Pancreatic Cancer Surveillance and Survival of High-Risk Individuals.

Importance: Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with increasing incidence. The majority of PDACs are incurable at presentation, but population-based screening is not recommended. Surveillance of high-risk individuals for PDAC may lead to early detection, but the survival benefit is unproven. Objective: To compare the survival of patients with surveillance-detected PDAC with US national data. Design, Setting, and Participants: This comparative cohort study was conducted in multiple US academic medical centers participating in the Cancer of the Pancreas Screening program, which screens high-risk individuals with a familial or genetic predisposition for PDAC. The comparison cohort comprised patients with PDAC matched for age, sex, and year of diagnosis from the Surveillance, Epidemiology, and End Results (SEER) program. The Cancer of the Pancreas Screening program originated in 1998, and data collection was done through 2021. The data analysis was performed from April 29, 2022, through April 10, 2023. Exposures: Endoscopic ultrasonography or magnetic resonance imaging performed annually and standard-of-care surgical and/or oncologic treatment. Main Outcomes and Measures: Stage of PDAC at diagnosis, overall survival (OS), and PDAC mortality were compared using descriptive statistics and conditional logistic regression, Cox proportional hazards regression, and competing risk regression models. Sensitivity analyses and adjustment for lead-time bias were also conducted. Results: A total of 26 high-risk individuals (mean [SD] age at diagnosis, 65.8 [9.5] years; 15 female [57.7%]) with PDAC were compared with 1504 SEER control patients with PDAC (mean [SD] age at diagnosis, 66.8 [7.9] years; 771 female [51.3%]). The median primary tumor diameter of the 26 high-risk individuals was smaller than in the control patients (2.5 [range, 0.6-5.0] vs 3.6 [range, 0.2-8.0] cm, respectively; P < .001). The high-risk individuals were more likely to be diagnosed with a lower stage (stage I, 10 [38.5%]; stage II, 8 [30.8%]) than matched control patients (stage I, 155 [10.3%]; stage II, 377 [25.1%]; P < .001). The PDAC mortality rate at 5 years was lower for high-risk individuals than control patients (43% vs 86%; hazard ratio, 3.58; 95% CI, 2.01-6.39; P < .001), and high-risk individuals lived longer than matched control patients (median OS, 61.7 [range, 1.9-147.3] vs 8.0 [range, 1.0-131.0] months; 5-year OS rate, 50% [95% CI, 32%-80%] vs 9% [95% CI, 7%-11%]). Conclusions and Relevance: These findings suggest that surveillance of high-risk individuals may lead to detection of smaller, lower-stage PDACs and improved survival.

Differential extracellular vesicle concentration and their biomarker expression of integrin αv/ß5, EpCAM, and glypican-1 in pancreatic cancer models.

Tumor-derived extracellular vesicles (EVs) show great potential as biomarkers for several diseases, including pancreatic cancer, due to their roles in cancer development and progression. However, the challenge of utilizing EVs as biomarkers lies in their inherent heterogeneity in terms of size and concentration, making accurate quantification difficult, which is highly dependent on the isolation and quantification methods used. In our study, we compared three EV isolation techniques and two EV quantification methods. We observed variations in EV concentration, with approximately 1.5-fold differences depending on the quantification method used. Interestingly, all EV isolation techniques consistently yielded similar EV quantities, overall size distribution, and modal sizes. In contrast, we found a notable increase in total EV amounts in samples from pancreatic cancer cell lines, mouse models, and patient plasma, compared to non-cancerous conditions. Moreover, individual tumor-derived EVs exhibited at least a 3-fold increase in several EV biomarkers. Our data, obtained from EVs isolated using various techniques and quantified through different methods, as well as originating from various pancreatic cancer models, suggests that EV profiling holds promise for the identification of unique and cancer-specific biomarkers in pancreatic cancer.

DNA mismatch and damage patterns revealed by single-molecule sequencing.

