tbuckley/cabot-search huggingface dataset:
Italian survey of second tumors in patients with diagnosis of GIST (gastrointestinal stromal tumor).
Authors: Silvia Gasperoni, Luca Messerini, Elena Fumagalli, Sara Manglaviti, Bruno Vincenzi, Alessandro Mazzocca, Maria A. Pantaleo, Margherita Nannini, Giuseppe Badalamenti, Lorena Incorvaia, Margaret Ottaviano, Giovannella Palmieri, Giovanni Grignani, Lorenzo D'Ambrosio, Giulia Meoni, Agnese Paderi, Sara Fancelli, Enrico Caliman, Lorenzo Tofani, Enrico Mini
Journal: Journal of Clinical Oncology (2019)

11032 Background: GISTs are the most common mesenchymal tumors of the digestive tract. As of recent, new links are being made between GISTS and secondary malignancies. However, whether the coexistence of GISTs with other tumors is stochastic, or the result of related pathogenetic mechanisms is still unknown. Methods: We retrospectively reviewed clinical and molecular features from all GIST patients with second tumors treated in seven Italian GIST reference centers. Qualitative variables were compared using the Fisher exact test. Results: Clinical data of 184 patients with diagnosis of GIST were evaluated. Median age at diagnosis was 66 years, KIT exon 11 resulted the most frequent mutation (73%) while seven patients (3.8%) had a genetic syndrome. The most common primary GIST localizations were stomach (54%) and small intestine (33%). Second tumors arose mostly from gastrointestinal and genitourinary tract. Fourtythree patients had two primary tumors other than GIST and five patients had three other primary malignancies. According to Miettinen criteria, 45% of non-metastatic patients at diagnosis belong to low or very low-risk classes. We highlighted a significant correlation (P=0.002) between risk class and second/third tumor localization, with considerably high percentage of GI second malignancies in low/very low risk GISTs (table). Conclusions: The high frequency of second/third tumors reported in low and very low GIST calls for a careful follow-up also in these patients. Furthermore, this population requires further genetic investigation, NGS analysis is ongoing. [Table: see text]
Concordance Between Electronic Clinical Documentation and Physicians’ Observed Behavior
Authors: Carl T. Berdahl, Gregory J. Moran, Owen McBride, Alexandra M. Santini, Ilya A. Verzhbinsky, David L. Schriger
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Following the adoption of electronic health records into a regulatory environment designed for paper records, there has been little investigation into the accuracy of physician documentation. <h3>Objective</h3> To quantify the percentage of emergency physician documentation of the review of systems (ROS) and physical examination (PE) that observers can confirm. <h3>Design, Setting, and Participants</h3> This case series took place at emergency departments in 2 academic medical centers between 2016 and 2018. Participants’ patient encounters were observed to compare real-time performance with clinical documentation. <h3>Exposures</h3> Resident physicians were shadowed by trained observers for 20 encounters (10 encounters per physician per site) to obtain real-time observational data; associated electronic health record data were subsequently reviewed. <h3>Main Outcomes and Measures</h3> Number of confirmed ROS systems (range, 0-14) divided by the number of documented ROS systems (range, 0-14), and number of confirmed PE systems (range, 0-14) divided by the number of documented PE systems (range, 0-14). <h3>Results</h3> The final study cohort included 9 licensed emergency medicine residents who evaluated a total of 180 patients (mean [SD] age, 48.7 [20.0] years; 91 [50.5%] women). For ROS, physicians documented a median (interquartile range [IQR]) of 14 (8-14) systems, while audio recordings confirmed a median (IQR) of 5 (3-6) systems. Overall, 755 of 1961 documented ROS systems (38.5%) were confirmed by audio recording data. For PE, resident physicians documented a median (IQR) of 8 (7-9) verifiable systems, while observers confirmed a median (IQR) of 5.5 (3-6) systems. Overall, 760 of 1429 verifiable documented PE systems (53.2%) were confirmed by concurrent observation. Interrater reliability for rating of ROS and PE was more than 90% for all measures. <h3>Conclusions and Relevance</h3> In this study of 9 licensed year emergency medicine residents, there were inconsistencies between the documentation of ROS and PE findings in the electronic health record and observational reports. These findings raise the possibility that some documentation may not accurately represent physician actions. Further studies should be undertaken to determine whether this occurrence is widespread. However, because such studies are unlikely to be performed owing to institution-level barriers that exist nationwide, payers should consider removing financial incentives to generate lengthy documentation.
Assessment of Subspecialty Choices of Men and Women in Internal Medicine From 1991 to 2016
Authors: Anna T. Stone, Kelly M. Carlson, Pamela S. Douglas, Kathleen L. Morris, Mary Norine Walsh
Journal: JAMA Internal Medicine (2019)

