Trajectory of Healthcare Contact Days for Veterans With Advanced Gastrointestinal Malignancy.

How and where patients with advanced cancer facing limited survival spend their time is critical. Healthcare contact days (days with healthcare contact outside the home) offer a patient-centered and practical measure of how much of a person's life is consumed by healthcare. We retrospectively analyzed contact days among decedent veterans with stage IV gastrointestinal cancer at the Minneapolis Veterans Affairs Healthcare System from 2010 to 2021. Among 468 decedents, the median overall survival was 4 months. Patients spent 1 in 3 days with healthcare contact. Over the course of illness, the percentage of contact days followed a "U-shaped" pattern, with an initial post-diagnosis peak, a lower middle trough, and an eventual rise as patients neared the end-of-life. Contact days varied by clinical factors and by sociodemographics. These data have important implications for improving care delivery, such as through care coordination and communicating expected burdens to and supporting patients and care partners.

The unequal burden of time toxicity.

Many cancer treatments impose large time investments on patients. We have termed these time burdens 'time toxicity' and have urged their consideration as adverse events of treatment. Here, we discuss time toxicity measures while considering inequitable access to healthcare, time as a resource, and patterns of time toxicity.

Chromatin-associated RNA sequencing (ChAR-seq) maps genome-wide RNA-to-DNA contacts.

RNA is a critical component of chromatin in eukaryotes, both as a product of transcription, and as an essential constituent of ribonucleoprotein complexes that regulate both local and global chromatin states. Here, we present a proximity ligation and sequencing method called Chromatin-Associated RNA sequencing (ChAR-seq) that maps all RNA-to-DNA contacts across the genome. Using Drosophila cells, we show that ChAR-seq provides unbiased, de novo identification of targets of chromatin-bound RNAs including nascent transcripts, chromosome-specific dosage compensation ncRNAs, and genome-wide trans-associated RNAs involved in co-transcriptional RNA processing.

Comparison of insertion characteristics of tapered and cylindrical transfixation pins in third metacarpal bones of equine cadavers.

OBJECTIVE To compare heat generation and mechanical bone damage for tapered and cylindrical transfixation pins during drilling, tapping, and pin insertion in equine third metacarpal bones. SAMPLE 16 pairs of cadaveric equine third metacarpal bones. PROCEDURES For cylindrical pin insertion, a 6.2-mm hole was drilled and tapped with a cylindrical tap, and then a standard 6.3-mm pin was inserted. For tapered pin insertion, a 6.0-mm hole was drilled, reamed with a tapered reamer, and tapped with a tapered tap, and then a 6.3-mm tapered pin was inserted. Paired t tests and 1-way ANOVAs were used to compare heat generation (measured by use of thermocouples and thermography), macrodamage (assessed by use of stereomicroscopy), and microdamage (assessed by examination of basic fuchsin-stained histologic specimens) between cylindrical and tapered pins and between tapered pins inserted to various insertion torques. RESULTS Tapered pin insertion generated less heat but resulted in more bone damage than did cylindrical pin insertion when pins were inserted to the same insertion torque. Insertion of tapered pins to increasing insertion torques up to 16 N•m resulted in increased heat generation and bone damage. CONCLUSIONS AND CLINICAL RELEVANCE Tapered pin insertion resulted in lower heat production than did cylindrical pin insertion. However, tapered pin insertion resulted in greater bone damage, which likely was attributable to differences in the tapered and cylindrical taps. A tapered pin may be preferable to a cylindrical pin for insertion in equine cortical bone provided that improvements in tap design can reduce bone damage during insertion.

RNA-dependent stabilization of SUV39H1 at constitutive heterochromatin.

Heterochromatin formed by the SUV39 histone methyltransferases represses transcription from repetitive DNA sequences and ensures genomic stability. How SUV39 enzymes localize to their target genomic loci remains unclear. Here, we demonstrate that chromatin-associated RNA contributes to the stable association of SUV39H1 with constitutive heterochromatin in human cells. We find that RNA associated with mitotic chromosomes is concentrated at pericentric heterochromatin, and is encoded, in part, by repetitive α-satellite sequences, which are retained in cis at their transcription sites. Purified SUV39H1 directly binds nucleic acids through its chromodomain; and in cells, SUV39H1 associates with α-satellite RNA transcripts. Furthermore, nucleic acid binding mutants destabilize the association of SUV39H1 with chromatin in mitotic and interphase cells - effects that can be recapitulated by RNase treatment or RNA polymerase inhibition - and cause defects in heterochromatin function. Collectively, our findings uncover a previously unrealized function for chromatin-associated RNA in regulating constitutive heterochromatin in human cells.

RNA-mediated regulation of heterochromatin.

