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Nadofaragene firadenovec is a gene therapy for BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) undergoing FDA review. Pembrolizumab is approved for treating BCG-unresponsive NMIBC patients with carcinoma in-situ (CIS). We evaluated the cost-effectiveness of these treatments compared with a hypothetical therapeutic alternative, at a willingness-to-pay (WTP) threshold of $150,000 per quality-adjusted life year (QALY) gained, in CIS and non-CIS BCG-unresponsive NMIBC populations.We developed a Markov cohort simulation model with a three-month cycle length and lifetime horizon to estimate total costs, QALYs and cost per additional QALY from the health sector perspective. Clinical inputs were informed by results of single-arm clinical trials evaluating the treatments and systematic literature reviews were conducted to obtain other model inputs. Sensitivity analyses were conducted to assess uncertainty in model results.Nadofaragene firadenovec, at a placeholder price 10% higher than the price of pembrolizumab, had an incremental cost-effectiveness ratio (ICER) of $263,000 and $145,000 per QALY gained in CIS and non-CIS populations, respectively. Pembrolizumab had an ICER of $168,000 per QALY gained for CIS. A 5.4% reduction in pembrolizumab's price would make it cost-effective. The model was sensitive to many inputs, especially probabilities of disease progression, initial treatment response and durability, and drug price.The cost-effectiveness of nadofaragene firadenovec will depend upon its price. Pembrolizumab, though not cost-effective in our base-case analysis, is an important alternative in this population with an unmet medical need. Comparative trials of these treatments are warranted to better estimate cost-effectiveness.

The Morelos district, located in the center of the Guerrero gold belt, Guerrero State, southern Mexico, has been the site of several recent gold ± copper skarn discoveries (total of ~8.5 Moz Au) associated with Upper Cretaceous-Paleocene granodiorite intrusions. The Limon, Guajes, and Media Luna skarn deposits developed along the contact of the El Limon granodiorite and the sedimentary host rocks. Native gold is associated with retrograde alteration of garnet-pyroxene skarn and is accompanied by native bismuth as well as telluride and sulfide minerals. The Media Luna deposit is characterized by a distinct magnesium-rich skarn mineralogy and contains an average of ~1 wt % Cu, in addition to gold and silver. This distinguishes it from the other gold-only skarn deposits in the Guerrero gold belt. This observation suggests that skarns in the Guerrero gold belt, which replaced magnesium-rich sedimentary protoliths, may host significant copper resources in addition to gold. Uranium-lead laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) zircon ages of the El Limon granodiorite range from 66.86 ± 0.40 to 65.88 ± 0.79 Ma. Preskarn molybdenite-quartz veins cut through the El Limon granodiorite and yield Re-Os molybdenite ages between 66.63 ± 0.22 and 65.55 ± 0.25 Ma. A series of pre-, syn-, and postskarn porphyritic dikes intruded the El Limon granodiorite, having zircon ages ranging from 65.9 ± 1.1 to 64.68 ± 0.38 Ma. The timing of skarn formation at Limon and Media Luna was constrained to 64.6 ± 1.2 to 63.2 ± 1.0 Ma, applying U-Pb LA-ICP-MS to garnet. The ubiquitous presence of garnet in skarn deposits and the time- and cost-efficiency of in situ geochronology are striking advantages of this method to constrain the timing of mineralization.