were women. 2 We examined changes in the internal medicine subspecialty choices of women and men from 1991 to 2016.
Commentary on “Indicators of impending pig kidney and heart xenograft failure: Relevance to clinical organ xenotransplantation” (Int J Surg 2019;Aug 21. Pii: S1743-9191(19)30215-8. doi:10.1016/j.ijsu.2019.08.024. [Epub ahead of print])
Authors: Suzanne Bertera
Journal: International Journal of Surgery (2019)
Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction
Authors: John J.V. McMurray, Scott D. Solomon, Silvio E. Inzucchi, Lars Køber, Mikhail N. Kosiborod, Felipe A. Martinez, Piotr Ponikowski, Marc S. Sabatine, Inder S. Anand, Jan Bělohlávek, Michael Böhm, Chern-En Chiang, Vijay K. Chopra, Rudolf A. de Boer, Akshay S. Desai, Mirta Diez, Jaroslaw Drozdz, Andrej Dukát, Junbo Ge, Jonathan G. Howlett, Tzvetana Katova, Masafumi Kitakaze, Charlotta E.A. Ljungman, Béla Merkely, Jose C. Nicolau, Eileen O’Meara, Mark C. Petrie, Pham N. Vinh, Morten Schou, Sergey Tereshchenko, Subodh Verma, Claes Held, David L. DeMets, Kieran F. Docherty, Pardeep S. Jhund, Olof Bengtsson, Mikaela Sjöstrand, Anna-Maria Langkilde
Journal: New England Journal of Medicine (2019)

In patients with type 2 diabetes, inhibitors of sodium–glucose cotransporter 2 (SGLT2) reduce the risk of a first hospitalization for heart failure, possibly through glucose-independent mechanisms. More data are needed regarding the effects of SGLT2 inhibitors in patients with established heart failure and a reduced ejection fraction, regardless of the presence or absence of type 2 diabetes.
The miracle cure
Authors: Fiona Godlee
Journal: BMJ (2019)

As miracle cures are hard to come by, any claims that a treatment is 100% safe and effective must always be viewed with intense scepticism. There is perhaps one exception. Physical activity has been called a miracle cure by no less a body than the Academy of Medical Sciences (http://bit.ly/2lTqDvc); and, like those who avail themselves of it, the supporting science grows stronger by the day. The BMJ recently published a systematic review showing a clear dose-response relation between …
Abstract 489: JTV-519 (K201) Reverses Abnormal Ca <sup>2+</sup> Release And Dynamic Ca <sup>2+</sup> Waves In Purkinje Cells From The Infarcted Canine Heart
Authors: Masanori Hirose, Bruno Stuyvers, Wen Dun, Hiroaki Shimokawa, Henk EDJ ter Keurs, Penelope Boyden
Journal: Circulation (2007)