The formation of condensed, transcriptionally repressed heterochromatin is essential for controlling gene expression throughout development, silencing parasitic DNA elements, and for genome stability and inheritance. Cells employ diverse mechanisms for controlling heterochromatin states through proteins that modify DNA and histones. An emerging theme is that chromatin-associated RNAs play important roles in regulating heterochromatin proteins by controlling their initial recruitment to chromatin, their stable association with chromatin, their spread along chromatin, or their enzymatic activity. Major challenges for the field include not only identifying regulatory RNAs, but understanding the underlying biochemical mechanisms for how RNAs associate with chromatin, the specificity of interactions between heterochromatin proteins and RNA, and how these binding events manifest in cells to orchestrate RNA-mediated regulation of heterochromatin.

Surgical Management of Achalasia in a Patient With Previous Gastric Bypass.

Patients with previous foregut surgery who develop additional foregut pathology can be a challenge. Those who have formerly undergone gastric bypass and later develop achalasia are at increased risk related to previous surgery. In this case report, we describe an alternative approach for the Dor fundoplication after laparoscopic Heller myotomy in the setting of the altered anatomy. The technique and advantages of this approach are detailed in the discussion of this patient.

Clinical safety of the ProMRI pacemaker system in patients subjected to thoracic spine and cardiac 1.5-T magnetic resonance imaging scanning conditions.

BACKGROUND: Permanent cardiac pacemakers have historically been considered a contraindication to magnetic resonance imaging (MRI). OBJECTIVE: The purpose of the ProMRI Phase B Study, a multicenter, prospective, single-arm, nonrandomized study, was to evaluate the clinical safety of the Biotronik ProMRI pacemaker system in patients undergoing thoracic spine and cardiac MRI. METHODS: The ProMRI Phase B study enrolled 245 patients with stable baseline pacing indices implanted with an Entovis pacemaker (DR-T or SR-T) and Setrox 53-cm and/or 60-cm lead(s). Device interrogation was performed at enrollment, pre- and post-MRI scan, and 1 and 3 months post-MRI. End-points were (1) freedom from MRI- and pacing system-related serious adverse device effects through 1 month post-MRI; (2) freedom from atrial and ventricular MRI-induced pacing threshold increase (>0.5 V); and (3) freedom from P- and R-wave amplitude attenuation (<50%), or P wave <1.5 mV, or R wave <5.0 mV at 1 month post-MRI. RESULTS: In total, 216 patients completed the MRI and 1-month post-MRI follow-up. One adverse event possibly related to the implanted system and the MRI procedure occurred, resulting in a serious adverse device effect-free rate of 99.6% (220/221; P < .0001. Freedom from atrial and ventricular pacing threshold increase was 100% (194/194, P < .001) and 100% (206/206, P < .001) respectively. Freedom from P- and R-wave amplitude attenuation was 98.2% (167/170, P < .001) and 100% (188/188, P < .001) respectively. CONCLUSION: The results of the ProMRI Phase B study demonstrate the clinical safety and efficacy of the ProMRI pacemaker system in patients subjected to thoracic spine and cardiac MRI conditions.

Clinical safety of the Iforia implantable cardioverter-defibrillator system in patients subjected to thoracic spine and cardiac 1.5-T magnetic resonance imaging scanning conditions.

BACKGROUND: Implantable cardioverter-defibrillators (ICDs) are generally considered a contraindication to magnetic resonance imaging (MRI). OBJECTIVE: The purpose of the ProMRI Phase C study, a multicenter, prospective, single-arm, nonrandomized study, was to evaluate the clinical safety of the Biotronik ProMRI Iforia ICD system during MRI. METHODS: Patients were enrolled after ICD implantation, with either a dual-chamber DR-T or single-lead VR-T DX system. Study-defined, nondiagnostic cardiac or thoracic spine MRI was performed at least 1 week after enrollment. ICDs were placed into MRI mode with ventricular fibrillation (VF) detection/therapy programmed "off" before scan and restored to non-MRI mode after scan. Interrogation was performed before, immediately after, and 1 month post-MRI. The primary end-points were (1) ventricular pacing threshold increase >0.5 V from pre-MRI to 1 month post-MRI; (2) R-wave amplitude decrease >50% from pre-MRI to 1 month post-MRI or R-wave amplitude <5 mV at 1 month post-MRI; and (3) MRI and ICD system-related serious adverse device effects. RESULTS: One hundred seventy patients were enrolled at 39 US centers. One hundred fifty-three patients underwent MRI (25.7% cardiac, 74.3% thoracic spine) and completed follow-up. Freedom from the primary end-points was met in all but 1 subject, in whom reduced R-wave amplitude was detected 1 month post-MRI. No serious adverse device effects occurred during the course of the study. CONCLUSION: These results demonstrate the clinical safety and efficacy of the ProMRI ICD system in patients subjected to thoracic spine and cardiac MRI imaging in 1.5-T scanners.

