Incidence and mortality trends of primary cutaneous melanoma: A 50-year Rochester Epidemiologic Project study.

Background: National cancer reporting-based registry data, although robust, lacks granularity for incidence trends. Expert opinion remains conflicted regarding the possibility of melanoma overdiagnosis in the context of rising incidence without a corresponding rise in mortality. Objective: To characterize 10- and 50-year trends in melanoma incidence and mortality. Methods: Multicenter, population-based epidemiologic study utilizing the Rochester Epidemiology Project for Olmsted County, Minnesota residents diagnosed with melanoma from 01/01/1970 to 12/21/2020. Age- and sex-adjusted incidence and disease-specific mortality are calculated. Results: Two thousand three hundred ten primary cutaneous melanomas were identified. Current age- and sex-adjusted incidence rates increased 11.1-fold since 1970s (P < .001). Over the last decade, there is an overall 1.21-fold (P < .002) increase, with a 1.36-fold increase (P < .002) among females and no significant increase among males (1.09-fold increase, P < .329). Melanoma-specific mortality decreased from 26.7% in 1970s to 1.5% in 2010s, with a hazard ratio (HR) reduction of 0.73 (P < .001) per 5-year period. Increased mortality was associated with Breslow thickness (HR 1.35, P < .001), age at diagnosis (HR 1.13, P = .001) left anatomic site (HR 1.98, P = .016), and nodular histogenic subtype (HR 3.08, P < .001). Limitations: Retrospective nature and focused geographic investigation. Conclusion: Melanoma incidence has continued to increase over the past decade, most significantly in females aged 40+. Trend variations among age and sex cohorts suggests external factors beyond overdiagnosis may be responsible. Disease-specific mortality of melanoma continues to decrease over the last 50 years.

Rehabilitation of Reconstructed Maxilla Using Denture-Guided Epithelial Regeneration in DCIA Flap: 10-Year Follow-Up.

This 10-year follow-up report describes the interdisciplinary comprehensive management of a patient with aneurysmal bone cyst of the maxilla in a 24-year-old patient. The treatment included resection and primary reconstruction with vascularized deep circumflex iliac artery-based composite free flap, implant placement, and peri-implant soft tissue management using denture-guided epithelial regeneration with interim dentures. Definitive management was done using implant-supported cast partial dentures, and the patient followed up for 10 years.

Theory vs. experiment: The rise of the dynamic view of proteins.

Over the past century, the scientific conception of the protein has evolved significantly. This paper focuses on the most recent stage of this evolution, namely, the origin of the dynamic view of proteins and the challenge it posed to the static view of classical molecular biology. Philosophers and scientists have offered two hypotheses to explain the origin of the dynamic view and its slow reception by structural biologists. Some have argued that the shift from the static to the dynamic view was a Kuhnian revolution, driven by the accumulation of dynamic anomalies, while others have argued that the shift was caused by new empirical findings made possible by technological advances. I analyze this scientific episode and ultimately reject both of these empiricist accounts. I argue that focusing primarily on technological advances and empirical discoveries overlooks the important role of theory in driving this scientific change. I show how the application of general thermodynamic principles to proteins gave rise to the dynamic view, and a commitment to these principles then led early adopters to seek out the empirical examples of protein dynamics, which would eventually convince their peers. My analysis of this historical case shows that empiricist accounts of modern scientific progress-at least those that aim to explain developments in the molecular life sciences-need to be tempered in order to capture the interplay between theory and experiment.

Mechanistic Origin of Ligand Effects on Exhaustive Functionalization During Pd-Catalyzed Cross-Coupling of Dihaloarenes.

We describe a detailed investigation into why bulky ligands-those that enable catalysis at "12e -" Pd0-tend to promote overfunctionalization during Pd-catalyzed cross-couplings of dihalogenated substrates. After one cross-coupling event takes place, PdL initially remains coordinated to the π system of the nascent product. Selectivity for mono- vs. difunctionalization arises from the relative rates of π-decomplexation versus a second oxidative addition. Under the Suzuki coupling conditions in this work, direct dissociation of 12e - PdL from the π-complex cannot outcompete oxidative addition. Instead, Pd must be displaced from the π-complex as 14e - PdL(L') by a second incoming ligand L'. The incoming ligand is another molecule of dichloroarene if the reaction conditions do not include π-coordinating solvents or additives. More overfunctionalization tends to result when increased ligand or substrate sterics raises the energy of the bimolecular transition state for separating 14e - PdL(L') from the mono-cross-coupled product. This work has practical implications for optimizing selectivity in cross-couplings involving multiple halogens. For example, we demonstrate that small coordinating additives like DMSO can largely suppress overfunctionalization and that precatalyst structure can also impact selectivity.

