Strain-Release-Driven Homologation of Boronic Esters:Application to the Modular Synthesis of Azetidines

Azetidines are important motifs in medicinal chemistry, but there are a limited number of methods for their synthesis. Herein, we present a new method for their modular construction by exploiting the high ring strain associated with azabicyclo[1.1.0]­butane. Generation of azabicyclo[1.1.0]­butyl lithium followed by its trapping with a boronic ester gives an intermediate boronate complex which, upon N-protonation with acetic acid, undergoes 1,2-migration with cleavage of the central C–N bond to relieve ring strain. The methodology is applicable to primary, secondary, tertiary, aryl, and alkenyl boronic esters and occurs with complete stereospecificity. The homologated azetidinyl boronic esters can be further functionalized through reaction of the N–H azetidine, and through transformation of the boronic ester. The methodology was applied to a short, stereoselective synthesis of the azetidine-containing pharmaceutical, cobimetinib

Effect of Growth Media, pH and Temperature on Yeast to Hyphal Transition in Candida albicans

The transition of C. albicans from unicellular yeast form to filamentous form i.e., pseudohyphae and hyphae is referred to as morphogenesis. C. albicans has the ability to respond to environmental conditions and accordingly changing its cell morphology. Three main morphological forms of C. albicans are unicellular yeast, pseudohyphae and hyphae. The effect of different growth media (Horse serum medium, RPMI-1640, MSGB), incubation temperatures (34˚C, 37˚C, 40˚C) and pH values (5.4, 6.4, 7.4) on germ tube production by C. albicans was evaluated. Horse serum medium noticeably promotes filamentation while RPMI-1640 medium shows moderate filamentation and MSGB media shows moderately low filamentation. The germ tube of C. albicans developed early in 1.5 hr at high temperature i.e., 40˚C. Incubation temperature of 37˚C was associated with highest germ tube formation while 34˚C shows low filamentation. A pH of 5.4 also induces low filamentation, pH 6.4 gives moderately lower than pH 7.4. A pH of 7.4 was best suited for germ tube induction. The peak of mycelium production appears between 1.5 and 6 hr after inoculation of C. albicans culture. These results suggested that environmental factors are important in selectively favoring yeast or hyphal form, most important being the growth medium, incubation temperature and external pH value

Localization of sound sources : a systematic review

Sound localization is a vast field of research and advancement which is used in many useful applications to facilitate communication, radars, medical aid, and speech enhancement to but name a few. Many different methods are presented in recent times in this field to gain benefits. Various types of microphone arrays serve the purpose of sensing the incoming sound. This paper presents an overview of the importance of using sound localization in different applications along with the use and limitations of ad-hoc microphones over other microphones. In order to overcome these limitations certain approaches are also presented. Detailed explanation of some of the existing methods that are used for sound localization using microphone arrays in the recent literature is given. Existing methods are studied in a comparative fashion along with the factors that influence the choice of one method over the others. This review is done in order to form a basis for choosing the best fit method for our use

Changes in Expression of Genes Representing Key Biologic Processes after Neoadjuvant Chemotherapy in Breast Cancer, and Prognostic Implications in Residual Disease.

Purpose The primary aim was to derive evidence for or against the clinical importance of several biologic processes in patients treated with neoadjuvant chemotherapy (NAC) by assessing expression of selected genes with prior implications in prognosis or treatment resistance. The secondary aim was to determine the prognostic impact in residual disease of the genes' expression.Experimental design Expression levels of 24 genes were quantified by NanoString nCounter on formalin-fixed paraffin-embedded residual tumors from 126 patients treated with NAC and 56 paired presurgical biopsies. The paired t test was used for testing changes in gene expression, and Cox regression and penalized elastic-net Cox Regression for estimating HRs.Results After NAC, 12 genes were significantly up- and 8 downregulated. Fourteen genes were significantly associated with time to recurrence in univariable analysis in residual disease. In a multivariable model, ACACB, CD3D, MKI67, and TOP2A added prognostic value independent of clinical ER(-), PgR(-), and HER2(-) status. In ER(+)/HER2(-) patients, ACACB, PAWR, and ERBB2 predicted outcome, whereas CD3D and PAWR were prognostic in ER(-)/HER2(-) patients. By use of elastic-net analysis, a 6-gene signature (ACACB, CD3D, DECORIN, ESR1, MKI67, PLAU) was identified adding prognostic value independent of ER, PgR, and HER2.Conclusions Most of the tested genes were significantly enriched or depleted in response to NAC. Expression levels of genes representing proliferation, stromal activation, metabolism, apoptosis, stemcellness, immunologic response, and Ras-ERK activation predicted outcome in residual disease. The multivariable gene models identified could, if validated, be used to identify patients needing additional post-neoadjuvant treatment to improve prognosis. Clin Cancer Res; 22(10); 2405-16. ©2016 AACR

Get screened: a pragmatic randomized controlled trial to increase mammography and colorectal cancer screening in a large, safety net practice

