Clinical outcomes and toxicity of proton beam radiation therapy for re-irradiation of locally recurrent breast cancer

Purpose: Repeat radiation therapy (RT) using photons/X-rays for locally recurrent breast cancer results in increased short and long-term toxicity. Proton beam RT (PBRT) can minimize dose to surrounding organs, thereby potentially reducing toxicity. Here, we report the toxicity and clinical outcomes for women who underwent re-irradiation to the chest wall for locally recurrent breast cancer using PBRT. Materials and methods: This was a retrospective study analyzing 16 consecutive patients between 2013 and 2018 with locally recurrent breast cancer who underwent re-irradiation to the chest wall with PBRT. For the recurrent disease, patients underwent maximal safe resection, including salvage mastectomy, wide local excision, or biopsy only per surgeons recommendations. Systemic therapy was used per the recommendation of the medical oncologist. Patients were treated with median dose of 50.4 Cobalt Gray Equivalent (CGyE) in 28 fractions at the time of re-irradiation. Follow-up was calculated from the start of second RT course. Acute toxicities were defined as those occurring during treatment or up to 8 weeks after treatment. Late toxicities were defined as those occurring more than 8 weeks after the completion of therapy. Toxicities were based on CTCAE 4.0. Results: The median age at original diagnosis and at recurrence was 49.8 years and 60.2 years, respectively. The median time between the two RT courses was 10.2 (0.7-20.2) years. The median follow-up time was 18.7 (2.5-35.2) months. No local failures were observed after re-irradiation. One patient developed distant metastasis and ultimately died. Grade 3-4 acute skin toxicity was observed in 5 (31.2%) patients. Four (25%) patients developed chest wall infections during or shortly (2 weeks) after re-irradiation. Late grade 3-4 fibrosis was observed in only 3 (18.8%) patients. Grade 5 toxicities were not observed. Hyperpigmentation was seen in 12 (75%) patients. Pneumonitis, telangiectasia, rib fracture, and lymphedema occurred in 2 (12.5%), 4 (25%), 1 (6.3%), and 1 (6.3%) patients, respectively. Conclusions: Re-irradiation with PBRT for recurrent breast cancer has acceptable toxicities. There was a high incidence of acute grade 3-4 skin toxicity and infections, which resolved, however, with skin care and antibiotics. Longer follow-up is needed to determine long-term clinical outcomes

High-quality gene assembly directly from unpurified mixtures of microarray-synthesized oligonucleotides

To meet the growing demand for synthetic genes more robust, scalable and inexpensive gene assembly technologies must be developed. Here, we present a protocol for high-quality gene assembly directly from low-cost marginal-quality microarray-synthesized oligonucleotides. Significantly, we eliminated the time- and money-consuming oligonucleotide purification steps through the use of hybridization-based selection embedded in the assembly process. The protocol was tested on mixtures of up to 2000 oligonucleotides eluted directly from microarrays obtained from three different chip manufacturers. These mixtures containing <5% perfect oligos, and were used directly for assembly of 27 test genes of different sizes. Gene quality was assessed by sequencing, and their activity was tested in coupled in vitro transcription/translation reactions. Genes assembled from the microarray-eluted material using the new protocol matched the quality of the genes assembled from >95% pure column-synthesized oligonucleotides by the standard protocol. Both averaged only 2.7 errors/kb, and genes assembled from microarray-eluted material without clonal selection produced only 30% less protein than sequence-confirmed clones. This report represents the first demonstration of cost-efficient gene assembly from microarray-synthesized oligonucleotides. The overall cost of assembly by this method approaches 5¢ per base, making gene synthesis more affordable than traditional cloning

Prevalence of and factors associated with late diagnosis of HIV in Malawi, Zambia, and Zimbabwe: Results from population-based nationally representative surveys

