centres. METHODS: This paper describes the box designed by our team and presents our surgical experience with the box. The box is made of transparent acrylic. It is sealed at all ends, with a negative-pressure environment. The hand ports were designed to allow maximum manoeuvrability for surgeons, without restricting hand movements. CONCLUSION: The proposed box will provide more protection to healthcare workers during tracheostomy. However, the box is yet to be validated.

Axion Dark Matter Experiment: Detailed design and operations.

Axion dark matter experiment ultra-low noise haloscope technology has enabled the successful completion of two science runs (1A and 1B) that looked for dark matter axions in the 2.66-3.1 µeV mass range with Dine-Fischler-Srednicki-Zhitnisky sensitivity [Du et al., Phys. Rev. Lett. 120, 151301 (2018) and Braine et al., Phys. Rev. Lett. 124, 101303 (2020)]. Therefore, it is the most sensitive axion search experiment to date in this mass range. We discuss the technological advances made in the last several years to achieve this sensitivity, which includes the implementation of components, such as the state-of-the-art quantum-noise-limited amplifiers and a dilution refrigerator. Furthermore, we demonstrate the use of a frequency tunable microstrip superconducting quantum interference device amplifier in run 1A, and a Josephson parametric amplifier in run 1B, along with novel analysis tools that characterize the system noise temperature.

Search for Invisible Axion Dark Matter in the 3.3-4.2 µeV Mass Range.

We report the results from a haloscope search for axion dark matter in the 3.3-4.2 µeV mass range. This search excludes the axion-photon coupling predicted by one of the benchmark models of "invisible" axion dark matter, the Kim-Shifman-Vainshtein-Zakharov model. This sensitivity is achieved using a large-volume cavity, a superconducting magnet, an ultra low noise Josephson parametric amplifier, and sub-Kelvin temperatures. The validity of our detection procedure is ensured by injecting and detecting blind synthetic axion signals.

A machine learning-based, decision support, mobile phone application for diagnosis of common dermatological diseases.

BACKGROUND: The integration of machine learning algorithms in decision support tools for physicians is gaining popularity. These tools can tackle the disparities in healthcare access as the technology can be implemented on smartphones. We present the first, large-scale study on patients with skin of colour, in which the feasibility of a novel mobile health application (mHealth app) was investigated in actual clinical workflows. OBJECTIVE: To develop a mHealth app to diagnose 40 common skin diseases and test it in clinical settings. METHODS: A convolutional neural network-based algorithm was trained with clinical images of 40 skin diseases. A smartphone app was generated and validated on 5014 patients, attending rural and urban outpatient dermatology departments in India. The results of this mHealth app were compared against the dermatologists' diagnoses. RESULTS: The machine-learning model, in an in silico validation study, demonstrated an overall top-1 accuracy of 76.93 ± 0.88% and mean area-under-curve of 0.95 ± 0.02 on a set of clinical images. In the clinical study, on patients with skin of colour, the app achieved an overall top-1 accuracy of 75.07% (95% CI = 73.75-76.36), top-3 accuracy of 89.62% (95% CI = 88.67-90.52) and mean area-under-curve of 0.90 ± 0.07. CONCLUSION: This study underscores the utility of artificial intelligence-driven smartphone applications as a point-of-care, clinical decision support tool for dermatological diagnosis for a wide spectrum of skin diseases in patients of the skin of colour.

Enhanced expression of recombinant proteins in Escherichia coli by co-expression with Vibrio parahaemolyticus CsgG, a pore-forming protein of the curli biogenesis pathway.