Recurrent point mutations in the kinetochore gene KNSTRN in cutaneous squamous cell carcinoma.

Here we report the discovery of recurrent mutations concentrated at an ultraviolet signature hotspot in KNSTRN, which encodes a kinetochore protein, in 19% of cutaneous squamous cell carcinomas (SCCs). Cancer-associated KNSTRN mutations, most notably those encoding p.Ser24Phe, disrupt chromatid cohesion in normal cells, occur in SCC precursors, correlate with increased aneuploidy in primary tumors and enhance tumorigenesis in vivo. These findings suggest a role for KNSTRN mutagenesis in SCC development.

Fluorescent protein applications in microscopy.

The use of fluorescent proteins (FPs) in modern cell biology and microscopy has had an extraordinary impact on our ability to investigate dynamic processes in living cells. FPs are unique in that fluorescence is encoded solely by the primary amino acid sequence of the FP and does not require enzymatic modification or cofactors. This genetically encoded fluorescence enables the expression of FPs in diverse cells and organisms and the detection of that fluorescence in living systems. This chapter focuses on microscopy-based applications of FP detection to monitor protein localization, dynamics, interaction, and the cellular environment.

HSA programs for groups: employer versus employee responsibilities.

Employers implementing a health savings account (HSA) program face a shared compliance burden with their employees. The law dictates that all HSAs are individual accounts that must be opened by an Internal Revenue Service (IRS)-approved custodian or trustee. The individual account features combined with a required third-party custodian place much of the compliance burden for HSAs on the employee and custodian rather than the employer. Employees are compensated for the additional burden because HSAs give them more control over their health care money, and employers are generally pleased with their own reduced compliance burden. The shared compliance responsibilities, however, create confusion and misunderstanding for both employers and employees. This article distinguishes between the responsibilities of the employer and the employees for HSAs.

The impact of health reform on HSAs.

The health care reform law contains only two direct changes to health savings accounts (HSAs): eliminating the ability to use the HSA for over-the-counter drugs and increasing the early withdrawal penalty from 10% to 20%. The indirect changes, however, could drastically curtail the growth of HSAs or even result in the end of HSAs. The actual impact is uncertain at this time because much of the detail of the law is left to regulatory interpretation. This article identifies and analyzes seven areas in the new law that could indirectly impact HSAs.

N-allyl-N-sulfonyl ynamides as synthetic precursors to amidines and vinylogous amidines. An unexpected N-to-C 1,3-sulfonyl shift in nitrile synthesis.

A detailed study of amidine synthesis from N-allyl-N-sulfonyl ynamides is described here. Mechanistically, this is a fascinating reaction consisting of diverging pathways that could lead to deallylation or allyl transfer depending upon the oxidation state of palladium catalysts, the nucleophilicity of amines, and the nature of the ligands. It essentially constitutes a Pd(0)-catalyzed aza-Claisen rearrangement of N-allyl ynamides, which can also be accomplished thermally. An observation of N-to-C 1,3-sulfonyl shift was made when examining these aza-Claisen rearrangements thermally. This represents a useful approach to nitrile synthesis. While attempts to render this 1,3-sulfonyl shift stereoselective failed, we uncovered another set of tandem sigmatropic rearrangements, leading to vinyl imidate formation. Collectively, this work showcases the rich array of chemistry one can discover using these ynamides.

A Rhodium(I)-Xylyl-BINAP Catalyzed Asymmetric Ynamide-[2 + 2 + 2] Cycloaddition in the Synthesis of Optically Enriched N,O-Biaryls.

A rhodium(I)-xylyl-BINAP catalyzed asymmetric [2 + 2 + 2] cycloaddition of achiral conjugated aryl ynamides with various diynes is described here. This asymmetric cycloaddition provides a series of structurally interesting chiral N,O-biaryls with excellent enantioselectivity along with a modest diastereoselectivity with respect to both C-C and C-N axial chirality.

Synthesis of alpha-keto-imides via oxidation of ynamides.

A de novo preparation of alpha-keto-imides via ynamide oxidation is described. With a number of alkyne oxidation conditions screened, a highly efficient RuO2-NaIO4 mediated oxidation and a DMDO oxidation have been identified to tolerate a wide range of ynamide types. In addition to accessing a wide variety of alpha-keto-imides, the RuO2-NaIO4 protocol provides a novel entry to the vicinal tricarbonyl motif via oxidation of push-pull ynamides, and imido acylsilanes from silyl-substituted ynamides. Chemoselective oxidation of ynamides containing olefins can be achieved by using DMDO, while the RuO2-NaIO4 protocol is not effective. These studies provide further support for the synthetic utility of ynamides.