We aim to describe the long-term follow-up data from our institution's POEM experience.
Per-oral endoscopic myotomy (POEM) is a well-established endoscopic therapy for achalasia with excellent ...short-term efficacy, but long-term outcomes data are limited.
Patients older than 4 years removed from POEM for treatment of achalasia were studied. Clinical success was defined as an Eckardt Symptom (ES) score ≤3 and freedom from reintervention for achalasia. Patients underwent esophagogastroduodenoscopy (EGD), high-resolution manometry, impedance planimetry, and timed barium esophagram (TBE) preoperatively and at least 4 years postoperatively. Objective gastroesophageal reflux disease (GERD) was defined LA Grade B or worse esophagitis on EGD.
One hundred and nineteen consecutive patients were included. Five patients died or had catastrophic events unrelated to achalasia or POEM. One hundred of the remaining patients (88%, 100/114) had long-term data available. Clinical follow-up for all patients was greater than 4 years postoperatively and the mean was 55 months. Mean current ES was significantly improved from preop (n = 100, 1 ± 1 vs 7 ± 2, P < 0.001). Overall clinical success was 88% and 92%. Five patients had a current ES >3 and 4 patients required procedural reintervention on the lower esophageal sphincter. Reinterventions were successful in 75% of patients (3/4), with current ES ≤3. The rate of objective GERD was 33% (15/45). Esophageal physiology was improved with a decrease in median integrated relaxation pressure (11 ± 4 vs 33 ± 15 mm Hg, P < 0.001), a decrease in median TBE column height (3 ± 3 vs 13 ± 8 cm, P < 0.001), and an increase in median distensibility index (5.1 ± 2 vs 1.1 ± 1 mm2/mm Hg, P < 0.001).
POEM provides durable symptom relief and improvement in physiologic esophagogastric junction relaxation parameters over 4.5 years postoperatively. Reinterventions are rare and effective.
Cystic fibrosis (CF) is a lethal autosomal recessive disorder that afflicts more than 70,000 people. People with CF experience multi-organ dysfunction resulting from aberrant electrolyte transport ...across polarized epithelia due to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CF-related lung disease is by far the most important determinant of morbidity and mortality. Here we report results from a multi-institute consortium in which single-cell transcriptomics were applied to define disease-related changes by comparing the proximal airway of CF donors (n = 19) undergoing transplantation for end-stage lung disease with that of previously healthy lung donors (n = 19). Disease-dependent differences observed include an overabundance of epithelial cells transitioning to specialized ciliated and secretory cell subsets coupled with an unexpected decrease in cycling basal cells. Our study yields a molecular atlas of the proximal airway epithelium that will provide insights for the development of new targeted therapies for CF airway disease.
Outpatient parenteral antimicrobial therapy (OPAT) has been widely used in clinical practice for many decades because of its associated cost savings, reductions in inpatient hospital days, and ...decreases in hospital-associated infections. Despite this long history, evolving practice patterns and new drug delivery devices continue to present challenges as well as opportunities for clinicians when designing appropriate outpatient antimicrobial regimens. One such change is the increasing use of extended and continuous infusion (CI) of antimicrobials to optimize the achievement of pharmacokinetic and pharmacodynamic targets. Elastomeric devices are also becoming increasingly popular in OPAT, including for the delivery of CI. In this article, we review the clinical evidence for CI in OPAT, as well as practical considerations of patient preferences, cost, and antimicrobial stability.
To investigate the temporal appearance of retinal, cognitive, and motor deficits in Goto-Kakizaki (GK) rats, a spontaneously occurring, polygenic model of type II diabetes. GK rats develop impaired ...insulin secretion at 2 weeks and fasting hyperglycemia at 4 weeks.
In male and female GK rats and Wistar controls, glucose tolerance test (hyperglycemia) and electroretinogram (ERG, retinal function) were performed at 4 and 8 weeks of age. Spectral domain-optical coherence tomography (retinal structure) was assessed at 6 weeks. Spatial alternation (cognitive function) and number of entries (exploratory behavior) were assessed via Y-maze at 4, 5, 6, 7, and 8 weeks. Rotarod (motor function) was performed at 4, 6, and 8 weeks.
By 4 weeks, the GK rats exhibited significant glucose intolerance (P < 0.001) and retinal deficits, including delays in ERG implicit times (flicker, P < 0.01; oscillatory potentials, P < 0.001). In addition, the GK rats showed greater ERG amplitudes (P < 0.001) and thinner retinas (P < 0.001). At 7 weeks, the GK rats showed deficits in cognitive function (P < 0.001) and exploratory behavior (P < 0.01). However, no motor function deficits were observed by 8 weeks. Interestingly, the male GK rats showed greater hyperglycemia (P < 0.05), but the female rats showed greater ERG delays (P < 0.001).