Mutations accumulate in the genome of every cell of the body throughout life, causing cancer and other diseases1,2. Most mutations begin as nucleotide mismatches or damage in one of the two strands of the DNA before becoming double-strand mutations if unrepaired or misrepaired3,4. However, current DNA-sequencing technologies cannot accurately resolve these initial single-strand events. Here we develop a single-molecule, long-read sequencing method (Hairpin Duplex Enhanced Fidelity sequencing (HiDEF-seq)) that achieves single-molecule fidelity for base substitutions when present in either one or both DNA strands. HiDEF-seq also detects cytosine deamination-a common type of DNA damage-with single-molecule fidelity. We profiled 134 samples from diverse tissues, including from individuals with cancer predisposition syndromes, and derive from them single-strand mismatch and damage signatures. We find correspondences between these single-strand signatures and known double-strand mutational signatures, which resolves the identity of the initiating lesions. Tumours deficient in both mismatch repair and replicative polymerase proofreading show distinct single-strand mismatch patterns compared to samples that are deficient in only polymerase proofreading. We also define a single-strand damage signature for APOBEC3A. In the mitochondrial genome, our findings support a mutagenic mechanism occurring primarily during replication. As double-strand DNA mutations are only the end point of the mutation process, our approach to detect the initiating single-strand events at single-molecule resolution will enable studies of how mutations arise in a variety of contexts, especially in cancer and ageing.

A Rigorous Multi-Laboratory Study of Known PDAC Biomarkers Identifies Increased Sensitivity and Specificity Over CA19-9 Alone.

A blood test that enables surveillance for early-stage pancreatic ductal adenocarcinoma (PDAC) is an urgent need. Independent laboratories have reported PDAC biomarkers that could improve biomarker performance over CA19-9 alone, but the performance of the previously reported biomarkers in combination is not known. Therefore, we conducted a coordinated case/control study across multiple laboratories using common sets of blinded training and validation samples (132 and 295 plasma samples, respectively) from PDAC patients and non-PDAC control subjects representing conditions under which surveillance occurs. We analyzed the training set to identify candidate biomarker combination panels using biomarkers across laboratories, and we applied the fixed panels to the validation set. The panels identified in the training set, CA19-9 with CA199.STRA, LRG1, TIMP-1, TGM2, THSP2, ANG, and MUC16.STRA, achieved consistent performance in the validation set. The panel of CA19-9 with the glycan biomarker CA199.STRA improved sensitivity from 0.44 with 0.98 specificity for CA19-9 alone to 0.71 with 0.98 specificity (p < 0.001, 1000-fold bootstrap). Similarly, CA19-9 combined with the protein biomarker LRG1 and CA199.STRA improved specificity from 0.16 with 0.94 sensitivity for CA19-9 to 0.65 with 0.89 sensitivity (p < 0.001, 1000-fold bootstrap). We further validated significantly improved performance using biomarker panels that did not include CA19-9. This study establishes the effectiveness of a coordinated study of previously discovered biomarkers and identified panels of those biomarkers that significantly increased the sensitivity and specificity of early-stage PDAC detection in a rigorous validation trial.

The role of family history in predicting germline pathogenic variant carriers who develop pancreatic cancer: Results of a multicenter collaboration.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) surveillance is recommended for some individuals with a pathogenic or likely pathogenic variant (PV/LPV) in a PDAC susceptibility gene; the recommendation is often dependent on family history of PDAC. This study aimed to describe PDAC family history in individuals with PDAC who underwent genetic testing to determine the appropriateness of including a family history requirement in these recommendations. METHODS: Individuals with PDAC with a germline heterozygous PV/LPV in ATM, BRCA1, BRCA2, EPCAM, MLH1, MSH2, MSH6, PALB2, or PMS2 (PV/LPV carriers) were assessed for family history of PDAC in first-degree relatives (FDRs) or second-degree relatives (SDRs) from nine institutions. A control group of individuals with PDAC without a germline PV/LPV was also assessed. RESULTS: The study included 196 PV/LPV carriers and 1184 controls. In the PV/LPV carriers, 25.5% had an affected FDR and/or SDR compared to 16.9% in the control group (p = .004). PV/LPV carriers were more likely to have an affected FDR compared to the controls (p = .003) but there was no statistical difference when assessing only affected SDRs (p = .344). CONCLUSIONS: Most PV/LPV carriers who developed PDAC did not have a close family history of PDAC and would not have met most current professional societies' recommendations for consideration of PDAC surveillance before diagnosis. However, PV/LPV carriers were significantly more likely to have a family history of PDAC, particularly an affected FDR. These findings support family history as a risk modifier in PV/LPV carriers, and highlight the need to identify other risk factors.

Forecasting Hepatitis C Virus Status for Children in the United States: A Modeling Study.

