Immune parameters as predictors of response to maintenance therapy in low grade non-Hodgkin's lymphoma patients

The non-Hodgkin's lymphomas (NHL) are a heterogeneous group of malignancies characterised by the uncontrolled proliferation of lymphoid cells. The Working Formulation divides these neoplasms into low, intermediate and high-grade categories according to their natural history. Low grade NHL (LG-NHL) is clinically indolent whereas high grade NHL is more aggressive. Most LG-NHL patients respond well to chemotherapy, but are rarely cured, making death from LG-NHL virtually inevitable. In this study on LG-NHL patients, all patients received combination chemotherapy for 6 weeks, which consisted of cyclophosphamide, oncovin (vincristine) and prednisone (COP). After this treatment patients received either oral cyclophosphamide or alpha-interferon (α-IFN) as maintenance treatment for a period of two years. The ability to predict patients' treatment response at diagnosis would be extremely helpful for both the patient and the clinician. This would enable appropriate therapy to be instituted at diagnosis, whether it be cyclophosphamide or α-IFN, which might increase the subsequent survival of these patients, as this would prevent patients from receiving treatment to which they would not respond. Furthermore, patients who were unlikely to respond to either of these two treatments could be targeted for alternative treatment or form part of a clinical research trial. LG-NHL patients were assessed at diagnosis for a number of immune parameters. These included: - natural killer activity (NKA), α-IFN enhanced NKA, mitogen and antigen proliferation, lymphokine activated kill against both KS62 and Daudi targets, phenotypic analysis of circulating lymphocytes, assessment of IL-2 levels after mitogen stimulation of lymphocytes, as well as the determination of plasma IL-2 levels. All these above-mentioned parameters were serially monitored over time in an attempt to predict early relapse. A statistically significant reduction in percentage of circulating CD3+ and CD8+ cells and an increase in percentage NK cells was found in patients at diagnosis as compared to normal controls. A reduction in percentage of circulating NK cells over time appeared to be a good prognostic indicator and an increase in percentage NK cells a poor prognostic indicator in this group of patients, although this was not statistically significant. When the in vitro α-IFN enhanced NKA was indicated as a percentage of NKA, a negative correlation appeared to exist between this in vitro response to α-IFN and the in vivo response, although this was not statistically significant (i.e. those patients showing the least α-IFN enhanced NKA were those that responded clinically and those with the highest α-IFN augmented NKA either relapsed or transformed to a higher grade of NHL). By incorporating the percentages of circulating lymphocytes present in the peripheral blood, into the multivariate discriminant analysis, it was possible to derive formulae to enable the prediction of response to either α-IFN or cyclophosphamide. This was a particularly exciting and apparently novel finding. The work presented here has therefore established both a possible negative indicator of α-IFN response (a high in vitro α-IFN response) and a positive indicator (the formula generated in the multivariate discriminant analysis using the flow cytometric phenotypic analysis). By making using of both of these factors, it would increase the chances of patients being selected for appropriate forms of treatment and minimise the chances of patients suffering a relapse. The Kaplan-Meier curve indicated that cyclophosphamide treatment was more beneficial than α-IFN therapy in this group of patients, although this did not attain statistical significance. Verification of all of these above-mentioned findings would need further confirmation in a larger study

Does globalisation face an existential threat?

The COVID-19 pandemic has been a significant shock for the global economy. With nations protecting their borders and even limiting some trade, does globalisation now face an existential threat? In reality, this is not an entirely new issue, write Michael Cox, Peter Watkins, and Linda Yueh (LSE Ideas)

National Register of Historic Places Eligibility Testing of Site 41SM385 Within TxDOT\u27s Tyler District, Smith County, Texas

PBS&J, an Atkins company, was contracted by the North East Texas Regional Mobility Authority to conduct National Register of Historic Places eligibility testing of site 41SM385, a prehistoric campsite on a small rise above the floodplain of Indian Creek in western Smith County, Texas. Testing investigations were conducted during March and September 2009. The site was subjected to a systematic program of shovel testing, mechanical trenching, and hand excavation in an effort to identify cultural features or living surfaces and optimize recovery of diagnostic faunal, floral, and artifactual remains. The recovered cultural artifacts indicate that site 41SM385 represents a probable Woodland and Caddo‐aged occupation on a small rise on the creek floodplain. The Woodland component is based on recovered small Gary and Kent projectile points characteristic of Woodland culture of the region. The Caddo component is based on ceramic sherds of probable Early or Middle Caddo origin identified at the site. Radiocarbon dating of four ceramic sherds supports these assessments with three sherds dating to the Early to Middle Caddo periods and one sherd dating to the Woodland period. The lack of identified cultural features suggests that the Woodland component probably represents a series of ephemeral usages of the location, probably as short‐term campsites. The Caddo‐aged artifacts at the site probably represent a series of ephemeral usage of the location, either as a resource procurement locus ancillary to nearby site 41SM404 or as a short‐term campsite. The testing program failed to locate living surfaces or cultural features containing in situ artifactual or organic remains preserved on the site. The absence of cultural features and the paucity of lithic tools or ceramic remains make more‐meaningful functional interpretation infeasible. For this reason, the site lacks the data resources that would warrant National Register of Historic Places isting or designation as a State Archeological Landmark. No further work is recommended