AIM: To test whether engineered nanopores on the outer membrane (OM) of Escherichia coli can increase expression of heterologous proteins by making additional nutrients available to the host. METHODS AND RESULTS: Outer membrane nanopores were generated by expressing recombinant Vibrio parahaemolyticus CsgG (rVpCsgG), which spontaneously assembles into a pore-forming channel on the OM, allowing spontaneous diffusion of small chemical entities from the exterior. Protein expression was probed using a reporter protein, sfGFP, expressed on a second compatible plasmid. OM pore formation was shown by acquired erythromycin sensitivity in cells transformed with rVpCsgG, influx of propidium iodide as well as by surface localization of recombinant CsgG by immunogold-labeled transmission electron microscopy. Expression of recombinant CsgG showed increased growth and also enhanced expression of sfGFP in minimal medium and is due to both enhanced transcription as well as translation. Similar enhancement of expression was also observed for a number of different proteins of different origin, sizes and nature. CONCLUSIONS: Our findings clearly demonstrate that engineered nanopores on the OM of E. coli enhance expression of different heterologous proteins in minimal medium. SIGNIFICANCE AND IMPACT OF THE STUDY: Vibrio parahaemolyticus CsgG ß-nanopore mediated co-expression strategy to improve recombinant protein expression is fully compatible with other methods of protein expression enhancement, and therefore can be a useful tool in biotechnology particularly for whole-cell bio-transformations for production of secondary metabolite.

Ni nanoparticle-confined covalent organic polymer directed diaryl-selenides synthesis.

The present work describes the preparation of a new covalent organic polymer (COP) and its application as a hetero support for diaryl selenides synthesis. A nitrogen rich COP (CGP) has been synthesized via SNAr reaction of cyanuric chloride with guanidinium hydrochloride. The successful confinement of COP with Ni nanoparticles through post-synthetic transformations (Ni@CGP) provides excellent catalytic activity for the transformation of aryl halides into diaryl selenides using elemental selenium powder. The synthetic transformations are well confirmed using various modern analytical and spectroscopic techniques which reveal high chemical and thermal durability. The N-rich framework of CGP fortifies the confinement of Ni NPs. Ni@CGP provides an efficient approach for diaryl selenides synthesis using a very cheap selenating reagent under water benign solvent conditions (DMSO : H2O) at room temperature with high reusability. Significantly, our work not only contributes the opportunity for developing economical and effective non-noble metal decorated COPs as heterogeneous catalysts, but also delivers an efficient approach to produce industrially important C-Se coupling products.

Extended Search for the Invisible Axion with the Axion Dark Matter Experiment.

This Letter reports on a cavity haloscope search for dark matter axions in the Galactic halo in the mass range 2.81-3.31 µeV. This search utilizes the combination of a low-noise Josephson parametric amplifier and a large-cavity haloscope to achieve unprecedented sensitivity across this mass range. This search excludes the full range of axion-photon coupling values predicted in benchmark models of the invisible axion that solve the strong CP problem of quantum chromodynamics.

Central institutional ethics committee needed to facilitate timely review of multicenter clinical trials.

A multicenter trial in India undergoes review by Institutional Ethics Committees (IECs) of all participating institutions. The failure to obtain approval even from a single institution's IEC creates a situation of inequitable access to clinical trials. The dichotomy in decisions of different IECs is attributed to lack of standardization and accountability in their functioning. The registration of IECs with Central Drugs Standard Control Organization notwithstanding, the current model of IEC review has failed to ensure uniformity in IEC decisions in multicenter trials. Alternative models that allow central review of multicenter clinical trials should be explored.

Efficacy of herbal extracts and closantel against fenbendazole-resistant Haemonchus contortus.

This study assessed the efficacy of closantel vis-à-vis herbal extracts with known anti-parasitic properties, against fenbendazole-resistant nematodes in goats maintained under a semi-intensive system of management at the University goat farm, Jabalpur. Fifty goats were randomly assigned to five groups, each comprising 10 animals, irrespective of their breed, age and sex. Each animal in Group I, II and III was orally administered with aqueous leaf extracts of neem (Azadirachta indica) at 1 g/kg body weight, sitaphal (Annona squamosa) at 1.5 g/kg body weight and tobacco (Nicotiana tabacum) at 1 g/kg body weight, respectively, whereas Group IV was an untreated control group. Each animal in Group V was orally treated with closantel at 10 mg/kg body weight. During the course of the study, all animals were maintained under an identical semi-intensive system of management. Compared to the untreated control group (Group IV), there was no conspicuous reduction in post-treatment (day 10) faecal egg counts (FEC) in animals administered with the herbal extracts (Groups I, II and III), which is suggestive of poor anti-parasitic activity. However, using the faecal egg count reduction test (FECRT), the overall efficacy of closantel was recorded as 95.64%. This supports the rotational use of closantel as a preferred choice over the benzimidazole group of anthelmintics and/or herbal extracts to meet the acute challenge of in situ development of drug-resistant gastrointestinal nematodes, especially Haemonchus contortus.