Introduction Late diagnosis of HIV (LD) increases the risk of morbidity, mortality, and HIV transmission. We used nationally representative data from population-based HIV impact assessment (PHIA) surveys in Malawi, Zambia, and Zimbabwe (2015–2016) to characterize adults at risk of LD and to examine associations between LD and presumed HIV transmission to cohabiting sexual partners. Methods We estimated the prevalence of LD, defined as CD4 count <350 cells/μL, among adults newly diagnosed with HIV during the surveys and odds ratios for associated factors. We linked newly diagnosed adults (index cases) to their household sexual partners and calculated adjusted odds ratios for associations between LD of the index case, viral load of the index case, and duration of HIV exposure in the relationship, and the HIV status of the household sexual partner. Results Of 1,804 adults who were newly diagnosed with HIV in the surveys, 49% (882) were diagnosed late. LD was associated with male sex, older age, and almost five times the odds of having an HIV-positive household sexual partner (adjusted odds ratio [aOR], 4.65 [95% confidence interval: 2.56–8.45]). Longer duration of HIV exposure in a relationship and higher viral load of the index case were both independently associated with higher odds of having HIV-positive household sexual partners. Individuals with HIV exposure of more than 5 years had more than three times (aOR 3.42 [95% CI: 1.63–7.18]) higher odds of being HIV positive than those with less than 2 years HIV exposure. The odds of being HIV positive were increased in individuals who were in a relationship with an index case with a viral load of 400–3499 copies/mL (aOR 4.06 [95% CI 0.45–36.46]), 3,500–9,999 copies/mL (aOR 11.32 [95% CI: 4.08–31.39]), 10,000–49,999 copies/mL (aOR 17.07 [95% CI: 9.18–31.72]), and ≥50,000 copies/mL (aOR 28.41 [95% CI: 12.18–66.28]) compared to individuals who were in a relationship with an index case with a viral load of <400 copies/mL. Conclusions LD remains a challenge in Southern Africa and is strongly associated with presumed HIV transmission to household sexual partners. Our study underscores the need for earlier HIV diagnosis, particularly among men and older adults, and the importance of index testing

Prevalence of nonsuppressed viral load and associated factors among HIV-positive adults receiving antiretroviral therapy in Eswatini, Lesotho, Malawi, Zambia and Zimbabwe (2015 to 2017): results from population-based nationally representative surveys.

INTRODUCTION The global target for 2020 is that ≥90% of people living with HIV (PLHIV) receiving antiretroviral therapy (ART) will achieve viral load suppression (VLS). We examined VLS and its determinants among adults receiving ART for at least four months. METHODS We analysed data from the population-based HIV impact assessment (PHIA) surveys in Eswatini, Lesotho, Malawi, Zambia and Zimbabwe (2015 to 2017). PHIA surveys are nationally representative, cross-sectional household surveys. Data collection included structured interviews, home-based HIV testing and laboratory testing. Blood samples from PLHIV were analysed for HIV RNA, CD4 counts and recent exposure to antiretroviral drugs (ARVs). We calculated representative estimates for the prevalence of VLS (viral load <1000 copies/mL), nonsuppressed viral load (NVL; viral load ≥1000 copies/mL), virologic failure (VF; ARVs present and viral load ≥1000 copies/mL), interrupted ART (ARVs absent and viral load ≥1000 copies/mL) and rates of switching to second-line ART (protease inhibitors present) among PLHIV aged 15 to 59 years who participated in the PHIA surveys in Eswatini, Lesotho, Malawi, Zambia and Zimbabwe, initiated ART at least four months before the survey and were receiving ART at the time of the survey (according to self-report or ARV testing). We calculated odds ratios and incidence rate ratios for factors associated with NVL, VF, interrupted ART, and switching to second-line ART. RESULTS We included 9200 adults receiving ART of whom 88.8% had VLS and 11.2% had NVL including 8.2% who experienced VF and 3.0% who interrupted ART. Younger age, male sex, less education, suboptimal adherence, receiving nevirapine, HIV non-disclosure, never having married and residing in Zimbabwe, Lesotho or Zambia were associated with higher odds of NVL. Among people with NVL, marriage, female sex, shorter ART duration, higher CD4 count and alcohol use were associated with lower odds for VF and higher odds for interrupted ART. Many people with VF (44.8%) had CD4 counts <200 cells/µL, but few (0.31% per year) switched to second-line ART. CONCLUSIONS Countries are approaching global VLS targets for adults. Treatment support, in particular for younger adults, and people with higher CD4 counts, and switching of people to protease inhibitor- or integrase inhibitor-based regimens may further reduce NVL prevalence

Development and validation of dissolution method for carvedilol compression-coated tablets