Abstract Background Most randomized controlled trials of interventions designed to promote cancer screening, particularly those targeting poor and minority patients, enroll selected patients. Relatively little is known about the benefits of these interventions among unselected patients. Methods/Design "Get Screened" is an American Cancer Society-sponsored randomized controlled trial designed to promote mammography and colorectal cancer screening in a primary care practice serving low-income patients. Eligible patients who are past due for mammography or colorectal cancer screening are entered into a tracking registry and randomly assigned to early or delayed intervention. This 6-month intervention is multimodal, involving patient prompts, clinician prompts, and outreach. At the time of the patient visit, eligible patients receive a low-literacy patient education tool. At the same time, clinicians receive a prompt to remind them to order the test and, when appropriate, a tool designed to simplify colorectal cancer screening decision-making. Patient outreach consists of personalized letters, automated telephone reminders, assistance with scheduling, and linkage of uninsured patients to the local National Breast and Cervical Cancer Early Detection program. Interventions are repeated for patients who fail to respond to early interventions. We will compare rates of screening between randomized groups, as well as planned secondary analyses of minority patients and uninsured patients. Data from the pilot phase show that this multimodal intervention triples rates of cancer screening (adjusted odds ratio 3.63; 95% CI 2.35 - 5.61). Discussion This study protocol is designed to assess a multimodal approach to promotion of breast and colorectal cancer screening among underserved patients. We hypothesize that a multimodal approach will significantly improve cancer screening rates. The trial was registered at Clinical Trials.gov NCT00818857http://deepblue.lib.umich.edu/bitstream/2027.42/78264/1/1472-6963-10-280.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78264/2/1472-6963-10-280.pdfPeer Reviewe

Deliberate self-harm and attachment: mediating and moderating roles of depression, anxiety, social support and interpersonal problems among Pakistani school going adolescents

Introduction: In Pakistan there is dearth of research on deliberate self-harm (DSH) and its predictors among adolescents. While the lack of research in Pakistan can be partly attributed to the sacrilegious status, criminalization and stigmatization attached to DSH, it is also an attribute of paucity of Urdu versions of the standardized psychological instruments. Previous research in developed countries has indicated that attachment theory can be used as a useful framework to understand the development of austere psychopathologies like DSH, as well as for studying pathways of interaction of interpersonal and intrapersonal factors of psychopathologies. In this study, standardized psychological instruments are translated into Urdu language as a first step. These instruments are then used to study pathways of interaction of interpersonal and intrapersonal factors of DSH, conceptualized within attachment framework. Method: The study was conducted in two steps. In step 1, Youth Health Risk Behavior Survey (YHRB), Inventory of Interpersonal Problems-32 (IIP-32) and Significant Others Scale (SOS), were translated into Urdu language. Along with these scales, Urdu translated versions of Hospital Anxiety and Depression Scale (HADS), Adolescent Relationship Scales Questionnaire (ARSQ), Life Events scale (LES) from CASE questionnaire and Family Affluence Scale-II (FAS-II) were reviewed for accuracy of translation through expert judgement and psychometric evaluation. Secondly, a cross sectional survey was conducted with 1290 adolescents (10 - 19 years age) using the translated Urdu versions of the instruments and demographic pro forma. Structural equation modelling was used to study the pathways of associations between predictors of DSH. Results: The extensive process of translation resulted in establishment of semantic, content, technical and construct equivalence of the translated instruments with the original English versions. Multiple imputation was performed to account for missing values in SPSS 20. Important structural adaptations were made in the scales based on factor analyses conducted in M plus. After modifications, all scales showed satisfactory CFI (≥ 0.90) and RMSEA (≤ 0.06). Results of the survey indicated that the prevalence of DSH (with, without and ambivalent suicidal intentions) was 7%. Two SEM models were constructed involving both mediation and moderation pathways. Results of Model 1 showed association of attachment with DSH was double mediated by social support, depression and anxiety. Model 2 also confirmed association of attachment with DSH with double mediation through relationship style problems, depression and anxiety. In order to understand the contextual picture of the concepts studied in this research both SEM models were also constructed by controlling for demographic factors. This resulted in confirming age, gender and family affluence as significant contributors but with very small effects. Discussion and conclusion: In the present study translation of the instruments helped in building a reservoir for future research. The results of translation and validation of instruments indicated that cultural differences, language needs and age must be accounted for while using standardized psychological instruments. Taking into consideration specific cultural and demographic background of Pakistan, this study also confirms the key role of attachment in influencing interaction of predictors of DSH. It is suggested that intrapersonal and interpersonal factors are influential points of intervention for designing clinical, school and community based awareness and prevention programs for DSH. The thesis also discusses the implications for policy guidelines along with recommendations for future research and other applications of the study

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

Background: Many patients with COVID-19 have been treated with plasma containing anti-SARS-CoV-2 antibodies. We aimed to evaluate the safety and efficacy of convalescent plasma therapy in patients admitted to hospital with COVID-19. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. The trial is underway at 177 NHS hospitals from across the UK. Eligible and consenting patients were randomly assigned (1:1) to receive either usual care alone (usual care group) or usual care plus high-titre convalescent plasma (convalescent plasma group). The primary outcome was 28-day mortality, analysed on an intention-to-treat basis. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings: Between May 28, 2020, and Jan 15, 2021, 11558 (71%) of 16287 patients enrolled in RECOVERY were eligible to receive convalescent plasma and were assigned to either the convalescent plasma group or the usual care group. There was no significant difference in 28-day mortality between the two groups: 1399 (24%) of 5795 patients in the convalescent plasma group and 1408 (24%) of 5763 patients in the usual care group died within 28 days (rate ratio 1·00, 95% CI 0·93–1·07; p=0·95). The 28-day mortality rate ratio was similar in all prespecified subgroups of patients, including in those patients without detectable SARS-CoV-2 antibodies at randomisation. Allocation to convalescent plasma had no significant effect on the proportion of patients discharged from hospital within 28 days (3832 [66%] patients in the convalescent plasma group vs 3822 [66%] patients in the usual care group; rate ratio 0·99, 95% CI 0·94–1·03; p=0·57). Among those not on invasive mechanical ventilation at randomisation, there was no significant difference in the proportion of patients meeting the composite endpoint of progression to invasive mechanical ventilation or death (1568 [29%] of 5493 patients in the convalescent plasma group vs 1568 [29%] of 5448 patients in the usual care group; rate ratio 0·99, 95% CI 0·93–1·05; p=0·79). Interpretation: In patients hospitalised with COVID-19, high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research