By accounting for surface-based light source emissions and top-of-atmosphere (TOA) downward lunar fluxes, we adapted the spherical harmonics discrete ordinate method (SHDOM) 3-dimensional (3-D) radiative transfer model (RTM) to simulate nighttime 3-D TOA radiances as observed from the Visible Infrared Imaging Radiometer Suite (VIIRS) Day/Night Band (DNB) on board the Suomi-NPP satellite platform. Used previously for daytime 3-D applications, these new SHDOM enhancements allow for the study of the impacts of various observing conditions and aerosol properties on simulated VIIRS-DNB TOA radiances. Observations over Dakar, Senegal, selected for its bright city lights and a large range of aerosol optical depth (AOD), were investigated for potential applications and opportunities for using observed radiances containing VIIRS-DNB “bright pixels” from artificial light sources to conduct aerosol retrievals. We found that using the standard deviation (SD) of such bright pixels provided a more stable quantity for nighttime AOD retrievals than direct retrievals from TOA radiances. Further, both the mean TOA radiance and SD of TOA radiances over artificial sources are significantly impacted by satellite viewing angles. Light domes, the enhanced radiances adjacent to artificial light sources, are strong functions of aerosol properties and especially aerosol vertical distribution, which may be further utilized for retrieving aerosol layer height in future studies. Through inter-comparison with both day- and nighttime Aerosol Robotic Network (AERONET) data, the feasibility of retrieving nighttime AODs using 3-D RTM SHDOM over artificial light sources was demonstrated. Our study shows strong potential for using artificial light sources for nighttime AOD retrievals, while also highlighting larger uncertainties in quantifying surface light source emissions. This study underscores the need for surface light emission source characterizations as a key boundary condition, which is a complex task that requires enhanced input data and further research. We demonstrate how quality-controlled nighttime light data from the NASA's Black Marble product suite could serve as a primary input into estimations of surface light source emissions for nighttime aerosol retrievals.

BackgroundEpithelial remodeling is a histopathologic feature of chronic inflammatory airway diseases including chronic rhinosinusitis (CRS). Cell type shifts and their relationship to CRS endotypes and severity are incompletely described.ObjectiveThe purpose of this study was to understand the relationship of epithelial cell remodeling to inflammatory endotypes and disease outcomes in CRS.MethodsUsing cell type transcriptional signatures derived from epithelial single cell sequencing, we analyzed bulk RNA sequencing data from sinus epithelial brushes obtained from patients with CRS with and without nasal polyps in comparison to healthy controls.ResultsThe airway epithelium in nasal polyposis displayed increased tuft cell transcripts and decreased ciliated cell transcripts along with an IL-13 activation signature. In contrast, chronic rhinosinusitis without polyps showed an IL-17 activation signature. IL-13 activation scores were associated with increased tuft cell, goblet cell and mast cell scores and decreased ciliated cell scores. Furthermore, the IL-13 score was strongly associated with a previously reported activated (“polyp”) tuft cell score and a prostaglandin E2 (PGE2) activation signature. The Lund-McKay score, a computed tomographic metric of sinus opacification, correlated positively with activated tuft cell, mast cell, PGE2, and IL-13 and negatively with ciliated cell transcriptional signatures.ConclusionsThese results demonstrate that cell type alterations and PGE2 stimulation are key components of IL-13 induced epithelial remodeling in nasal polyposis, while IL-17 signaling is more prominent in CRS without polyps, and that clinical severity correlates with the degree of IL-13 induced epithelial remodeling.Key MessagesCell type signatures from single cell RNA sequencing, applied to bulk sequenced RNA sinus brushes, suggest increased tuft cells and mast cells and decreased ciliated cells in nasal polyp epithelium.IL-17 signaling rather than IL-13 signaling is observed in epithelium from CRSsNP.IL-13-drives epithelial remodeling and prostaglandin E2 signatures correlated with clinical measures of sinus opacification in CRS.Capsule SummaryMeasures of epithelial remodeling, including both IL-13 and PGE2 induced epithelial activation and cell type specific transcript alterations, correlate with a radiographic metric of disease severity in CRSwNP.