In GK rats, retinal function deficits developed prior to cognitive or motor deficits. Future studies will investigate common mechanistic links, long-term functional and vascular changes, and whether early retinal deficits can predict cognitive dysfunction or late-stage retinal disease.
Background/objectives
Although studies have shown posttraumatic stress disorder (PTSD) associated with risk of suicide, the relationship in later life, especially for overdose death, remains unclear. ...Thus, the aim of the current study was to determine associations between PTSD, suicide, and unintended overdose death in mid‐ to late‐life.
Methods
A nationwide cohort study integrating Department of Veterans Affairs' (VA) data, Centers for Medicare & Medicaid Services data, and national cause‐specific mortality data. Participants were US veterans aged ≥50 years with PTSD diagnoses at baseline (2012–2013) and were propensity‐matched 1:1 with patients without PTSD based on sociodemographics, Charlson Comorbidity Index, and neuropsychiatric disorders (N = 951,018). Information on suicide attempts and unintended death by overdose through December 31, 2017 was provided by the VA's National Suicide Prevention Applications Network (non‐fatal attempts) and Mortality Data Repository (death).
Results
Veterans with PTSD (N = 475,509) had increased risk of suicide attempt (Hazard Ratio HR, 1.59; 95% CI, 1.54–1.65; p < 0.001), non‐fatal attempt (HR, 1.74; 95% CI, 1.67–1.81; p < 0.001), drug overdose death overall (HR, 1.32; 95% CI, 1.22–1.42; p < 0.001), and suicide overdose death (HR, 1.44; 95% CI, 1.15–1.80; p = 0.002), even after adjusting for sociodemographics, Charlson comorbidity index, and neuropsychiatric disorders. We found increased risk for overdose death by narcotics (HR, 1.30; 95% CI, 1.15–1.46; p < 0.001), antiepileptic/sedative‐hypnotics (HR, 1.29; 95% CI, 1.02–1.62; p = 0.032), and for other/unspecified drugs (HR, 1.35; 95% CI, 1.20–1.51; p < 0.001), the last category indicative of polydrug. Results remained robust when examined for unintentional, suicide, and undetermined intent for cause‐specific death by other/unspecified drugs.
Conclusions
PTSD persists throughout mid‐ to late‐life with considerable increased risk for non‐fatal suicide attempts and suicide overdose death. These findings suggest the importance of drug‐monitoring in preventing late‐life suicide.
A new general synthetic approach to sequenced macromolecules was developed and applied to the synthesis of polymers comprising lactic acid (L), glycolic acid (G), and ε-caprolactone (C)-derived ...monomer units. The new method employs entropy-driven ring-opening metathesis polymerization (ED-ROMP) to prepare copolymers with embedded sequences and controlled molecular weights. Cyclic macromonomer precursors were prepared by ring-closing metathesis of ethylene glycol (Eg)-linked sequenced oligomers bearing terminal olefins. ED-ROMP of the resulting macrocycles using Grubbs’ second generation catalyst yielded poly(CL-Eg-LC-Oed), poly(CLL-Eg-LLC-Oed), poly(LGL-Eg-LGL-Oed), and poly(LGL-Eg-LGL-Hed) (Oed = octenedioc acid; Hed = hexenedioc acid). Hydrogenation produced the saturated sequenced copolymers. Molecular weight was well-controlled and could be adjusted by varying the monomer-to-catalyst ratio. M ns of 26–60 kDa were obtained (dispersities = 1.1–1.3). The methodology proved general for three different sequences and two olefinic metathesis groups.
Background
Esophagogastric junction distensibility index (DI), measured using the functional luminal imaging probe (FLIP), correlates with symptomatic outcomes after interventions for achalasia. The ...objective of this study was to determine if the intraoperative measurement of DI using FLIP was associated with improved clinical outcomes following per-oral endoscopic myotomy (POEM) for achalasia when compared with procedures in which FLIP was not utilized.
Methods
Patients undergoing POEM from 2012 to 2017 at a single institution by a single surgeon were studied. Use of FLIP during this time period was based on catheter and technician availability, resulting in two patient cohorts. In patients in whom FLIP was used, operative video recordings were reviewed to determine when DI measurements led to the performance of additional myotomy. Postoperative Eckardt symptom scores (ES) at 12 months and postoperative physiologic studies were compared between patients with and without intraoperative FLIP. Associations were assessed using Mann–Whitney
U
and Chi-square tests.
Results
143 patients were included in the analysis (61 with intraoperative FLIP and 82 without FLIP). Video recordings were available for 85% of the FLIP cohort. Review of these operative recordings revealed that 65% of patients who underwent FLIP had additional myotomy performed following the initial postmyotomy FLIP measurement. At 12 months after POEM, the FLIP cohort had significantly more clinical successes (defined as ES ≤ 3) than patients in whom FLIP was not used (93% vs. 81%,
p
< 0.05).
