Non-invasive detection of neuroendocrine prostate cancer through targeted cell-free DNA methylation

Castration-resistant prostate cancer (CRPC) is a heterogeneous disease associated with phenotypic subtypes that drive therapy response and outcome differences. Histologic transformation to castration-resistant neuroendocrine prostate cancer (CRPC-NE) is associated with distinct epigenetic alterations, including changes in DNA methylation. The current diagnosis of CRPC-NE is challenging and relies on metastatic biopsy. We developed a targeted DNA methylation assay to detect CRPC-NE using plasma cell-free DNA (cfDNA). The assay quantifies tumor content and provides a phenotype evidence score that captures diverse CRPC phenotypes, leveraging regions to inform transcriptional state. We tested the design in independent clinical cohorts (n=222 plasma samples) and qualified it achieving an AUC>0.93 for detecting pathology-confirmed CRPC-NE (n=136). Methylation-defined cfDNA tumor content was associated with clinical outcomes in two prospective phase II clinical trials geared towards aggressive variant CRPC and CRPC-NE. These data support the application of targeted DNA methylation for CRPC-NE detection and patient stratification

Mortality in Hip Fracture Patients During the COVID-19 Pandemic: A Retrospective Analysis in a District General Hospital in the United Kingdom

Introduction Hip fracture is commonly seen in elderly patients because of low-energy trauma. It carries significant morbidity and mortality. Scoring systems such as the Nottingham hip fracture score (NHFS) have shown a good correlation with increased mortality as the value of these scores increases. In our study, we aim to ascertain the hip fracture mortality in our population, compare the mortality in hip fractures compared to previously reported figures in literature and nationally reported figures during the first year of the COVID-19 pandemic, and also ascertain the usefulness of NHFS in predicting mortality in hip fractures. Methods We gathered mortality data on hip fracture patients admitted to our unit from January 1, 2020 to December 31, 2020.&nbsp;NHFS was calculated for all patients and the 30-day mortality rate was compared to previously reported hip fracture mortality rates using the standard mortality ratio (SMR). One-year mortality was stratified by placing patients in high and low NHFS groups. The log-rank test was used to compare hip fracture survival at one month and at one year in the high NHFS (NHFS &gt;4) group and low NHFS group (NHFS value 4 or below). Additionally, a log-rank test was used to compare one-month and one-year survival in hip fractures managed with hemiarthroplasty, dynamic hip screw and intramedullary nail. Results In 2020, 388 patients were admitted with hip fractures to our unit. The crude mortality rate was 3.9% at 30 days and 20.88% at one year. Compared to the National Hip Fracture Database report for 2020, the incidence risk ratio for mortality was 0.46 (p-value&lt;0.05). The SMR at 30 days was 0.34 (CI=0.17-0.51) and the SMR at one year was 0.63 (CI=0.49-0.77). The survival rate was higher at 30 days and one year in the low NHFS group compared to the high NHFS group (p-value&lt;0.01). The survival rate at one month and one year were similar in groups managed with hemiarthroplasty, dynamic hip screws, and intramedullary nails (p-value&gt;0.05). Conclusions Hip fracture mortality has been decreasing steadily and we noted a lower rate of hip fracture mortality compared to figures reported previously as per NHFS studies even though the study was conducted during the COVID-19 pandemic period. We also noted lower 30-day mortality in our hospital as compared to the national 30-day mortality rate for hip fracture patients in 2020. &nbsp;</p

Impact of COVID-19 Pandemic on the Length of Hospital Stay in Hip Fracture Patients: A Single Centre Study