A Review of Atomic-Force Microscopy in Skin Barrier Function Assessment.

Skin barrier function (SBF) disorders are a class of pathologies that affect a significant portion of the world population. These disorders cause skin lesions with intense itch, impacting patients' physical and psychological well-being as well as their social functioning. It is in the interest of patients that their disorder be monitored closely while under treatment to evaluate the effectiveness of the ongoing therapy and any potential adverse reactions. Symptom-based assessment techniques are widely used by clinicians; however, they carry some limitations. Techniques to assess skin barrier impairment are critical for understanding the nature of the disease and for helping personalize treatment. This review recalls the anatomy of the skin barrier and describes an atomic-force microscopy approach to quantitatively monitor its disorders and their response to treatment. We review a panel of studies that show that this technique is highly relevant for SBF disorder research, and we aim to motivate its adoption into clinical settings.

Referral Pathways for Children with Atopic Diseases in Denmark.

Atopic diseases such as atopic dermatitis, food allergy, allergic rhinoconjunctivitis, and/or asthma are common. In Denmark, however, there are multiple referral pathways for these diseases in the healthcare system and they are poorly understood. To describe how children with atopic diseases navigate their way through the Danish healthcare system, a questionnaire was distributed to children aged ≤ 17 years, who were being treated for atopic diseases between August 2020 and June 2021, either by a practising specialist or a hospital department, in the Capital Region of Denmark. A total of 279 children completed the questionnaire and most were referred to a specialist or to a hospital by their general practitioner. No "common track" to hospital existed for patients with ≥ 3 atopic diseases. These patients were more often referred to a hospital compared with children with 2 atopic diseases or fewer (odds ratio [OR] 3.79; 95% CI 2.07-7.24). The primary determinants for hospital treatment were food allergy (OR 4.69; 95% CI 2.07-10.61) and asthma (OR 2.58; 95% CI 1.18-5.63). In conclusion, children with multiple atopic diseases were more likely to be referred to hospital departments than to practising specialists, mainly due to food allergies.

Assessment of the antinociceptive, respiratory-depressant, and reinforcing effects of the low pKa fluorinated fentanyl analogs, FF3 and NFEPP.

RATIONALE: Recent studies report that fentanyl analogs with relatively low pKa values produce antinociception in rodents without other mu opioid-typical side effects due to the restriction of their activity to injured tissue with relatively low pH values. However, it is unclear if and to what degree these compounds may produce mu opioid-typical side effects (respiratory depression, reinforcing effects) at doses higher than those required to produce antinociception. OBJECTIVES: The present study compared the inflammatory antinociceptive, respiratory-depressant, and reinforcing effects of fentanyl and two analogs of intermediate (FF3) and low (NFEPP) pKa values in terms of potency and efficacy in male and female Sprague-Dawley rats. METHODS: Nociception was produced by administration of Complete Freund's Adjuvant into the hind paw of subjects, and antinociception was measured using an electronic Von Frey test. Respiratory depression was measured using whole-body plethysmography. Reinforcing effects were measured in self-administration using a progressive-ratio schedule of reinforcement. The dose ranges tested for each drug encompassed no effect to maximal effects. RESULTS: All compounds produced full effects in all measures but varied in potency. FF3 and fentanyl were equipotent in antinociception and self-administration, but FF3 was less potent than fentanyl in respiratory depression. NFEPP was less potent than fentanyl in every measure. The magnitude of potency difference between antinociception and other effects was greater for FF3 than for NFEPP or fentanyl, indicating that FF3 had the widest margin of safety when relating antinociception to respiratory-depressant and reinforcing effects. CONCLUSIONS: Low pKa fentanyl analogs possess potential as safer analgesics, but determining the optimal degree of difference for pKa relative to fentanyl will require further study due to some differences between the current results and findings from prior work with these analogs.