The present study describes the development and validation of a dissolution method for carvedilol compression-coated tablets. Dissolution test was performed using a TDT-06T dissolution apparatus. Based on the physiological conditions of the body, 0.1N hydrochloric acid was used as dissolution medium and release was monitored for 2 hours to verify the immediate release pattern of the drug in acidic pH, followed by pH 6.8 in citric-phosphate buffer for 22 hours, to simulate a sustained release pattern in the intestine. Influences of rotation speed and surfactant concentration in medium were evaluated. Samples were analysed by validated UV visible spectrophotometric method at 286 nm. 1% sodium lauryl sulphate (SLS) was found to be optimum for improving carvedilol solubility in pH 6.8 citric-phosphate buffer. Analysis of variance showed no significant difference between the results obtained at 50 and 100 rpm. The discriminating dissolution method was successfully developed for carvedilol compression-coated tablets. The conditions that allowed dissolution determination were USP type I apparatus at 100 rpm, containing 1000 ml of 0.1N HCl for 2 hours, followed by pH 6.8 citric-phosphate buffer with 1% SLS for 22 hours at 37.0 ± 0.5 ºC. Samples were analysed by UV spectrophotometric method and validated as per ICH guidelines.O presente estudo descreve o desenvolvimento e a validação de método de dissolução para comprimidos revestidos de carvedilol. O teste de dissolução foi efetuado utilizando-se o aparelho para dissolução TDT-06T. Com base nas condições fisiológicas do organismo, utilizou-se ácido clorídrico 0,1 N como meio de dissolução e a liberação foi monitorada por 2 horas para se verificar o padrão de liberação imediata do fármaco em condições de pH baixo, seguidas por pH 6,8 em tampão cítrico-fosfato por 22 horas, para simular o padrão de liberação controlada no intestino. Avaliou-se a influência da velocidade de rotação e a concentração de tensoativo no meio. As amostras foram analisadas por método espectrofotométrico UV-visível validado, em 286 nm. O laurilsulfato sódico a 1% (SLS) mostrou-se ótimo para aumentar a solubilidade do carvedilol em pH 6,8 em tampão cítrico-fosfato. A análise da variância não mostrou diferença significativa entre os resultados obtidos a 50 e a 100 rpm. O método da dissolução discriminante foi desenvolvido com sucesso para os comprimidos revestidos de carvedilol. As condições que permitiram a determinação da dissolução foram: aparelho USP tipo I a 100 rpm, contendo 1000 mL de HCL 0,1 N por 2 horas, seguido de pH 6,8 com tampão cítrico-fosfato, com 1% de SLS por 22 horas a 37,0 ± 0,5 ºC. Amostras foram analisadas por método espectrofotométrico e validadas pelas normas ICH

Istraživanja 3,4-diaril-1,2,5-oksadiazola i njihovih N-oksida: Potraga za boljim COX-2 inhibitorima

A series of 3,4-diaryl-1,2,5-oxadiazoles and 3,4-diaryl-1,2,5-oxadiazole N-oxides were prepared and evaluated for COX-2 and COX-1 binding affinity in vitro and for anti-inflammatory activity by the rat paw edema method. p-Methoxy (p-OMe) substituted compounds 9, 21, 34, 41, 42 showed COX-2 enzyme inhibition higher than that showed by compounds with other substituents. 3,4-Di(4-methoxyphenyl)-1,2,5-oxadiazole N-oxide (42) showed COX-2 enzyme inhibition of 54% at 22 µmol L-1 and COX-1 enzyme inhibition of 44% at 88 µmol L-1 concentrations, but showed very low in vivo anti-inflammatory activity. Its deoxygenated derivative (21) showed lower COX-2 enzyme inhibition (26% at 22 µmol L-1) and higher COX-1 enzyme inhibition (53% at 88 µmol L-1) but marked in vivo anti-inflammatory activity (71% at 25 mg kg-1) vs. celecoxib (48% at 12.5 mg kg-1). Molecular modeling (docking) studies showed that the methoxy group is positioned in the vicinity of the COX-2 secondary pocket and it also participates in hydrogen bonding interactions in the COX-2 active site. These preliminary studies suggest that the p-methoxy (p-OMe) group in one of benzene rings may give potentially active leads in this series of oxadiazole/N-oxides.Sintetizirana je serija 3,4-diaril-1,2,5-oksadiazola i 3,4-diaril-1,2,5-oksadiazol N-oksida i ocijenjena njihova sposobnost vezivanja na COX-2 i COX-1 in vitro i protuupalno djelovanje na edem šape štakora. Spojevi sa p-metoksi (p-OMe) supstituentom 9, 21, 34, 41, 42 bolje su inhibirali COX-2 nego ostali spojevi. 3,4-Di(4-metoksifenil)-1,2,5-oksadiazol N-oksid (42) inhibirao je COX-2 za 54% u koncentraciji od 22 µmol L-1, a COX-1 za 44% u koncentraciji 88 µmol L-1, ali je in vivo slabo djelovao protuupalno. Njegov deoksigenirani derivat 21 pokazao je slabiju inhibiciju COX-2 enzima (26% u koncentraciji 22 µmol L-1) i jaču inhibiciju COX-1 (71% u koncentraciji 25 mg kg-1) što je bolje od standarda celekoksiba (48% u koncentraciji 12,5 mg kg-1). Molekularno je modeliranje pokazalo da je metoksi skupina smještena u blizini sekundarnog džepa na enzimu COX-2 i da utječe na vodikove veze interakcija na aktivnom mjestu COX-2. Ova preliminarna istraživanja sugeriraju da bi se u seriji oksadiazol/N-oksida mogao naći predvodni spoj s p-metoksi skupinom na benzenskom prstenu