JTV-519 (K201) has been shown to be anti-arrhythmic in the ischemic/reperfusion setting. The mechanism is unknown. Purpose: To investigate the effects of JTV-519(K201) (Aetas Pharm Co.) in Purkinje cells dispersed from the subendocardium of the 48hr infarcted canine heart (IZPCs). IZPCs are the source of the triggered ventricular arrhythmias that occur at this time post coronary artery occlusion. Methods: Ca 2+ release events (elevations of basal [Ca 2+ ] equivalent to F/F 0 3.4 SD over F 0 ) in both intact and permeabilized single IZPCs were imaged using 2DCM with Fluo-4 and analyzed using a custom IDL program. Results: In intact IZPCs, the Ca 2+ release event (ev) rate was increased in the Subsarcolemmal region (SSL, a layer of ∼ 5μm thickness below the membrane; 0.0161±0.0031 ev/μm 2 /sec, n=cells=30, 1198 ev) but not in the Core region, when compared to normal Purkinje cells (NZPCs; SSL, 0.0089±0.0018 ev/μm 2 /sec, n=34, 747 ev, p&lt;0.05). SR Ca 2+ ontent as estimated by rapid caffeine (20mM) application was comparable between NZPCs and IZPCs in both subcellular regions. Superfusion of JTV-519(K201) (1μM) normalized the SSL Ca 2+ event rate in intact IZPCs (to 0.0086±0.0016 ev/μm 2 /sec, n=17, 510ev, p&lt;0.05 vs untreated IZPC value) without a change in SR Ca 2+ content. The incidence of spontaneous Ca 2+ waves is increased in intact IZPCs (0.0016/μm 2 /sec*1000, n=57) and was also normalized by JTV-519(K201)(0.0004/ μm 2 /sec*1000, n=30). In saponin-treated IZPCs ([Ca 2+ ] cyto= 100nM), JTV-519(K201) normalized the enhanced Ca 2+ event rate (from 0.0246±0.0030 ev/μm 2 /sec, n=28 to 0.0110±0.0023 ev/μm 2 /sec, n=7, P&lt;0.05). Conclusion: In Purkinje cells that survive in the infarcted heart, the enhanced subcellular Ca 2+ event rate is due to enhanced Ca 2+ induced Ca 2+ release. This leads to cell wide Ca 2+ waves and arrhythmias. By normalizing Ca 2+ sensitivity of Ca 2+ release channels of IZPCs, JTV519(K201) reduces the spontaneous Ca 2+ event rate, the incidence of Ca 2+ waves and thus the likelihood of infarct Purkinje cell induced triggered arrhythmias.
Nosocomial outbreak of crusted scabies in immunosuppressed patients caused by <i>Sarcoptes scabiei</i> var. <i>canis</i>
Authors: L. Stingeni, M. Tramontana, M. Principato, I. Moretta, S. Principato, L. Bianchi, K. Hansel
Journal: British Journal of Dermatology (2019)
Legally protecting apologies shrinks the clinician-patient relationship
Authors: Rick Iedema, Jane Sandal, Mary Adams
Journal: BMJ (2019)

Leung and Porter’s article on candour and apologising promotes a legal angle on incident disclosure rather than a human one.1 You could (and many do) argue that the legal perspective is the one that matters because that’s where big sums of money and reputations are at stake. Others regard this “legalisation” of …
Phase II study of oral S-1 monotherapy in metastatic colorectal cancer after failure of both irinotecan and oxaliplatin-containing regimen
Authors: B. Cho, H. Choi, H. Jeung, S. Rha, J. Ahn, J. Roh, Y. Kim, H. Chung
Journal: Journal of Clinical Oncology (2006)

3597 Background: There has been a considerable increase in the number of patients (pts) with mCRC pretreated with both irinotecan and oxaliplatin. Little is known about third-line therapy in this group of pts. We conducted a phase II trial of oral S-1 in pts with advanced colorectal cancer who failed on both irinotecan and oxaliplatin. Methods: This phase II study was designed to evaluate the activity and toxicity of S-1 monotherapy in 31 advanced colorectal cancer pts (P 0 = 3%, P 1 = 15%; α = 0.05, power = 80%, drop-out rate 10 %). S-1 was administered orally twice daily, 70 mg/m 2 /day for 14 days followed by 1-week rest. Eligibility criteria included ECOG 0–2; measurable lesion; adequate organ functions; signed informed consent. Results: As of 1 st September 2005, 21 pts were enrolled. Median age of all pts 55 years. There were 10 male and 11 females. Thirteen of 21 patients were treated with oxaliplatin-containing regimens as a first-line therapy for metastatic diseases. The median number of treatments was 3 courses (range, 1–10). The relative dose intensity was 1.0 (0.83 - 1.0) with a median dose of120 mg (100 -140 mg). Nineteen out of 21 patients were evaluable. The confirmed response rate was 21.1% (4/19, 1 CR, 3 PR). The median PFS was 11 weeks, and median OS was not reached. The most frequent adverse reaction was skin pigmentation (47.6%). Grade 3 toxicities was skin pigmentation in 1 patients (4.8%), neutropenia in 1 (4.8%), and anemia in 1 (4.8%), respectively. Conclusion: This results shows that S-1 produces a promising response rate with an acceptable safety profile in refractory, mCRC. S-1 has the potential to become a valuable option as a third-line salvage regimen in irinotecan and oxaliplatin pretreated mCRC pts. Clinical trial of combination therapy with S-1 will be warranted. No significant financial relationships to disclose.
Author Correction: Do no harm: a roadmap for responsible machine learning for health care
Authors: Jenna Wiens, Suchi Saria, Mark Sendak, Marzyeh Ghassemi, Vincent X. Liu, Finale Doshi-Velez, Kenneth Jung, Katherine Heller, David Kale, Mohammed Saeed, Pilar N. Ossorio, Sonoo Thadaney-Israni, Anna Goldenberg
Journal: Nature Medicine (2019)
Vaping among US teens has doubled since 2017
Authors: Gareth Iacobucci
Journal: BMJ (2019)

The prevalence of vaping among teenagers in the US has more than doubled since 2017, new survey figures have shown.