Protocol for mass spectrometric profiling of lysine malonylation by lysine acetyltransferase in CRISPRi K562 cell lines.

Lysine malonylation is a protein posttranslational modification. We present a protocol to generate stable gene-knockdown K562 cell lines through lentiviral infection of a CRISPR interference (CRISPRi) system followed by lysine malonylation measurement using mass spectrometry (MS). We detail guide RNA (gRNA) vector cloning, lentiviral infection, cell line purification, protein digestion, malonyl-lysine enrichment, desalting, and MS acquisition and analysis. For complete details on the use and execution of this protocol, please refer to Zhang et al.1 and Bons et al.2.

Meta-Analysis of Genome-Wide Association Studies Reveals Genetic Mechanisms of Supraventricular Arrhythmias.

BACKGROUND: Substantial data support a heritable basis for supraventricular tachycardias, but the genetic determinants and molecular mechanisms of these arrhythmias are poorly understood. We sought to identify genetic loci associated with atrioventricular nodal reentrant tachycardia (AVNRT) and atrioventricular accessory pathways or atrioventricular reciprocating tachycardia (AVAPs/AVRT). METHODS: We performed multiancestry meta-analyses of genome-wide association studies to identify genetic loci for AVNRT (4 studies) and AVAP/AVRT (7 studies). We assessed evidence supporting the potential causal effects of candidate genes by analyzing relations between associated variants and cardiac gene expression, performing transcriptome-wide analyses, and examining prior genome-wide association studies. RESULTS: Analyses comprised 2384 AVNRT cases and 106 489 referents, and 2811 AVAP/AVRT cases and 1,483 093 referents. We identified 2 significant loci for AVNRT, which implicate NKX2-5 and TTN as disease susceptibility genes. A transcriptome-wide association analysis supported an association between reduced predicted cardiac expression of NKX2-5 and AVNRT. We identified 3 significant loci for AVAP/AVRT, which implicate SCN5A, SCN10A, and TTN/CCDC141. Variant associations at several loci have been previously reported for cardiac phenotypes, including atrial fibrillation, stroke, Brugada syndrome, and electrocardiographic intervals. CONCLUSIONS: Our findings highlight gene regions associated with ion channel function (AVAP/AVRT), as well as cardiac development and the sarcomere (AVAP/AVRT and AVNRT) as important potential effectors of supraventricular tachycardia susceptibility.

Access to Complex Scaffolds Through [2 + 2] Cycloadditions of Strained Cyclic Allenes.

We report the strain-induced [2 + 2] cycloadditions of cyclic allenes for the assembly of highly substituted cyclobutanes. By judicious choice of trapping agent, complex scaffolds bearing heteroatoms, fused rings, contiguous stereocenters, spirocycles, and quaternary centers are ultimately accessible. Moreover, we show that the resulting cycloadducts can undergo thermal isomerization. This study provides an alternative strategy to photochemical [2 + 2] cycloadditions for accessing highly functionalized cyclobutanes, while validating the use of underexplored strained intermediates for the assembly of complex architectures.

Safety of early discharge after elective lumbar spine surgery with subfascial drains and association with significant reduction in length of stay.