OBJECTIVE The American Spine Registry (ASR) is a collaborative effort between the American Academy of Orthopaedic Surgeons and the American Association of Neurological Surgeons. The goal of this study was to evaluate how representative the ASR is of the national practice with spinal procedures, as recorded in the National Inpatient Sample (NIS). METHODS The authors queried the NIS and the ASR for cervical and lumbar arthrodesis cases performed during 2017–2019. International Classification of Diseases, 10th Revision and Current Procedural Terminology codes were used to identify patients undergoing cervical and lumbar procedures. The two groups were compared for the overall proportion of cervical and lumbar procedures, age distribution, sex, surgical approach features, race, and hospital volume. Outcomes available in the ASR, such as patient-reported outcomes and reoperations, were not analyzed due to nonavailability in the NIS. The representativeness of the ASR compared to the NIS was assessed via Cohen’s d effect sizes, and absolute standardized mean differences (SMDs) of < 0.2 were considered trivial, whereas > 0.5 were considered moderately large. RESULTS A total of 24,800 arthrodesis procedures were identified in the ASR for the period between January 1, 2017, and December 31, 2019. During the same time period, 1,305,360 cases were recorded in the NIS. Cervical fusions comprised 35.9% of the ASR cohort (8911 cases) and 36.0% of the NIS cohort (469,287 cases). The two databases presented trivial differences in terms of patient age and sex for all years of interest across both cervical and lumbar arthrodeses (SMD < 0.2). Trivial differences were also noted in the distribution of open versus percutaneous procedures of the cervical and lumbar spine (SMD < 0.2). Among lumbar cases, anterior approaches were more common in the ASR than in the NIS (32.1% vs 22.3%, SMD = 0.22), but the discrepancy among cervical cases in the two databases was trivial (SMD = 0.03). Small differences were illustrated in terms of race, with SMDs < 0.5, and a more significant discrepancy was identified in the geographic distribution of participating sites (SMDs of 0.7 and 0.74 for cervical and lumbar cases, respectively). For both of these measures, SMDs in 2019 were smaller than those in 2018 and 2017. CONCLUSIONS The ASR and NIS databases presented a very high similarity in proportions of cervical and lumbar spine surgeries, as well as similar distributions of age and sex, and distribution of open versus endoscopic approach. Slight discrepancies in anterior versus posterior approach among lumbar cases and patient race, and more significant discrepancies in geographic representation were also identified, yet decreasing trends in differences suggested the improving representativeness of the ASR over the course of time and its progressive growth. These conclusions are important to underline the external validity of quality investigations and research conclusions to be drawn from analyses in which the ASR is used.

OBJECTIVE The Quality Outcomes Database (QOD) was established in 2012 by the NeuroPoint Alliance, a nonprofit organization supported by the American Association of Neurological Surgeons. Currently, the QOD has launched six different modules to cover a broad spectrum of neurosurgical practice—namely lumbar spine surgery, cervical spine surgery, brain tumor, stereotactic radiosurgery (SRS), functional neurosurgery for Parkinson’s disease, and cerebrovascular surgery. This investigation aims to summarize research efforts and evidence yielded through QOD research endeavors. METHODS The authors identified all publications from January 1, 2012, to February 18, 2023, that were produced by using data collected prospectively in a QOD module without a prespecified research purpose in the context of quality surveillance and improvement. Citations were compiled and presented along with comprehensive documentation of the main study objective and take-home message. RESULTS A total of 94 studies have been produced through QOD efforts during the past decade. QOD-derived literature has been predominantly dedicated to spinal surgical outcomes, with 59 and 22 studies focusing on lumbar and cervical spine surgery, respectively, and 6 studies focusing on both. More specifically, the QOD Study Group—a research collaborative between 16 high-enrolling sites—has yielded 24 studies on lumbar grade 1 spondylolisthesis and 13 studies on cervical spondylotic myelopathy, using two focused data sets with high data accuracy and long-term follow-up. The more recent neuro-oncological QOD efforts, i.e., the Tumor QOD and the SRS Quality Registry, have contributed 5 studies, providing insights into the real-world neuro-oncological practice and the role of patient-reported outcomes. CONCLUSIONS Prospective quality registries are an important resource for observational research, yielding clinical evidence to guide decision-making across neurosurgical subspecialties. Future directions of the QOD efforts include the development of research efforts within the neuro-oncological registries and the American Spine Registry—which has now replaced the inactive spinal modules of the QOD—and the focused research on high-grade lumbar spondylolisthesis and cervical radiculopathy.