Academics at the University of Michigan who carry out annual surveys of teenage vaping prevalence released their latest data to the New England Journal of Medicine in a letter published on 18 September.1

The annual surveys track the prevalence of vaping among 12th grade (18-19 years old), 10th grade (15-16), and 8th grade (13-14) students.2 The data show significant increases from 2018 to 2019 at each of the three grade levels in the number of students who said they …
Abstract P154: Systematic Review of Dietary Salt Reduction Policies: Evidence for an Effectiveness Hierarchy?
Authors: LirijeHyseni, AlexElliot-Green, FfionLloyd-Williams, MartinO’Flaherty, ChrisKypridemos, RoryMcGill, LoisOrton, HelenBromley, FrancescoCappuccio, SimonCapewell
Journal: Circulation (2016)

Background: Non-communicable disease (NCD) prevention strategies now prioritise four major risk factors: food, tobacco, alcohol and physical activity. Dietary salt intake is on average 5g/day higher than the recommended intake leading to high blood pressure, cardiovascular disease and gastric cancer. Substantial reductions in salt intake are therefore urgently needed. However, debate continues about the most effective approaches. We therefore systematically reviewed the evidence on possible interventions to inform future prevention programmes. We hypothesised an effectiveness hierarchy whereby “upstream structural” interventions targeting populations are more powerful than “downstream, agentic” interventions targeting individuals. Methods: We searched six electronic databases using a pre-piloted search strategy focussing on the effectiveness of population interventions to reduce salt intake. Retrieved papers were screened, appraised and graded for quality independently by two researchers. Extracted data w...
MCUB Regulates the Molecular Composition of the Mitochondrial Calcium Uniporter Channel to Limit Mitochondrial Calcium Overload During Stress
Authors: Jonathan P. Lambert, Timothy S. Luongo, Dhanendra Tomar, Pooja Jadiya, Erhe Gao, Xueqian Zhang, Anna Maria Lucchese, Devin W. Kolmetzky, Neil S. Shah, John W. Elrod
Journal: Circulation (2019)

The mitochondrial calcium uniporter (mtCU) is an ≈700-kD multisubunit channel residing in the inner mitochondrial membrane required for mitochondrial Ca2+ (mCa2+) uptake. Here, we detail the contribution of MCUB, a paralog of the pore-forming subunit MCU, in mtCU regulation and function and for the first time investigate the relevance of MCUB to cardiac physiology.We created a stable MCUB knockout cell line (MCUB-/-) using CRISPR-Cas9n technology and generated a cardiac-specific, tamoxifen-inducible MCUB mutant mouse (CAG-CAT-MCUB x MCM; MCUB-Tg) for in vivo assessment of cardiac physiology and response to ischemia/reperfusion injury. Live-cell imaging and high-resolution spectrofluorometery were used to determine intracellular Ca2+ exchange and size-exclusion chromatography; blue native page and immunoprecipitation studies were used to determine the molecular function and impact of MCUB on the high-molecular-weight mtCU complex.Using genetic gain- and loss-of-function approaches, we show that MCUB expression displaces MCU from the functional mtCU complex and thereby decreases the association of mitochondrial calcium uptake 1 and 2 (MICU1/2) to alter channel gating. These molecular changes decrease MICU1/2-dependent cooperative activation of the mtCU, thereby decreasing mCa2+ uptake. Furthermore, we show that MCUB incorporation into the mtCU is a stress-responsive mechanism to limit mCa2+ overload during cardiac injury. Indeed, overexpression of MCUB is sufficient to decrease infarct size after ischemia/reperfusion injury. However, MCUB incorporation into the mtCU does come at a cost; acute decreases in mCa2+ uptake impair mitochondrial energetics and contractile function.We detail a new regulatory mechanism to modulate mtCU function and mCa2+ uptake. Our results suggest that MCUB-dependent changes in mtCU stoichiometry are a prominent regulatory mechanism to modulate mCa2+ uptake and cellular physiology.
Effective targeted antitumor activity of the antimicrobial agent taurolidine against relapsed/refractory neuroblastoma: Cytotoxicity, target modulation and tumor xenograft studies.
Authors: Lucy Swift, Chunfen Zhang, Antony Pfaffle, Paul Chew, Olga Kovalchuk, Tanya Maria Trippett, Aru Narendran
Journal: Journal of Clinical Oncology (2019)