BACKGROUND: Virtually all cases of hepatitis C virus (HCV) infection in children in the United States occur through vertical transmission, but it is unknown how many children are infected. Cases of maternal HCV infection have increased in the United States, which may increase the number of children vertically infected with HCV. Infection has long-term consequences for a child's health, but treatment options are now available for children ≥3 years old. Reducing HCV infections in adults could decrease HCV infections in children. METHODS: Using a stochastic compartmental model, we forecasted incidence of HCV infections in children in the United States from 2022 through 2027. The model considered vertical transmission to children <13 years old and horizontal transmission among individuals 13-49 years old. We obtained model parameters and initial conditions from the literature and the Centers for Disease Control and Prevention's 2021 Viral Hepatitis Surveillance Report. RESULTS: Model simulations assuming direct-acting antiviral treatment for children forecasted that the number of acutely infected children would decrease slightly and the number of chronically infected children would decrease even more. Alone, treatment and early screening in individuals 13-49 years old reduced the number of forecasted cases in children and, together, these policy interventions were even more effective. CONCLUSIONS: Based on our simulations, acute and chronic cases of HCV infection are remaining constant or slightly decreasing in the United States. Improving early screening and increasing access to treatment in adults may be an effective strategy for reducing the number of HCV infected children in the United States.

The Pancreatic Cancer Early Detection (PRECEDE) Study is a Global Effort to Drive Early Detection: Baseline Imaging Findings in High-Risk Individuals.

BACKGROUND: Pancreatic adenocarcinoma (PC) is a highly lethal malignancy with a survival rate of only 12%. Surveillance is recommended for high-risk individuals (HRIs), but it is not widely adopted. To address this unmet clinical need and drive early diagnosis research, we established the Pancreatic Cancer Early Detection (PRECEDE) Consortium. METHODS: PRECEDE is a multi-institutional international collaboration that has undertaken an observational prospective cohort study. Individuals (aged 18-90 years) are enrolled into 1 of 7 cohorts based on family history and pathogenic germline variant (PGV) status. From April 1, 2020, to November 21, 2022, a total of 3,402 participants were enrolled in 1 of 7 study cohorts, with 1,759 (51.7%) meeting criteria for the highest-risk cohort (Cohort 1). Cohort 1 HRIs underwent germline testing and pancreas imaging by MRI/MR-cholangiopancreatography or endoscopic ultrasound. RESULTS: A total of 1,400 participants in Cohort 1 (79.6%) had completed baseline imaging and were subclassified into 3 groups based on familial PC (FPC; n=670), a PGV and FPC (PGV+/FPC+; n=115), and a PGV with a pedigree that does not meet FPC criteria (PGV+/FPC-; n=615). One HRI was diagnosed with stage IIB PC on study entry, and 35.1% of HRIs harbored pancreatic cysts. Increasing age (odds ratio, 1.05; P<.001) and FPC group assignment (odds ratio, 1.57; P<.001; relative to PGV+/FPC-) were independent predictors of harboring a pancreatic cyst. CONCLUSIONS: PRECEDE provides infrastructure support to increase access to clinical surveillance for HRIs worldwide, while aiming to drive early PC detection advancements through longitudinal standardized clinical data, imaging, and biospecimen captures. Increased cyst prevalence in HRIs with FPC suggests that FPC may infer distinct biological processes. To enable the development of PC surveillance approaches better tailored to risk category, we recommend adoption of subclassification of HRIs into FPC, PGV+/FPC+, and PGV+/FPC- risk groups by surveillance protocols.

Trends in Indications and Contraindications for Cervical Disk Arthroplasty from 2009 to 2019.

STUDY DESIGN: Cross-sectional study. OBJECTIVE: Assess trends of indications and contraindications for the use of Cervical Disk Arthroplasty (CDA). SUMMARY OF BACKGROUND DATA: As spine surgeons become more familiar with CDA, there have been expansions in indications. METHODS: The Medicare Provider Analysis and Review Limited Data Sets for 2009, 2014, and 2019 were utilized. Patients undergoing elective CDA were included. Diagnosis for index surgery and "contraindications" as defined by original CDA Investigative Device Exemption (IDE) criteria were assessed. Variables were identified by the International Classification of Diseases (ICD)-9 or ICD-10 diagnosis and procedural codes. RESULTS: A total of 1067 elective CDA patients were included. There were 230 patients in 2009, 300 patients in 2014, and 537 patients in 2019. The proportion of patients aged >65 increased from 35% to 51% ( P <0.001). Incidence of CDA for radiculopathy increased from 57% to 69% ( P <0.001), myelopathy increased from 23% to 78% ( P <0.001), and spondylosis without radiculopathy or myelopathy decreased from 19% to 3% ( P <0.001). There were increased incidences of ankylosing spondylitis (0.4% to 2.8%, P =0.007), long-term steroid use (1% to 2%, P =0.039), morbid obesity (2% to 6%, P =0.019), and osteoporosis (1% to 5%, P =0.014). The incidence of hybrid CDA and anterior cervical discectomy and fusion (ACDF) decreased from 28% to 23% ( P =0.007). CONCLUSION: From 2009 to 2019, the number of CDA performed in older patients increased. An increase in the use of CDA for the treatment of myelopathy and radiculopathy and a decrease in the treatment of isolated cervical spondylosis was observed. The proportion of CDA performed in patients with original IDE trial "contraindications" increased. Further research into the efficacy of CDA for patients with contraindications is warranted.