Established and emerging biomarkers for the prediction of type 1 diabetes: a systematic review

Type 1 diabetes (T1D) is an autoimmune disease with a prolonged and variable latent period that culminates in the destruction of pancreatic β-cells and the development of hyperglycemia. There is a need for diagnostic biomarkers to detect more accurately detect individuals with prediabetes to expedite targeting for prevention and intervention strategies. To assess the current ability to predict the insidious development of T1D, we conducted a comprehensive systematic review for established and prospective predictive markers of T1D using the Medline, OVID, and EMBASE databases. Resulting citations were screened for relevance to subject. Our research generated five major categories of markers that are either currently used or forthcoming: genetic, autoantibodies, risk score quantification, cellular immunity, and β-cell function. The current standard used to assess T1D onset or predisposition focuses on autoimmune pathology and disease-associated autoantibodies. Research studies in general go beyond autoantibody screening and assess genetic predisposition, and quantitate risk of developing disease based on additional factors. However, there are few currently used techniques that assess the root of T1D: β-cell destruction. Thus, novel techniques are discussed with the potential to gauge degrees of β-cell stress and failure via protein, RNA, and DNA analyses

Comparison of British Thyroid Association, American College of Radiology TIRADS and artificial intelligence TIRADS with histological correlation : diagnostic performance for predicting thyroid malignancy and unnecessary fine needle aspiration rate

OBJECTIVES: To compare diagnostic performance of British Thyroid Association (BTA), American College of Radiology Thyroid Imaging Reporting and Data System (ACR-TIRADS) and Artificial Intelligence TIRADS (AI-TIRADS) for thyroid nodule malignancy. To determine comparative unnecessary fine needle aspiration (FNA) rates. METHODS: 218 thyroid nodules with definitive histology obtained during 2017 were included. Ultrasound images were reviewed retrospectively in consensus by two subspecialist radiologists, blinded to histopathology, and nodules assigned a BTA, ACR-TIRADS and AI-TIRADS grade. Nodule laterality and size were recorded to allow accurate histopathological correlation and determine which nodules met criteria for FNA. RESULTS: 77 (35.3%) nodules were malignant. Deeming ultrasound Grade 4-5 as test-positive and 1-2 as test-negative, sensitivity and specificity for BTA was 98.28 and 42.55%, for ACR-TIRADS: 95.24 and 40.57% and for AI-TIRADS: 93.44 and 45.71%. FNA was indicated in 101 (71.6%), 67 (47.5%) and 65 (46.1%) benign nodules utilising BTA, ACR-TIRADS and AI-TIRADS respectively. The unnecessary FNA rate was significantly higher with BTA (46.3%) compared to ACR-TIRADS (30.7%) and AI-TIRADS (29.8%) p 93% for all systems when considering ultrasound Grade 4-5 as malignant and Grade 1-2 as benign. ACR-TIRADS and AI-TIRADS both had a significantly lower rate of recommended FNA in benign nodules compared to BTA. ADVANCES IN KNOWLEDGE: BTA, ACR-TIRADS and AI-TIRADS have comparable diagnostic performance with high sensitivity but relatively low specificity for predicting thyroid nodule malignancy in this cohort using histology as gold-standard. Using Grade 1-2 as benign and 4-5 as malignant there were more false negatives with TIRADS but this improved when taking other features into account while BTA had a significantly higher rate of unnecessary FNA