Background Hip fracture is a debilitating injury, especially in older individuals, which is associated with significant morbidity and mortality. In recent decades, there has been a great focus on early rehabilitation and discharge after hip fractures. The aim of such efforts is to minimize the financial and clinical burden of this condition. We conducted our study during the COVID-19 pandemic and compared the length of hospital stay (LOS) in 2020 to the LOS in 2019. Additionally, we studied the factors which may impact the LOS, such as premorbid status according to established scoring systems, the type of fracture, an operation performed, and time to surgery. &nbsp; Methods We collected the data regarding the length of stay (in days) for all hip fracture patients admitted to our unit from 1st January 2019 until 31st December 2020. We then compared the mean LOS for both years using the t-test. We calculated the Nottingham Hip Fracture Score (NHFS) and American Society of Anaesthesiologists (ASA) scores for patients admitted in 2020 and calculated the correlation between increasing values of these scores and the LOS. We also compared the mean LOS for patients admitted in 2020 based on the type of fracture and type of management. We studied the correlation between the time to surgery and the LOS for patients admitted in 2020. &nbsp; Results Three hundred and eighty-eight patients were admitted with hip fractures in 2020, and 452 were admitted in 2019. LOS in 2020 was significantly lower (23.39 days) compared to 2019 (31.36 days) with p&lt;0.01. While evaluating data from 2019, it was noted that there was a small positive correlation between LOS and NHFS (r=0.231, p&lt;0.001) and LOS and ASA (r=0.18, p&lt;0.001). The mean LOS for intracapsular fractures was noted to be lower than that of extracapsular fractures, but this was not statistically significant (p=0.17). An ANOVA test showed that the mean LOS for patients undergoing hemiarthroplasty, dynamic hip screws (DHS), and intramedullary nails (IMN) was significantly longer than for patients managed with total hip replacement or patients managed non-operatively (F=3.551, p&lt;0.01). &nbsp; Conclusion Hip fracture patients admitted to our department were discharged quicker during the first year of the COVID-19 pandemic. The LOS for hip fractures increases with an increase in their NHFS or ASA scores. Extracapsular and intracapsular fractures lead to roughly the same periods of inpatient stay. Patients undergoing hemiarthroplasty, DHS, or IMN stay longer in the hospital compared to other treatment modalities.</p

Genetic Interactions between the Drosophila Tumor Suppressor Gene ept and the stat92E Transcription Factor

Tumor Susceptibility Gene-101 (TSG101) promotes the endocytic degradation of transmembrane proteins and is implicated as a mutational target in cancer, yet the effect of TSG101 loss on cell proliferation in vertebrates is uncertain. By contrast, Drosophila epithelial tissues lacking the TSG101 ortholog erupted (ept) develop as enlarged undifferentiated tumors, indicating that the gene can have anti-growth properties in a simple metazoan. A full understanding of pathways deregulated by loss of Drosophila ept will aid in understanding potential links between mammalian TSG101 and growth control.We have taken a genetic approach to the identification of pathways required for excess growth of Drosophila eye-antennal imaginal discs lacking ept. We find that this phenotype is very sensitive to the genetic dose of stat92E, the transcriptional effector of the Jak-Stat signaling pathway, and that this pathway undergoes strong activation in ept mutant cells. Genetic evidence indicates that stat92E contributes to cell cycle deregulation and excess cell size phenotypes that are observed among ept mutant cells. In addition, autonomous Stat92E hyper-activation is associated with altered tissue architecture in ept tumors and an effect on expression of the apical polarity determinant crumbs.These findings identify ept as a cell-autonomous inhibitor of the Jak-Stat pathway and suggest that excess Jak-Stat signaling makes a significant contribution to proliferative and tissue architectural phenotypes that occur in ept mutant tissues