Resource Utilization Following Anterior Versus Posterior Cervical Decompression and Fusion for Acute Central Cord Syndrome.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: The purpose of this study is to compare the impact of anterior cervical decompression and fusion (ACDF) versus posterior cervical decompression and fusion (PCDF) for the treatment of acute traumatic central cord syndrome (CCS) on hospital episodes of care in terms of (1) cost, (2) length of hospital stay, and (3) discharge destination. SUMMARY OF BACKGROUND DATA: Acute traumatic CCS is the most common form of spinal cord injury in the United States. CCS is commonly treated with surgical decompression and fusion. Hospital resource utilization based on surgical approach remains unclear. METHODS: Patients undergoing ACDF and PCDF for acute traumatic CCS were identified using the 2019 Medicare Provider Analysis and Review Limited Data Set and Centers for Medicare and Medicaid Services 2019 Impact File. Multivariate models for hospital cost of care, length of stay, and discharge destination were performed, controlling for confounders. Subanalysis of accommodation and revenue center cost drivers was performed. RESULTS: There were 1474 cases that met inclusion criteria: 673 ACDF (45.7%) and 801 PCDF (54.3%). ACDF was independently associated with a decreased cost of $9802 ( P <0.001) and a 59.2% decreased risk of discharge to nonhome destinations (adjusted odds ratio: 0.408, P <0.001). The difference in length of stay was not statistically significant. On subanalysis of cost drivers, ACDF was associated with decreased charges ($55,736, P <0.001) compared with PCDF, the largest drivers being the intensive care unit ($15,873, 28% of total charges, P <0.001) and medical/surgical supply charges ($19,651, 35% of total charges, P <0.001). CONCLUSIONS: For treatment of acute traumatic CCS, ACDF was associated with almost $10,000 less expensive cost of care and a 60% decreased risk of discharge to nonhome destination compared with PCDF. The largest cost drivers appear to be ICU and medical/surgical-related. These findings may inform value-based decisions regarding the treatment of acute traumatic CCS. However, injury and patient clinical factors should always be prioritized in surgical decision-making, and increased granularity in reimbursement policies is needed to prevent financial disincentives in the treatment of patients with CCS better addressed with posterior approach-surgery.

Pancreatic Cysts Greater Than 1 cm Are Associated With an Increased Risk for Developing Pancreatic Cancer in Individuals From Pancreatic-Cancer Prone Kindreds Undergoing Surveillance.

BACKGROUND: The International Cancer of the Pancreas Screening Consortium recommended annual imaging for individuals at increased risk for developing a pancreatic ductal adenocarcinoma (PDAC) who did not have concerning pancreatic findings or a cyst <3 cm without worrisome features. We aimed to determine if 3-cm cyst size accurately predicted advanced precursor lesions in high-risk individuals undergoing surveillance. METHODS: Imaging for high-risk individuals (HRIs) undergoing PDAC surveillance from 2007 to 2021 was reviewed and pancreatic abnormalities were recorded including dominant cyst size and number of cysts. Subjects were excluded if they had the following: (1) no follow-up imaging after baseline, (2) solid lesion at baseline, or (3) development of solid lesion without having cyst on prior imaging. RESULTS: Five of the 77 HRIs found to have a cystic lesion on surveillance developed a PDAC: 3 with cystic lesion >1 cm as compared with only 2 of 67 HRIs with cystic lesions <1 cm (P < 0.05). None of these cysts developed worrisome findings and 4/5 PDACs did not arise from visualized cystic precursor lesion. CONCLUSIONS: Patients with a cyst ≥1 cm were at increased risk for developing PDAC compared with patients with cyst <1 cm. Pancreatic ductal adenocarcinoma usually did not arise from a recognized cystic lesion.