e21502 Background: Neuroblastoma (NB) is the most common extracranial solid tumor and one of the most complex and difficult to treat diseases in pediatrics. Currently, even with highly aggressive treatment protocols, the prognosis for patients with high-risk and relapsed NB remains poor. Hence, there is a clear need to identify new agents and novel therapeutic strategies for the treatment of these children. Taurolidine (TRD) is derived from the aminosulfoacid taurine and has known anti-microbial and anti-inflammatory properties. TRD has demonstrated anti-neoplastic activity against a range of aggressive human tumors. We present mechanistic evidence and supportive preclinical data from in vitro and animal models of refractory NB for the development of an early phase clinical trial incorporating TRD. Methods: For in vitro activity studies, a panel of cell lines derived from patients with relapsed NB (n = 6) and normal control cells were treated with increasing concentrations of TRD and cell viability was measured by alamar blue assay. Phase-contrast light microscopy, western blotting, time-lapse video microscopy and analysis of global gene expression by RNA-Seq were used to evaluate target modulation and induction of cell death pathways. Bioluminescence imaging of mice bearing NB xenografts treated with TRD was used to investigate the efficacy of TRD in vivo. Results: Cell survival data showed that TRD is cytotoxic against NB cell lines in vitro (mean IC50 value 100 µM, range 65-135 µM). Phase-contrast and time-lapse video microscopy confirmed the antitumor effects of TRD. Western blot analyses identified that TRD induced target modulation and an effective apoptotic cascade, resulting in PARP cleavage. Gene expression analyses and signaling pathway activation scores indicated alterations in the Notch, MAPK and IL-10 signaling pathways. Xenograft studies further validated the in vivo activity of TRD with decreased tumor burden in treated mice and a measurable improvement in survival. Conclusions: Our study provides key pre-clinical data on the activity and mechanism of action of TRD against NB. The findings support the rationale for further evaluation of TRD for the treatment of relapsed/refractory NB patients in an early phase clinical trial.
Roseola Infantum (Exanthem Subitum)
Authors: William Berenberg, Stanley Wright, Charles A. Janeway
Journal: New England Journal of Medicine (1949)

THE problem of fever in infancy is one of the most common and difficult ones confronting the general practitioner and pediatrician. In 1910 Zahorsky1 described a febrile exanthem occurring in infants and young children, which he termed roseola infantum. This disease was characterized by a relatively asymptomatic febrile course of three to five days, followed by the appearance of a morbilliform eruption. Several years later Veeder2 helped confirm this syndrome as a specific pathologic entity and suggested the name exanthem subitum. Since that time the disease has attracted wide interest in pediatric circles. However, since patients afflicted with this condition . . .
Structure and Pharmacology of Voltage-Gated Sodium and Calcium Channels
Authors: William A. Catterall, Michael J. Lenaeus, Tamer M. Gamal El-Din
Journal: The Annual Review of Pharmacology and Toxicology (2019)

Voltage-gated sodium and calcium channels are evolutionarily related transmembrane signaling proteins that initiate action potentials, neurotransmission, excitation-contraction coupling, and other physiological processes. Genetic or acquired dysfunction of these proteins causes numerous diseases, termed channelopathies, and sodium and calcium channels are the molecular targets for several major classes of drugs. Recent advances in the structural biology of these proteins using X-ray crystallography and cryo-electron microscopy have given new insights into the molecular basis for their function and pharmacology. Here we review this recent literature and integrate findings on sodium and calcium channels to reveal the structural basis for their voltage-dependent activation, fast and slow inactivation, ion conductance and selectivity, and complex pharmacology at the atomic level. We conclude with the theme that new understanding of the diseases and therapeutics of these channels will be derived from application of the emerging structural principles from these recent structural analyses.