Beirt fhílí a scríobh dánta caointe dá máthair

na shaothar ceannródaíoch, The English Elegy: Studies in the Genre from Spencer to Yeats (1985), maíonn Peter Sacks, ‘the traditional forms and figures of elegy relate to the experience of loss and the search for consolation.’ Is géire, áfach, an dúshlán eiseach ar an bhás, dar leis an charachtar Pozzo a chruthaíonn Beckett in Waiting For Godot (1986:83): They give birth astride of a grave, the light gleams an instant, then it’s night once more. Soláthraíonn an dá dhearcadh thuas comhthéacs don alt seo a chuireann dánta caointe le Cathal Ó Searcaigh agus le Seamus Heaney i gcuimhne ar a máithreacha i gcomparáid lena chéile. Is iad na dánta a ndíreofar orthu san alt seo ná ‘III’ agus ‘VI’ le Heaney as a shraith d’ocht ndán mholta The Haw Lantern a chéadfhoilsíodh in 1987, agus an dá dhán mholta ‘Na Pionnaí Gruaige’ in An tAm Marfach ina Mairimid (2010) agus ‘Caoineadh’ as An Bealach ’na Bhaile (1993) le Cathal Ó Searcaigh. Ba nós ciotainta é i measc na nGael an duine marbh a chaoineadh, dar le Ó Súilleabháin (1961: 101): ‘Is minic a mholtar an duine atá ar lár go hard agus léirítear a dhea-thréithe sa dán’. Cé go léirítear an moladh céanna sna dánta a scríobh Heaney agus Ó Searcaigh, tá difríochtaí eatarthu atá téamach agus teoiriciúil. Is soiléir go bhfuil dánta molta an bheirt fhilí tochtmhar agus coscrach, ach is é tuairim scríbhneoirí an ailt seo go léiríonn an dá dhán ‘III’ agus ‘VI’ as Clearances le Heaney go bhfuil coimhlint phearsanta iontu murab ionann is dánta Uí Shearcaigh. Tá dobrón frithráiteach ar Heaney a léiríonn teannas as broinn idir é féin agus a mháthair. Ar an láimh eile, tá Ó Searcaigh an-ghoilliúnach go fóill agus é ag moladh a mháthar go hard gan teannas ar bith le sonrú ina shaothar. Ar a bharr sin, ó thaobh dearcadh teoiriciúil de, tá difear suntasach idir an stíl teanga a úsáideann an bheirt fhilí ina gcuid filíochta. Is follasach in ‘Caoineadh’ agus tá sé intuigthe in ‘Na Pionnaí Gruaige’ go bhfuil bás mháthair Uí Shearcaigh ceangailte le creimeadh na Gaeilge, creimeadh a tharlaíonn gach uair a chailltear duine den tseanghlúin agus creimeadh ar cuireadh tús leis le polasaí an choilíneachais. Maidir le Heaney, áfach, tá an taobh pearsanta agus an taobh polaitiúil ceangailte le chéile, rud atá intuigthe ón ainm Clearances a thugann sé ar a shraith dánta, ainm corraitheach atá ceangailte le córas coilíneachais na Sasanach in Éirinn. Tá difríocht theoiriciúil eile idir an bheirt fhilí. Éiríonn le Heaney dánta a chumadh a léiríonn go haeistéitiúil an dóigh a n-athraíonn sé an dobrón atá air trí fhilíocht a chumadh a bhfuil brí uilíoch inti. Dar le Corcoron (1998: 157–8): In Clearances grief is transformed into a new kind of outwardly directed energy. Death is luminous as well as negative, a ‘bright nowhere’ in which a soul ‘ramifies’. The reality and idea of death becomes an entirely undesired but necessary enlargement of imaginative capacity

Foghlaim na filíochta ag an tríú leibhéal: éisteacht ghníomhach agus féidearthachtaí maidir le fonn agus fiosracht a spreagadh i measc na mac léinn

Is é aidhm an taighde seo a fháil amach an gcuirfidh modh eile teagaisc, a chuireann béim ar cheol agus ar aithris na filíochta agus ar fhoghlaim ghníomhach, fonn ar mhic léinn staidéar a dhéanamh uirthi agus an músclóidh sé fiosracht na mac léinn inti. Tá an taighde seo bunaithe ar fhiosrú oideolaíoch. Cuireann Watkins & Mortimore (1999: 3) síos ar theagasc bunaithe ar fhiosrú oideolaíoch mar seo a leanas, ‘any conscious activity by one person designed to enhance the learning of another’. Cuireann Campbell & Groundwater-Smith (2010: 13) síos ar thaighde cleachtóra mar ‘Practitioner research, located in the larger field of practice-based and applied research, is distinguished by its focus on research done by practitioners themselves, usually an investigation of practice with a view to evaluation or improvement’. Is é aidhm an taighdeora sa chás seo a chleachtas féin maidir le teagasc na filíochta a fheabhsú agus a fhorbairt agus taithí dhearfach ar an fhilíocht a thabhairt do na mic léinn. Ó thaithí an taighdeora, is minic a bhíonn dearcadh diúltach ag mic léinn tríú leibhéal ar fhoghlaim na filíochta agus a shíleann siad go bhfuil sí leadránach. Baineadh úsáid as cur chuige eile teagaisc sa taighde seo le hiarracht a dhéanamh a suim a mhúscailt inti. Rinneadh fiosrú oideolaíoch lena fháil amach an gcuideodh sé le foghlaim na filíochta dá n-éistfeadh na mic léinn le teachtaireacht phearsanta a chuir an file Cathal Ó Searcaigh chucu maidir le foghlaim na filíochta, dá n-éistfeadh siad leis an fhile ag aithris a chuid filíochta, dá léifeadh siad féin cuid dánta de chuid Uí Shearcaigh os ard agus dá mbeadh siad féin gníomhach san fhoghlaim. Deir Creely (2019: 1): ‘I contend that an experiential basis to poetry teaching has the potential for positive reception by students and may promote a deeper and more sustained understanding of poetry and poetic language.