Outcomes for Patients with Non-metastatic Triple-negative Breast Cancer in New Zealand.

AIMS: Triple-negative breast cancer (TNBC) has inferior outcomes to other subtypes of breast cancer. We studied the demographics and baseline breast cancer characteristics of patients in New Zealand with TNBC and assessed survival outcomes and prognostic/predictive factors. MATERIALS AND METHODS: We searched the New Zealand breast cancer registry database and identified patients with TNBC without distant metastatic disease. We retrieved demographic, tumour characteristic and treatment information. Locoregional recurrence-free survival, breast cancer-specific survival (BSS), metastasis-free survival (MRFS) and overall survival were determined. Predefined univariate and multivariate analyses were carried out investigating the association of survival outcomes with treatment and tumour characteristics. RESULTS: In total, 1390 patients were identified, with a median follow-up of 3.5 years. The median age was 55 years. Thirty-eight per cent were node positive and 79% were grade III. Mastectomy was carried out in 53%, adjuvant radiation delivered in 66% and chemotherapy in 69%. The significant predictive factors for overall survival, BSS and MRFS were radiotherapy, chemotherapy and neoadjuvant chemotherapy. The significant prognostic indicators were lymphovascular invasion, nodal status and tumour size. On Kaplan-Meier analysis, the 5 year overall survival was 72%. The median time to death for those who died was 3.55 years with 92% of deaths within 5 years. Seventy-four per cent of patients had distant metastasis as a first recurrence and isolated local recurrences occurred in only 4.5%. Metastatic disease occurred in lung (55.9%) and was in multiple sites in 51%. CONCLUSION: We report a large population-based series of TBNC without distant metastatic disease at diagnosis highlighting the unique behavioural characteristics of TNBC. Traditional therapies are positively associated with survival outcomes, and yet, particularly in the setting of recurrent disease, prognosis remains poor. Increased research into more effective systemic agents and the most effective timing of delivery of these may result in improved outcomes.

Impact of change in head and neck position on ultrasound localisation of the cricothyroid membrane: an observational study.

The ideal position for performing surgical cricothyroidotomy is with full neck extension. Some authors have recommended marking the cricothyroid membrane before general anaesthesia, typically with the patient's head and neck in a neutral position. The primary aim of this observational study was to determine whether skin marks made over the centre of the cricothyroid membrane with the head and neck in the neutral position moved outside the boundaries of the membrane when the neck was subsequently extended. The secondary aim was to assess changes in the height of the cricothyroid membrane between the neutral and extended positions. Twenty-two volunteers completed the study. With the head and neck in the neutral position, the distance between the upper and lower borders ('height') of the cricothyroid membrane was measured by a radiologist using ultrasound. The skin was marked over the mid-point of the membrane. The subject then maximally extended the neck, and the measurements and marking were repeated. The skin marking over the centre point of the cricothyroid membrane moved by median (IQR [range]) 5 (4-6 [0-10]) mm when the head and neck were moved from a neutral to a fully extended position. The initial skin mark moved to lie outside the boundary of the cricothyroid membrane in 12 of 22 subjects after extending the neck. The height of the cricothyroid membrane increased by 30% with the neck extended. We recommend that marking the skin in preparation for cricothyroidotomy should be performed with the neck extended, not with the head and neck in the neutral position as previously suggested.

Search for Invisible Axion Dark Matter with the Axion Dark Matter Experiment.

This Letter reports the results from a haloscope search for dark matter axions with masses between 2.66 and 2.81 µeV. The search excludes the range of axion-photon couplings predicted by plausible models of the invisible axion. This unprecedented sensitivity is achieved by operating a large-volume haloscope at subkelvin temperatures, thereby reducing thermal noise as well as the excess noise from the ultralow-noise superconducting quantum interference device amplifier used for the signal power readout. Ongoing searches will provide nearly definitive tests of the invisible axion model over a wide range of axion masses.