MAPS-SNMA ShaD.O.w D.O. Day Rowan SOM Pipeline Program: A Pilot Study

Prior to being a medical student, a majority of pre-medical students have not encountered the course load intensity, academic rigor, and time management required by a medical school curriculum. Diversifying the workforce has been shown to have benefits, especially at the micro or patient level, since having racial or ethnic concordance between providers and patients has been associated with increased levels of satisfaction and improvements in certain clinical outcomes. The number of MDs increased to 841,321 or 91.8% versus 72,961 DOs or 8.0% creating the need for minorities to be knowledgeable of both MD and DO paths to becoming a physician. To provide more knowledge of osteopathic medicine and osteopathic physicians, the Minority Association of Premedical Students (M.A.P.S.) and the the Student National Medical Association (S.N.M.A.) of Rowan University School of Osteopathic Medicine have implemented a ShaDOw DO Day program for the graduate students of Rowan University Graduate School of Biomedical Sciences. The ShaDOw DO Day program will give MAPS students the opportunity to witness the resilience, discipline, and motivation that successful medical students possess.This program will also provide MAPS students with the opportunity to explore a potential career in medicine. Students will gain a perspective on osteopathic principles and osteopathic manipulative medicine. Participants of the program will also be introduced to the quality education an osteopathic medical school such as RowanSOM instills in its students to produce competent and compassionate physicians. Therefore, it is imperative that graduate students learn from medical students to increase their knowledge of osteopathic medicine. To analyze the effectiveness of this program, pre-assessment and post-assessment surveys were given to the participants. Overall, an increase in the understanding of osteopathic medicine and consideration of a career in a health profession and/or medicine was observed demonstrating both the need and success of our program initiative

Evaluation of an ambulatory system for the quantification of cough frequency in patients with chronic obstructive pulmonary disease

BACKGROUND: To date, methods used to assess cough have been primarily subjective, and only broadly reflect the impact of chronic cough and/or chronic cough therapies on quality of life. Objective assessment of cough has been attempted, but early techniques were neither ambulatory nor feasible for long-term data collection. We evaluated a novel ambulatory cardio-respiratory monitoring system with an integrated unidirectional, contact microphone, and report here the results from a study of patients with COPD who were videotaped in a quasi-controlled environment for 24 continuous hours while wearing the ambulatory system. METHODS: Eight patients with a documented history of COPD with ten or more years of smoking (6 women; age 57.4 ± 11.8 yrs.; percent predicted FEV(1 )49.6 ± 13.7%) who complained of cough were evaluated in a clinical research unit equipped with video and sound recording capabilities. All patients wore the LifeShirt(® )system (LS) while undergoing simultaneous video (with sound) surveillance. Video data were visually inspected and annotated to indicate all cough events. Raw physiologic data records were visually inspected by technicians who remained blinded to the video data. Cough events from LS were analyzed quantitatively with a specialized software algorithm to identify cough. The output of the software algorithm was compared to video records on a per event basis in order to determine the validity of the LS system to detect cough in COPD patients. RESULTS: Video surveillance identified a total of 3,645 coughs, while LS identified 3,363 coughs during the same period. The median cough rate per patient was 21.3 coughs·hr(-1 )(Range: 10.1 cghs·hr(-1 )– 59.9 cghs·hr(-1)). The overall accuracy of the LS system was 99.0%. Overall sensitivity and specificity of LS, when compared to video surveillance, were 0.781 and 0.996, respectively, while positive- and negative-predictive values were 0.846 and 0.994. There was very good agreement between the LS system and video (kappa = 0.807). CONCLUSION: The LS system demonstrated a high level of accuracy and agreement when compared to video surveillance for the measurement of cough in patients with COPD

Proinsulin and heat shock protein 90 as biomarkers of beta-cell stress in the early period after onset of type 1 diabetes

Rapid evaluation of therapies designed to preserve β cells in persons with type 1 diabetes (T1D) is hampered by limited availability of sensitive β-cell health biomarkers. In particular, biomarkers elucidating the presence and degree of β-cell stress are needed. We characterized β-cell secretory activity and stress in 29 new-onset T1D subjects (10.6 ± 3.0 years, 55% male) at diagnosis and then 8.2 ± 1.2 weeks later at first clinic follow-up. We did comparisons with 16 matched healthy controls. We evaluated hemoglobin A1c (HbA1c), β-cell function (random C-peptide [C] and proinsulin [PI]), β-cell stress (PI:C ratio), and the β-cell stress marker heat shock protein (HSP)90 and examined these parameters' relationships with clinical and laboratory characteristics at diagnosis. Mean diagnosis HbA1c was 11.3% (100 mmol/mol) and 7.6% (60 mmol/mol) at follow-up. C-peptide was low at diagnosis (P < 0.001 vs controls) and increased at follow-up (P < 0.001) to comparable with controls. PI did not differ from controls at diagnosis but increased at follow-up (P = 0.003) signifying increased release of PI alongside improved insulin secretion. PI:C ratios and HSP90 concentrations were elevated at both time points. Younger subjects had lower C-peptide and greater PI, PI:C, and HSP90. We also examined islets isolated from prediabetic nonobese diabetic mice and found that HSP90 levels were increased ∼4-fold compared with those in islets isolated from matched CD1 controls, further substantiating HSP90 as a marker of β-cell stress in T1D. Our data indicate that β-cell stress can be assessed using PI:C and HSP90. This stress persists after T1D diagnosis. Therapeutic approaches to reduce β-cell stress in new-onset T1D should be considered