Identifying Persons Who Inject Drugs in Medical Examiner Data in Maricopa County, AZ

ObjectiveTo determine whether data from the Office of the Medical Examiner are useful for conducting injection drug use surveillance in Maricopa County, Arizona, and to describe the characteristics of decedents who died from a drug overdose, were investigated by the county’s medical examiner, and had an indication of injection drug use.IntroductionThe rate of drug overdose deaths in the United States has increased steadily since 2000. Injection drug use, a practice associated with infectious disease transmission, has likely increased along with this upward trend in drug overdoses. Injection drug use surveillance is difficult to conduct at a public health department because there are no specific Internal Classification of Diseases codes to identify this risk behavior in hospital discharge or vital registration data. Maricopa County Department of Public Health Office of Epidemiology aimed to identify indications of injection drug use within data from the Office of the Medical ExaminerMethodsThe Office of Epidemiology receives toxicology results for deaths which were ruled by the Maricopa County’s medical examiner as substance use related, also referred to as overdose deaths. We explored data from decedents who were investigated by the Maricopa County’s medical examiner between 7/1/2016-6/30/2017, had a cause of death from a drug overdose, and screened positive for at least one commonly injected drug (i.e., opioids - general, heroin, methamphetamine, or cocaine). To narrow our search for indications of injection drug use, we requested preliminary investigation reports and medical examiner reports for a random sample of reports (10% from each drug class) from the Office of the Medical Examiner. Preliminary investigation reports, produced by a scene investigator, included the decedent’s medical history, risk factors, circumstances of death, circumstances of death discovery, and scene characteristics. Medical examiner reports included toxicology screen results, autopsy findings, and the cause of death. The Office of the Medical Examiner provided these reports to the Office of Epidemiology in portable document format (PDF) for this analysis. We built a query to identify keywords related to injection drug use (e.g. inject, syringe, needle) and injection injuries (e.g. cellulitis, abscess). We used PDF XChangeViewer’s Optical Character Recognition (OCR) function to convert the PDF reports to text data and used Python’s String and Collections modules to parse text data for occurrences of keywords within the reports. Reports that included at least one keyword were manually reviewed and classified as probable or ruled out for injection drug use, and characteristics of those with a probable indication of injection drug use were described.ResultsDuring the period of interest, 1,127 deaths were caused by drug overdose, of which 930 decedents screened positive for opioids (N=673, 59.7% of drug overdose deaths), heroin (358, 38.5%), methamphetamine (445, 39.5%), and/or cocaine (100, 11%). Indications of injection drug use were identified within 48 (32.7%) of the 147 preliminary investigation and medical examiner reports that were reviewed (Table). Common indicators of injection drug use included: history of drug use as a reported risk factor; presence of prescription drugs, illicit drugs, or drug paraphernalia at the scene; body position at the scene; and injuries associated with needle use identified during the autopsy. The most common terms that indicated injection drug use were “syringe”, “intravenous”, “needle”, and “inject”. Among persons who had an indication of injection drug use, 85.4% were male, 52.1% were between the ages of 20 and 39 years, and 85.4% were white.ConclusionsData from the Office of the Medical Examiner’s preliminary investigation and medical examiner reports provided rich context for understating the underlying risk factors and circumstances that contributed to drug overdose deaths. Injection drug use paraphernalia found at the scene of death and injuries found during autopsy were well-documented in these reports, which helped us quantify the proportion of decedents who died from overdose that may have injected drugs, by drug class. We were able to describe basic characteristics of this sample, which were consistent with previously published reports describing people who inject drugs. This surveillance method has limitations, however. Decedents reviewed by a medical examiner represent a subset of the drug using population, and findings may not be generalized to the full population. Other data sources and analytical methods must be employed to accurately estimate the number of people who inject drugs in Maricopa County and to describe their characteristics and experiences