Eccentric glenoid bone loss patterns (B and C type glenoid) pose a difficult challenge when performing shoulder arthroplasty. Anatomic total shoulder arthroplasty with preferential high side reaming (ATSA+HSR) has been an accepted method to treat this problem. Reverse shoulder arthroplasty (RSA) has become an alternative method to manage these cases with eccentric glenoid wear. The purpose of this study was to compare the early two-year outcomes with the mid-term outcomes for patients undergoing ATSA+HSR versus RSA for eccentric glenoid wear patterns with an intact rotator cuff.From 2008-2014 there were 242 shoulder arthroplasties performed in the setting of eccentric glenoid wear patterns. Of that initial cohort 101 ATSA+HSR and 93 RSA had both two-year and final follow-up with a minimum of 7 years from surgery. American shoulder and elbow scores (ASES), Simple Shoulder Test (SST), range of motion, patient satisfaction and radiographs were evaluated for each cohort and contrasted at the two-year follow-up point and last follow-up time point.Average follow-up in the ATSA+HSR cohort was 8.3 years compared to 7.8 years in the RSA cohort. At the two-year follow-up point the ATSA+HSR group had better average ASES scores (85 vs 80 [p.001]), SST scores (10 vs 9.6 [p.001]), forward elevation (162ATSA with high-side reaming had better outcomes scores and range of motion with a similar patient satisfaction rating to RSA at the two-year point. Over time, the ATSA+HSR results deteriorated and at final mid-term follow-up the RSA group had more durable results with better outcome scores, a higher patient satisfaction rating, and a lower revision rate.

Recognizing sport-related concussion (SRC) is challenging and relies heavily on subjective symptom reports. An objective, biological marker could improve recognition and understanding of SRC. There is emerging evidence that salivary micro-ribonucleic acids (miRNAs) may serve as biomarkers of concussion; however, it remains unclear whether concussion-related miRNAs are impacted by exercise. We sought to determine whether 40 miRNAs previously implicated in concussion pathophysiology were affected by participation in a variety of contact and non-contact sports. Our goal was to refine a miRNA-based tool capable of identifying athletes with SRC without the confounding effects of exercise.This case-control study harmonized data from concussed and non-concussed athletes recruited across 10 sites. Levels of salivary miRNAs within 455 samples from 314 individuals were measured with RNA sequencing. Within-subjects testing was used to identify and exclude miRNAs that changed with either: (a) a single episode of exercise (166 samples from 83 individuals) or (b) season-long participation in contact sports (212 samples from 106 individuals). The miRNAs that were not impacted by exercise were interrogated for SRC diagnostic utility using logistic regression (172 samples from 75 concussed and 97 non-concussed individuals).Two miRNAs (miR-532-5p, miR-182-5p) decreased (adjusted p0.05) after a single episode of exercise, and 1 miRNA (miR-4510) increased only after contact sports participation. Twenty-three miRNAs changed at the end of a contact sports season. Two of these miRNAs (miR-26b-3p, miR-29c-3p) were associated (R0.50; adjusted p0.05) with the number of head impacts sustained in a single football practice. Among the 15 miRNAs not confounded by exercise or season-long contact sports participation, 11 demonstrated a significant difference (adjusted p0.05) between concussed and non-concussed participants, and 6 displayed moderate ability (AUC0.70) to identify concussion. A single ratio (miR-27a-5p/miR-30a-3p) displayed the highest accuracy (AUC = 0.810, sensitivity = 82.4%, specificity = 73.3%) for differentiating concussed and non-concussed participants. Accuracy did not differ between participants with SRC and non-SRC (z = 0.5, p = 0.60).Salivary miRNA levels may accurately identify SRC when not confounded by exercise. Refinement of this approach in a large cohort of athletes could eventually lead to a non-invasive, sideline adjunct for SRC assessment.