OBJECTIVE: After lumbar spine surgery, postoperative drain removal often delays discharge. Whether inpatient drain removal reduces the risk of surgical site infection (SSI) or hematoma remains controversial. Therefore, in patients undergoing elective lumbar spine surgery, the authors sought to determine the impact of inpatient versus outpatient drain removal on the following variables: 1) length of hospital stay (LOS), and 2) postoperative complications. METHODS: A single-center retrospective cohort study in which the authors used prospectively collected data of patients undergoing primary, elective, 1- or 2-level lumbar spine decompression and/or fusion was undertaken between 2016 and 2022. Patients with intraoperative or postoperative CSF leaks were excluded. The primary exposure variable was inpatient versus outpatient drain removal. The primary outcome was LOS, and secondary outcomes were postoperative complications, including 90-day postoperative SSI or hematoma. Multivariable logistic and linear regression were performed, controlling for age, body mass index, instrumentation, number of levels, antibiotics at discharge, and surgeons involved. RESULTS: Of 483 patients included, 325 (67.3%) had inpatient drain removal and 158 (32.7%) had outpatient drain removal. Patients with outpatient drain removal were significantly younger (58.6 ± 12.4 vs 61.2 ± 13.2 years, p = 0.040); more likely to have 1-level surgery (75.9% vs 56.6%, p < 0.001); and less likely to receive instrumentation (50.6% vs 69.5%, p < 0.001). Postoperatively, patients with outpatient drain removal had a shorter LOS (0.7 ± 0.6 vs 2.3 ± 1.6 days, p < 0.001); were more likely to be discharged home (98.1% vs 92.3%, p = 0.015); were more likely to be discharged on antibiotics (76.6% vs 3.1%, p < 0.001); were less likely to be on opioids (32.3% vs 88.3%, p < 0.001); and were more likely to have Jackson-Pratt compared to Hemovac drains (96.2% vs 34.5%, p < 0.001). No difference was found in SSI (3.7% vs 3.8%, p > 0.999) or hematoma (0.9% vs 0.6%, p > 0.999), as well as reoperation or readmission due to SSI or hematoma. On multivariable regression, outpatient drain removal was significantly associated with shorter LOS (ß = -1.15, 95% CI -1.56 to -0.73, p < 0.001). No association was found with SSI/hematoma (p > 0.05). CONCLUSIONS: Outpatient drain removal after elective lumbar spine surgery was associated with a significantly decreased LOS without a significant increase in postoperative SSI or hematoma. Although the choice of drain removal and the LOS may be subject to surgeons' preference, these results may support the feasibility and safety of outpatient drain removal, and the potential cost savings resulting from shortened hospital stays. Drawbacks may exist regarding added burden to the patient and the surgeon's team to accommodate 1-week follow-up appointments for drain removal.

Comparison of Americium(III) and Neodymium(III) Monothiophosphate Complexes.

Mixed-donor ligands, such as those containing a combination of O/N or O/S, have been studied extensively for the selective extraction of trivalent actinides, especially Am3+ and Cm3+, from lanthanides during the recycling of used nuclear fuel. Oxygen/sulfur donor ligand combinations also result from the hydrolytic and/or radiolytic degradation of dithiophosphates, such as the Cyanex class of extractants, which are initially converted to monothiophosphates. To understand potential differences between the binding of such degraded ligands to Nd3+ and Am3+, the monothiophosphate complexes [M(OPS(OEt)2)5(H2O)2]2- (M3+ = Nd3+, Am3+) were prepared and characterized by single-crystal X-ray diffraction and optical spectroscopy and studied as a function of pressure up to ca. 14 GPa using diamond-anvil techniques. Although Nd3+ and Am3+ have nearly identical eight-coordinated ionic radii, these structures reveal that while the M-O bond distances in these complexes are almost equal, the M-S distances are statistically different. Moreover, for [Nd(OPS(OEt)2)5(H2O)2]2-, the hypersensitive 4I9/2 → 4G5/2 transition shifts as a function of pressure by -11 cm-1/GPa. Whereas for [Am(OPS(OEt)2)5(H2O)2]2-, the 7F0 → 7F6 transition shows a slightly stronger pressure dependence with a shift of -13 cm-1/GPa and also exhibits broadening of the 5f → 5f transitions at high pressures. These data likely indicate an increased involvement of the 5f orbitals in bonding with Am3+ relative to that of Nd3+ in these complexes.

Electron beam response corrections for an ultra-high-dose-rate capable diode dosimeter.