In vitro antiplasmodial efficacy of synthetic coumarin-triazole analogs.

Twenty two diverse coumarin-triazole derivatives were synthesized by alkylation of 7-hydroxy-4-methyl-coumarin followed by click chemistry at 7-position. These compounds were evaluated for their in vitro antiplasmodial activity against chloroquine sensitive strain of Plasmodium falciparum (3D7). Compound 9 (7-[1-(2, 4-dimethoxy-phenyl)-1H- [1-3] triazol-4-ylmethoxy]-4-methyl-chromen-2-one) was found most active with IC50 value 0.763 ±â€¯0.0124 µg/mL. Further, the structure of compound 20 was characterized by single crystal X-ray diffraction. In view of impressive results, we considered it worthwhile to validate the results of in vitro antiplasmodial activity by assessing whether these compounds are capable of hampering the catalytic activity of DNA gyrase, thus preventing its supercoiling function.

Immunomodulatory activity of glycodelin: implications in allograft rejection.

Glycodelin is an immunomodulator, indispensable for the maintenance of pregnancy in humans. The glycoprotein induces apoptosis in activated CD4+ T cells, monocytes and natural killer (NK) cells, and suppresses the activity of cytotoxic T cells, macrophages and dendritic cells. This study explores the immunosuppressive property of glycodelin for its possible use in preventing graft rejection. Because glycodelin is found only in certain primates, the hypothesis was investigated in an allograft nude mouse model. It is demonstrated that treatment of alloactivated mononuclear cells with glycodelin thwarts graft rejection. Glycodelin decreases the number of activated CD4+ and CD8+ cells and down-regulates the expression of key proteins known to be involved in graft demise such as granzyme-B, eomesodermin (EOMES), interleukin (IL)-2 and proinflammatory cytokines [tumour necrosis factor (TNF)-α and IL-6], resulting in a weakened cell-mediated immune response. Immunosuppressive drugs for treating allograft rejection are associated with severe side effects. Glycodelin, a natural immunomodulator in humans, would be an ideal alternative candidate.

Piezoelectrically Tuned Multimode Cavity Search for Axion Dark Matter.

The µeV axion is a well-motivated extension to the standard model. The Axion Dark Matter eXperiment (ADMX) collaboration seeks to discover this particle by looking for the resonant conversion of dark-matter axions to microwave photons in a strong magnetic field. In this Letter, we report results from a pathfinder experiment, the ADMX "Sidecar," which is designed to pave the way for future, higher mass, searches. This testbed experiment lives inside of and operates in tandem with the main ADMX experiment. The Sidecar experiment excludes masses in three widely spaced frequency ranges (4202-4249, 5086-5799, and 7173-7203 MHz). In addition, Sidecar demonstrates the successful use of a piezoelectric actuator for cavity tuning. Finally, this publication is the first to report data measured using both the TM_{010} and TM_{020} modes.

Pharmacophore modelling, virtual screening and molecular docking studies on PLD1 inhibitors.

Lipid metabolism plays a significant role in influenza virus replication and subsequent infection. The regulatory mechanism governing lipid metabolism and viral replication is not properly understood to date, but both Phospholipase D (PLD1 and PLD2) activities are stimulated in viral infection. In vitro studies indicate that chemical inhibition of PLD1 delays viral entry and reduction of viral loads. The current study reports a three-dimensional pharmacophore model based on 35 known PLD1 inhibitors. A sub-set of 25 compounds was selected as the training set and the remaining 10 compounds were kept in the test set. One hundred and twelve pharmacophore models were generated; a six-featured pharmacophore model (AADDHR.57) with survival score (2.69) produced a statistically significant three-dimensional quantitative structure-activity relationship model with r2 = 0.97 (internal training set), r2 = 0.71 (internal test set) and Q2 = 0.64. The predictive power of the pharmacophore model was validated with an external test set (r2 = 0.73) and a systematic virtual screening work-flow was employed showing an enrichment factor of 23.68 at the top 2% of the dataset (active and decoys). Finally, the model was used for screening of the filtered PubChem database to fetch molecules which can be proposed as potential PLD1 inhibitors for blocking influenza infection.