PURPOSE For survivors of childhood cancer treated with doxorubicin, dexrazoxane is cardioprotective for at least 5 years. However, longer-term data are lacking. METHODS Within the Children's Oncology Group and the Dana Farber Cancer Institute's Childhood Acute Lymphoblastic Leukemia Consortium, we evaluated four randomized trials of children with acute lymphoblastic leukemia or Hodgkin lymphoma, who received doxorubicin with or without dexrazoxane, and a nonrandomized trial of patients with osteosarcoma who all received doxorubicin with dexrazoxane. Cumulative doxorubicin doses ranged from 100 to 600 mg/m2 across these five trials, and dexrazoxane was administered uniformly (10:1 mg/m2 ratio) as an intravenous bolus before doxorubicin. Cardiac function was prospectively assessed in survivors from these trials, plus a matched group of survivors of osteosarcoma treated with doxorubicin without dexrazoxane. Two-dimensional echocardiograms and blood biomarkers were analyzed centrally in blinded fashion. Multivariate analyses adjusted for demographic characteristics, cumulative doxorubicin dose, and chest radiotherapy determined the differences and associations by dexrazoxane status. RESULTS From 49 participating institutions, 195 participants were assessed at 18.1 ± 2.7 years since cancer diagnosis (51% dexrazoxane-exposed; cumulative doxorubicin dose 297 ± 91 mg/m2). Dexrazoxane administration was associated with superior left ventricular fractional shortening (absolute difference, +1.4% [95% CI, 0.3 to 2.5]) and ejection fraction (absolute difference, +1.6% [95% CI, 0.0 to 3.2]), and lower myocardial stress per B-type natriuretic peptide (–6.7 pg/mL [95% CI, –10.6 to –2.8]). Dexrazoxane was associated with a reduced risk of having lower left ventricular function (fractional shortening < 30% or ejection fraction < 50%; odds ratio, 0.24 [95% CI, 0.07 to 0.81]). This protective association was primarily seen in those treated with cumulative doxorubicin doses ≥ 250 mg/m2. CONCLUSION Among young adult-aged survivors of childhood cancer, dexrazoxane was associated with a cardioprotective effect nearly 20 years after initial anthracycline exposure.

Background Laparoscopic and robotic approaches to colonic cancer surgery appear to provide similar outcomes. The present study aimed to compare short-term and survival outcomes of laparoscopic and robotic colectomy for colonic cancer. Methods This retrospective review of patients with stage I–III colonic cancer who underwent laparoscopic or robotic colonic resection was undertaken using data from the National Cancer Database (2013–2019). Patients were matched using the propensity score matching method. The primary outcome was 5-year overall survival. Secondary outcomes included conversion to open surgery, duration of hospital stay, 30- and 90-day mortality, unplanned readmission, and positive resection margins. Results The original cohort included 40 457 patients with stage I–III colonic adenocarcinoma, with a mean(s.d.) age of 67.4(12.9) years. Some 33 860 (83.7 per cent) and 6597 (17.3 per cent) patients underwent laparoscopic and robotic colectomy respectively. After matching, 6210 patients were included in each group. Robotic colectomy was associated with marginally longer overall survival for women, and patients with a Charlson score of 0, stage II–III disease or left-sided tumours. The robotic group had a significantly lower rate of conversion (6.6 versus 11 per cent; P < 0.001) and shorter hospital stay (median 3 versus 4 days) than the laparoscopic group. The two groups had similar rates of 30-day mortality (1.3 versus 1 per cent for laparoscopic and robotic procedures respectively), 90-day mortality (2.1 versus 1.8 per cent), 30-day unplanned readmission (3.7 versus 3.8 per cent), and positive resection margins (2.8 versus 2.5 per cent). Conclusion In this study population, robotic colectomy was associated with less conversion to open surgery and a shorter hospital stay compared with laparoscopic colectomy.

Aim: The armamentarium of options available for soft tissue reconstruction of the scalp spans the reconstructive ladder. The purpose of this paper is to describe a case series of patients with exposed cranium and dura who were successfully reconstructed using esterified hyalomatrix (eHAM, Hyalomatrix, Medline Industries Inc., US). Methods: After obtaining Institutional Review Board approval, a retrospective review of the senior author's (ALF) patient database was completed. Patients who underwent scalp reconstruction using eHAM were identified. Each patient's chart was reviewed and data collected on demographics, days to skin graft, duration of follow-up, pathology, comorbidities and complications. Results: This case series consisted of five patients aged ≥18 years, with scalp wounds exposing dura or cranium, who were treated with eHAM as a bridge to definitive coverage with a skin graft. Each wound successfully granulated the exposed critical structure with the use of the eHAM. The mean time to skin graft coverage was 41 days, with a range of 13–79 days. Of the series of five patients, four had a follow-up of ≥12 weeks. The mean defect size was 90.2cm2. Conclusion: Complex scalp reconstruction can be accomplished using healing by secondary intention, skin grafts, local flaps, tissue expansion and free tissue transfer. As shown in this case series, another option available in select patients is using a dermal substitute such as eHAM. This is one treatment option available to reconstructive surgeons in multiple specialties.