BACKGROUND: Ultra-high-dose-rate (UHDR) electron beams have been commonly utilized in FLASH studies and the translation of FLASH Radiotherapy (RT) to the clinic. The EDGE diode detector has potential use for UHDR dosimetry albeit with a beam energy dependency observed. PURPOSE: The purpose is to present the electron beam response for an EDGE detector in dependence on beam energy, to characterize the EDGE detector's response under UHDR conditions, and to validate correction factors derived from the first detailed Monte Carlo model of the EDGE diode against measurements, particularly under UHDR conditions. METHODS: Percentage depth doses (PDDs) for the UHDR Mobetron were measured with both EDGE detectors and films. A detailed Monte Carlo (MC) model of the EDGE detector has been configured according to the blueprint provided by the manufacturer under an NDA agreement. Water/silicon dose ratios of EDGE detector for a series of mono-energetic electron beams have been calculated. The dependence of the water/silicon dose ratio on depth for a FLASH relevant electron beam was also studied. An analytical approach for the correction of PDD measured with EDGE detectors was established. RESULTS: Water/silicon dose ratio decreased with decreasing electron beam energy. For the Mobetron 9 MeV UHDR electron beam, the ratio decreased from 1.09 to 1.03 in the build-up region, maintained in range of 0.98-1.02 at the fall-off region and raised to a plateau in value of 1.08 at the tail. By applying the corrections, good agreement between the PDDs measured by the EDGE detector and those measured with film was achieved. CONCLUSIONS: Electron beam response of an UHDR capable EDGE detector was derived from first principles utilizing a sophisticated MC model. An analytical approach was validated for the PDDs of UHDR electron beams. The results demonstrated the capability of EDGE detector in measuring PDDs of UHDR electron beams.

Prognostic value of pulmonary diffusing capacity for carbon monoxide and ventilation-perfusion SPECT findings in pulmonary arterial hypertension.

Reduced pulmonary diffusing capacity for carbon monoxide (DLCO) can be observed in pulmonary arterial hypertension (PAH) and associates with increased mortality. However, the prognostic value of DLCO when corrected for haemoglobin (DLCOc), an independent modifier of DLCO, remains understudied. Additionally, the prognostic role of ventilation (V)-perfusion (Q) emission computed tomography (V/Q SPECT) findings in patients with PAH, which may concurrently be performed to rule out chronic thromboembolic pulmonary hypertension, is uncertain. A retrospective cohort study was conducted on 152 patients with PAH referred to a tertiary hospital for evaluation from January 2011 to January 2020. Lung function tests, clinical data and V/Q SPECT were ascertained. Cox regression analysis was performed to evaluate the association between DLCOc, DLCO and V/Q SPECT defects at referral with all-cause mortality. In equally adjusted Cox regression analysis, each percentage increase in DLCOc % predicted (%pred) (hazard ratio (HR) 0.97; 95% CI: 0.94-0.99) and DLCO%pred (HR 0.97; 95% CI: 0.94-0.99) was similarly associated with all-cause mortality. There was no detectable difference in area under the curve for prediction of all-cause mortality by DLCOc%pred and DLCO%pred (C-index 0.71 and 0.72, respectively, P = 0.85 for difference). None of the defects noted on V/Q SPECT were significantly associated with mortality, but mismatched defects were associated with lower values of DLCOc%pred and DLCO%pred. DLCOc%pred and DLCO%pred perform equally as prognostic markers in PAH, supporting the use of either metric when available for prognostic stratification.

The Intersection of Growth Mindset and Accreditation in Pharmacy Education.

OBJECTIVES: To describe existing growth mindset literature within pharmacy and health care education, describe how a growth mindset can be beneficial in the accreditation process, and propose potential ways to promote a growth mindset in faculty, preceptors, students, and staff within pharmacy education. FINDINGS: To help pharmacy learners develop a growth mindset, existing literature emphasizes the need for a shift toward and aligning assessment with a growth mindset, helping to create self-directed adaptive learners, leading to health care providers who can adjust their practice to tackle expected and unexpected challenges throughout their careers. Strategies to create a culture of growth mindset identified include training faculty and learners on growth mindset and developing new assessments that track a learner's growth. Recommendations for pharmacy educators include encouraging educators to assess their own growth mindset and use a variety of teaching methods and provide feedback on learner effort that encourages the process of learning rather than focusing on individual attributes, traits, and results. SUMMARY: Growth mindset intersects with accreditation standards for both professional degree programs and providers of continuing pharmacy education. Continuing professional development process is one way to encourage faculty, staff, and students to develop a growth mindset. While a growth mindset can have many positive impacts on pharmacy accreditation, it is essential to recognize that achieving and maintaining accreditation is a multifaceted process involving numerous factors. A growth mindset can positively influence pharmacy education accreditation by fostering a culture of continuous improvement, innovation, resilience, student-centeredness, data-driven decision-making, collaboration, and effective leadership.