Conclusions
Use of intraoperative FLIP during POEM resulted in the surgeon performing additional myotomy in over half of cases and was associated with improved clinical outcomes. This study demonstrates the potential for a FLIP-tailored myotomy to improve outcomes in patients undergoing surgical myotomy for achalasia.
Lung adenocarcinoma (LUAD) is the most prevalent subtype of lung cancer and presents clinically with a high degree of biological heterogeneity and distinct clinical outcomes. The current paradigm of ...LUAD etiology posits alveolar epithelial type II (AT2) cells as the primary cell of origin, while the role of AT1 cells in LUAD oncogenesis remains unknown. Here, we examine oncogenic transformation in mouse Gram-domain containing 2 (Gramd2)+ AT1 cells via oncogenic KRASG12D. Activation of KRASG12D in AT1 cells induces multifocal LUAD, primarily of papillary histology. Furthermore, KRT8+ intermediate cell states were observed in both AT2- and AT1-derived LUAD, but SCGB3A2+, another intermediate cell marker, was primarily associated with AT1 cells, suggesting different mechanisms of tumor evolution. Collectively, our study reveals that Gramd2+ AT1 cells can serve as a cell of origin for LUAD and suggests that distinct subtypes of LUAD based on cell of origin be considered in the development of therapeutics.
Display omitted
•AT1 cells can give rise to KRAS-driven LUAD using transgenic mouse models•Alveolar cell of origin influences histologic presentation of LUAD•KRT8+ intermediate cell state marker is associated with both subtypes of LUAD•KRT8+ cells were SCGB3A2+ only in AT1-derived LUAD
Yang et al. show that alveolar epithelial type I (AT1) cells can serve as a cell of origin for lung adenocarcinoma (LUAD). In addition, cell of origin can be associated with known properties of LUAD, including histologic subtypes and transcriptomic signatures, suggesting different mechanisms in tumor evolution.
Background
The functional luminal imaging probe (FLIP) can evaluate esophagogastric junction (EGJ) distensibility and esophageal peristalsis in real time. FLIP measurements performed during ...diagnostic endoscopy can accurately discriminate between healthy controls and patients with achalasia based on EGJ-distensibility and distinct motility patterns termed repetitive antegrade contractions (RACs) and repetitive retrograde contractions (RRCs). We sought to evaluate real-time motility changes in patients undergoing surgical myotomy for achalasia.
Methods
FLIP measurements using a stepwise volumetric distention protocol were performed at three time points during assessment and performance of laparoscopic Heller myotomy and POEM: (1) During preoperative outpatient endoscopy, (2) Intraoperatively following induction of anesthesia, and (3) Intraoperatively after myotomy completion. EGJ-distensibility, contractility, RACs, and RRCs were measured.
Results
FLIP measurements were performed in 32 patients. The EGJ-distensibility index was similar between the preoperative and initial operative measurements (1.1 vs 1.4 mm
2
/mmHg,
p
= NS). There was a significant increase in distensibility following surgical myotomy (1.4 to 4.7 mm
2
/mmHg,
p
< 0.01). Intraoperative contractile patterns varied between achalasia subtypes. Contractility was seen in < 20% of assessments in patients with types I and II achalasia. Type III patients demonstrated contractility in 100% of assessments, with 70% exhibiting RRCs and 60% RACs. There was a reduction in the frequency of RRC presence (70% to 20%), and contractile vigor (80% to 0% of patients with lumen occluding contractions) in type III patients following surgical myotomy.
Conclusions
This first report of real-time intraoperative measurement of esophageal motility using FLIP demonstrates the feasibility of such assessments during surgical myotomy for achalasia. Patients with type I and II achalasia exhibited rare intraoperative contractility, while the presence of motility was the norm in those with type III. Patients with type III achalasia demonstrated an immediate reduction in repetitive contraction motility patterns and contractile vigor following myotomy.
Rift Valley fever (RVF) is a disease of animals and humans associated with abortions in ruminants and late-gestation miscarriages in women. Here, we use a rat model of congenital RVF to identify ...tropisms, pathologies, and immune responses in the placenta during vertical transmission. Infection of late-gestation pregnant rats resulted in vertical transmission to the placenta and widespread infection throughout the decidua, basal zone, and labyrinth zone. Some pups from infected dams appeared normal while others had gross signs of teratogenicity including death. Histopathological lesions were detected in placenta from pups regardless of teratogenicity, while teratogenic pups had widespread hemorrhage throughout multiple placenta layers. Teratogenic events were associated with significant increases in placental pro-inflammatory cytokines, type I interferons, and chemokines. RVFV displays a high degree of tropism for all placental tissue layers and the degree of hemorrhage and inflammatory mediator production is highest in placenta from pups with adverse outcomes. Given the potential for RVFV to emerge in new locations and the recent evidence of emerging viruses, like Zika and SARS-CoV-2, to undergo vertical transmission, this study provides essential understanding regarding the mechanisms by which RVFV crosses the placenta barrier.
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