Aim: The choice of whether to perform protective ileostomy (PI) after anterior resection (AR) is mainly guided by risk factors (RFs) responsible for the development of anastomotic leakage (AL). However, clear guidelines about PI creation are still lacking in the literature and this is often decided according to the surgeon's preferences, experiences or feelings. This qualitative study aims to investigate, by an open-ended question survey, the individual surgeon's decision-making process regarding PI creation after elective AR. Method: Fifty four colorectal surgeons took part in an electronic survey to answer the questions and describe what usually led their decision to perform PI. A content analysis was used to code the answers. To classify answers, five dichotomous categories (In favour/Against PI, Listed/Unlisted RFs, Typical/Atypical, Emotions/Non-emotions, Personal experience/No personal experience) have been developed. Results: Overall, 76% of surgeons were in favour of PI creation and 88% considered listed RFs in the question of whether to perform PI. Atypical answers were reported in 10% of cases. Emotions and personal experience influenced surgeons' decision-making process in 22% and 49% of cases, respectively. The most frequently considered RFs were the distance of the anastomosis from the anal verge (96%), neoadjuvant chemoradiotherapy (88%), a positive intraoperative leak test (65%), blood loss (37%) and immunosuppression therapy (35%). Conclusion: The indications to perform PI following rectal cancer surgery lack standardization and evidence-based guidelines are required to inform practice. Until then, expert opinion can be helpful to assist the decision-making process in patients who have undergone AR for adenocarcinoma.

The non-passerine type specimens in Naturalis Biodiversity Center, Leiden are listed as an update to Van den Hoek Ostende et al. (1997) ‘Type-specimens of birds in the National Museum of Natural History, Leiden, Part 1. Non-Passerines’ and Roselaar and Prins (2000) ‘List of type specimens of birds in the Zoological Museum of the University of Amsterdam (ZMA), including taxa described by ZMA staff but without types in the ZMA’. All new names published by Temminck and Schlegel are listed, even when types are not in Naturalis but in other collections. We have added 380 new names and deleted 13 names originally listed in Van den Hoek Ostende et al. (1997).

IgE Abs, best known for their role in allergic reactions, have only rarely been used in immunotherapies. Nevertheless, they offer a potential alternative to the more commonly used IgGs. The affinity of IgE Ag binding influences the type of response from mast cells, so any immunotherapies using IgEs must balance Ag affinity with desired therapeutic effect. One potential way to harness differential binding affinities of IgE is in protein aggregation diseases, where low-affinity binding of endogenous proteins is preferred, but enhanced binding of clusters of disease-associated aggregated proteins could target responses to the sites of disease. For this reason, we sought to create a low-affinity IgE against the prion protein (PrP), which exists in an endogenous monomeric state but can misfold into aggregated states during the development of prion disease. First, we determined that mast cell proteases tryptase and cathepsin G were capable of degrading PrP. Then we engineered a recombinant IgE Ab directed against PrP from the V region of a PrP-specific IgG and tested its activation of the human mast cell line LAD2. The αPrP IgE bound LAD2 through Fc receptors. Crosslinking receptor-bound αPrP IgE activated SYK and ERK phosphorylation, caused Fc receptor internalization, and resulted in degranulation. This work shows that a recombinant αPrP IgE can activate LAD2 cells to release enzymes that can degrade PrP, suggesting that IgE may be useful in targeting diseases that involve protein aggregation.