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Anisotropic study of ReSe

Transition metal dichalcogenides (TMDCs) are extensively in demand as photodetectors due to their extraordinary electrical and optical properties. In this work, we have reported the synthesis of high-quality bulk single crystals of rhenium diselenide (ReSe2) by the DVT technique. X-ray diffraction, Raman spectroscopy, and elemental mapping confirmed the crystal structure, crystallinity, and phase singularity of the material. TEM and SEM confirm the crystallinity and layered structure of the grown material. Owing to these unique properties, we have utilized the ReSe2 crystal to construct a high-performance anisotropic photodetector. The crystals’ photodetection capacity was confirmed in terms of typical detector parameters such as responsivity, detectivity, and rise time for white light under different intensities, biasing voltages, and wavelengths. The anisotropy in the properties due to its unique layered structure is also explored here. Observing the encouraging results, ReSe2 is a potential choice in 2D TMDCs for electrical and optoelectronic applications

Effect of Difference in Fatty Acid Chain Lengths of Medium-Chain Lipids on Lipid-Surfactant-Water Phase Diagrams and Drug Solubility

Lipids consisting of medium chain fatty acids are commonly used in the development of lipid-based selfemulsifying and self-microemulsifying drug delivery systems. However, no systematic approach to selecting one lipid over another has been reported in the literature. In this study, propylene glycol (PG) monoester (PG monocaprylate, Capmul PG-8®) and PG diester (PG dicaprylocaprate, Captex 200P®) of C8-fatty acids were compared with PG monoester (PG monolaurate, Capmul PG-12®) and PG diester (PG dilaurate, Capmul PG-2L®) of C12-fatty acids with respect to their phase diagrams, and especially for their ability to form microemulsions in the presence of a common surfactant, Cremophor EL®, and water. The solubility of two model drugs, danazol and probucol, in the lipids and lipid/surfactant mixtures were also compared. The effect of the chain length of medium-chain fatty acids (C8 versus C12) on the phase diagrams of the lipids was minimal. Both shorter and longer chain lipids formed essentially similar microemulsion and emulsion regions in the presence of Cremophor EL® and water, although the C12-fatty acid esters formed larger gel regions in the phase diagrams than the C8-fatty acid esters. When monoesters were mixed with their respective diesters at 1:1 ratios, larger microemulsion regions with lower lipid particle sizes were observed compared to those obtained with individual lipids alone. While the solubility of both danazol and probucol increased greatly in all lipids studied, compared to their aqueous solubility, the solubility in C12-fatty acid esters was found to be lower than in C8-fatty acid esters when the lipids were used alone. This difference in solubility due to the difference in fatty acid chain length, practically disappeared when the lipids were combined with the surfactant

Assessment of Suitability of Saxagliptin Hydrochloride for Development of Controlled Release Parenteral Formulation by Preformulation Studies

The main objective of pre-formulation study is to develop the stable, elegant, safe and effective drug delivery system by establishing drug kinetic profile, formulation compatibility with different excipients and physico-chemical parameters of new drug molecules. This could provide key evidence for implementing formulation design or requirement of the molecular alteration. So, in the present study preformulation studies were performed on Saxagliptin Hydrochloride (SXG) to assess its suitability for parenteral formulation. SXG is a potent and selective reversible inhibitor of dipeptidyl peptidase-4 used to treat type –II diabetes mellitus. The authenticity of SXG was established by differential scanning calorimetry (DSC) and fourier transform infrared spectroscopy(FTIR) spectra. An ultraviolet–visible (UV) spectrophotometric and high performance liquid chromatography (HPLC) methods were employed for determination of SXG in bulk API (active pharmaceutical ingredient). The UV method was linear within the range of 1-40 μg/ml. The proposed methodology is robust which can be concluded from the lower percentage standard deviation percentage co efficient of variance (% CV) values of intraday and inter day variability. The retention time was observed 1.3 min of SXG in HPLC method. The higher regression coefficient value (0.999) indicates the methodology is robust.&nbsp