To evaluate the influence of drug price dynamics in cost-effectiveness analyses (CEAs).We evaluated scenarios involving typical US drug price increases during the exclusivity period and price decreases after the loss of exclusivity (LOE). Worked examples are presented using the Institute for Clinical and Economic Review's assessments of tezepelumab for the treatment of severe asthma and targeted immune modulators for rheumatoid arthritis.Tezepelumab case: Yearly 2% price increases during the period of exclusivity and a post-LOE price decrease of 25% yielded an incremental cost per QALY gained that increased over the base case from $430,300 to $444,600 (+3.2%). Yearly 2% price increases followed by a steeper post-LOE price reduction of 40% resulted in a cost per QALY gained of $401,400 (6.8% reduction versus the base case). Rheumatoid arthritis case: Incorporating post-LOE price reductions for etanercept (intervention) and adalimumab (comparator) ranging from 25% to 40% yielded an incremental cost per QALY of $121,000 and $122,300, respectively (3% increase from the base case of $119,200/QALY). Including a 2% yearly price increase during the projected exclusivity periods of both intervention and comparator increased the cost per QALY gained by more than 60%.Two biologic treatment cases incorporating price dynamics in CEA had varied impacts on the cost-effectiveness ratio depending on the magnitude of pre-LOE price increase and post-LOE price decrease, and whether the LOE also affected the comparator. Yearly price increase magnitude during the period of exclusivity, among other factors, may counterbalance the effects of lower post-LOE intervention prices.

The most common cause of acute kidney injury (AKI) in critically ill patients is sepsis. Kidney macrophages consist of both F4/80

Elexacaftor/tezacaftor/ivacaftor (ETI) improves pulmonary disease in people with cystic fibrosis (PwCF), but its effect on gastrointestinal symptoms, which also affect quality of life, is not clear.PROMISE is a 56-center prospective, observational study of ETI in PwCF12 years and at least one F508del allele. Gastrointestinal symptoms, evaluated by validated questionnaires: Patient Assessment of Upper Gastrointestinal Disorders-Symptom (PAGI-SYM), Patient Assessment of Constipation-Symptom (PAC-SYM), Patient Assessment of Constipation-Quality of Life (PAC-QOL)), fecal calprotectin, steatocrit and elastase-1 were measured before and 6 months after ETI initiation. Mean difference and 95% confidence intervals were obtained from linear regression with adjustment for age and sex.438 participants fully completed at least 1 questionnaire. Mean (SD) for baseline PAGI-SYM, PAC-SYM, and PAC-QOL total scores were 0.56 (0.59), 0.47 (0.45), and 0.69 (0.53) out of maximum 5, 4, and 5, respectively (higher score indicates greater severity). Corresponding age- and sex-adjusted 6 months mean changes (95% CI) in total scores were -0.15 (-0.21, -0.09) for PAGI-SYM, -0.14 (-0.19, -0.09) for PAC-SYM, and -0.15 (-0.21, -0.10) for PAC-QOL. While statistically significant, changes were small and unlikely to be of clinical importance. Fecal calprotectin showed a change (95% CI) from baseline of -66.2 µg/g (-86.1, -46.2) at 6 months, while fecal elastase and steatocrit did not meaningfully change.After 6 months of ETI, fecal markers of inflammation decreased. Gastrointestinal symptoms improved, but the effect size was small. Pancreatic insufficiency did not improve.

People with cystic fibrosis (PwCF) suffer from gastrointestinal (GI) symptoms affecting their quality of life (QOL). Despite the relevance of GI symptoms to the overall health of PwCF, a paucity of studies only have comprehensively assessed the prevalence, severity and QOL of GI symptoms in both children and adults with Cystic Fibrosis (CF).Eligible participants ≥2 years of age across 26 US CF centers were followed for 4 weeks. Three validated GI electronic patient-reported outcome measures (ePROMs) with a recall period of 2 weeks and a stool-specific questionnaire were administered weekly over four weeks. Total and domain scores of ePROMs were evaluated overall and in subgroups using linear mixed-effect models.Of 402 enrolled, 58% were ≥ 18 years of age (52% male). The mean (SD) of the total score for PAC-SYM was 0.52 (0.55), for PAGI-SYM was 0.63 (0.67), and for PAC-QOL was 0.67 (0.55). For specific ePROM questions, prevalence of moderate to very severe symptoms were as follows: straining (20.3%), fullness (18.3%), incomplete bowel movements (17.1%), bloating (16.4%), distension (16.4%), abdominal pain (upper-5.1%, lower-7.5%). Comparing participants ≥18 versus18, a higher prevalence of bloating (63.7% versus 27.3%), lower abdominal pain (39.8% vs 26.2%), stomach fullness (75.6% versus 56.2%), and abdominal distension (60.2% versus 34.9%) was found. Both age groups reported high treatment dissatisfaction as measured with PAC-QOL, mean 1.39 (95% CI: 1.30, 1.47).GI symptoms were reported in all age ranges irrespective of gender, with higher prevalence observed amongst older and female subgroups. Dissatisfaction with GI targeted treatments were reported in a large proportion of participants despite therapy, highlighting an unmet need for clinical interventions.GOV: NCT03801993.

This Perspective reviews the use of Transition Path Sampling methods to study enzymatically catalyzed chemical reactions. First applied by our group to an enzymatic reaction over 15 years ago, the method has uncovered basic principles in enzymatic catalysis such as the protein promoting vibration, and it has also helped harmonize such ideas as electrostatic preorganization with dynamic views of enzyme function. It is now being used to help uncover principles of protein design necessary to artificial enzyme creation.

Background Inflammatory bowel disease (IBD) commonly leads to iron deficiency anemia (IDA). Rates of screening and treatment of IDA are often low. A clinical decision support system (CDSS) embedded in an electronic health record could improve adherence to evidence-based care. Rates of CDSS adoption are often low due to poor usability and fit with work processes. One solution is to use human-centered design (HCD), which designs CDSS based on identified user needs and context of use and evaluates prototypes for usefulness and usability. Objectives this study aimed to use HCD to design a CDSS tool called the IBD Anemia Diagnosis Tool, IADx. Methods Interviews with IBD practitioners informed creation of a process map of anemia care that was used by an interdisciplinary team that used HCD principles to create a prototype CDSS. The prototype was iteratively tested with “Think Aloud” usability evaluation with clinicians as well as semi-structured interviews, a survey, and observations. Feedback was coded and informed redesign. Results Process mapping showed that IADx should function at in-person encounters and asynchronous laboratory review. Clinicians desired full automation of clinical information acquisition such as laboratory trends and analysis such as calculation of iron deficit, less automation of clinical decision selection such as laboratory ordering, and no automation of action implementation such as signing medication orders. Providers preferred an interruptive alert over a noninterruptive reminder. Conclusion Providers preferred an interruptive alert, perhaps due to the low likelihood of noticing a noninterruptive advisory. High levels of desire for automation of information acquisition and analysis with less automation of decision selection and action may be generalizable to other CDSSs designed for chronic disease management. This underlines the ways in which CDSSs have the potential to augment rather than replace provider cognitive work.

PURPOSE To evaluate the efficacy and tolerability of two doses of gefitinib (Iressa [ZD1839]; AstraZeneca, Wilmington, DE), a novel epidermal growth factor receptor tyrosine kinase inhibitor, in patients with pretreated advanced non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS This was a randomized, double-blind, parallel-group, multicenter phase II trial. Two hundred ten patients with advanced NSCLC who were previously treated with one or two chemotherapy regimens (at least one containing platinum) were randomized to receive either 250-mg or 500-mg oral doses of gefitinib once daily. RESULTS Efficacy was similar for the 250- and 500-mg/d groups. Objective tumor response rates were 18.4% (95% confidence interval [CI], 11.5 to 27.3) and 19.0% (95% CI, 12.1 to 27.9); among evaluable patients, symptom improvement rates were 40.3% (95% CI, 28.5 to 53.0) and 37.0% (95% CI, 26.0 to 49.1); median progression-free survival times were 2.7 and 2.8 months; and median overall survival times were 7.6 and 8.0 months, respectively. Symptom improvements were recorded for 69.2% (250 mg/d) and 85.7% (500 mg/d) of patients with a tumor response. Adverse events (AEs) at both dose levels were generally mild (grade 1 or 2) and consisted mainly of skin reactions and diarrhea. Drug-related toxicities were more frequent in the higher-dose group. Withdrawal due to drug-related AEs was 1.9% and 9.4% for patients receiving gefitinib 250 and 500 mg/d, respectively. CONCLUSION Gefitinib showed clinically meaningful antitumor activity and provided symptom relief as second- and third-line treatment in these patients. At 250 mg/d, gefitinib had a favorable AE profile. Gefitinib 250 mg/d is an important, novel treatment option for patients with pretreated advanced NSCLC.