Elective Single-Level Primary Anterior Cervical Decompression and Fusion for Degenerative Spondylotic Cervical Myelopathy Is Associated With Decreased Resource Utilization Versus Posterior Cervical Decompression and Fusion.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To compare elective single-level anterior cervical discectomy and fusion (ACDF) versus posterior cervical decompression and fusion (PCDF) for degenerative cervical myelopathy (DCM) in terms of (1) cost, (2) length of hospital stay, and (3) discharge destination in Medicare patients. A sub-analysis of potential cost drivers was also performed. BACKGROUND: In the era of value-based medicine, there is substantial interest in reducing the cost of care. Both ACDF and PCDF are used to treat DCM but carry different morbidity and risk profiles that can impact hospital resource utilization. However, this has not been assessed on a national level. METHODS: Patients undergoing single-level elective ACDF and PCDF surgery were identified using the 2019 Medicare Provider Analysis and Review (MedPAR) Limited Data Set (LDS) and Centers for Medicare and Medicaid Services (CMS) 2019 Impact File. Multivariate models of hospital cost of care, length of stay, and discharge destination were performed, controlling for confounders. A univariate sub-analysis of 9 revenue centers was performed. RESULTS: In all, 3942 patients met the inclusion criteria. The mean cost of elective single-level cervical fusion for myelopathy was $18,084±10,783, and the mean length of stay was 2.45±2.95 d. On multivariate analysis, ACDF was independently associated with decreased cost of $5,814 ( P <0.001), shorter length of stay by 1.1 days ( P <0.001), and decreased risk of nonhome discharge destination by 58% (adjusted odds ratio: 0.422, P <0.001).On sub-analysis of 9 revenue centers, medical/surgical supply ($10,497, 44%), operating room charges ($5401, 23%), and accommodations ($3999, 17%) were the largest drivers of charge differences. CONCLUSIONS: Single-level elective primary ACDF for DCM was independently associated with decreased cost, decreased hospital length of stay, and a lower rate of nonhome discharge compared with PCDF. Medical and surgical supply, operating room, and accommodation differences between ACDF and PCDF are potential areas for intervention. Increased granularity in reimbursement structures is warranted to prevent the creation of disincentives to the treatment of patients with DCM with pathology that is better addressed with PCDF. LEVEL OF EVIDENCE: Level-III Retrospective Cohort Study.

Solvation Structure of Methanol-in-Salt Electrolyte Revealed by Small-Angle X-ray Scattering and Simulations.

The solvation structure of water-in-salt electrolytes was thoroughly studied, and two competing structures─anion solvated structure and anion network─were well-defined in recent publications. To further reveal the solvation structure in those highly concentrated electrolytes, particularly the influence of solvent, methanol was chosen as the solvent for this proposed study. In this work, small-angle X-ray scattering, small-angle neutron scattering, Fourier-transform infrared spectroscopy, and Raman spectroscopy were utilized to obtain the global and local structural information. With the concentration increment, the anion network formed by TFSI- became the dominant structure. Meanwhile, the hydrogen bonds among methanol were interrupted by the TFSI- anion and formed a new connection with them. Molecular dynamic simulations with two different force fields (GAFF and OPLS-AA) are tested, and GAFF agreed with synchrotron small-angle X-ray scattering/wide-angle X-ray scattering (SAXS/WAXS) results well and provided insightful information about molecular/ion scale solvation structure. This article not only deepens the understanding of the solvation structure in highly concentrated solutions, but more importantly, it provides additional strong evidence for utilizing SAXS/WAXS to validate molecular dynamics simulations.

Pressure dependent structure of amorphous magnesium aluminosilicates: The effect of replacing magnesia by alumina at the enstatite composition.

The effect of replacing magnesia by alumina on the pressure-dependent structure of amorphous enstatite was investigated by applying in situ high-pressure neutron diffraction with magnesium isotope substitution to glassy (MgO)0.375(Al2O3)0.125(SiO2)0.5. The replacement leads to a factor of 2.4 increase in the rate-of-change of the Mg-O coordination number with pressure, which increases from 4.76(4) at ambient pressure to 6.51(4) at 8.2 GPa, and accompanies a larger probability of magnesium finding bridging oxygen atoms as nearest-neighbors. The Al-O coordination number increases from 4.17(7) to 5.24(8) over the same pressure interval at a rate that increases when the pressure is above ∼3.5 GPa. On recovering the glass to ambient conditions, the Mg-O and Al-O coordination numbers reduce to 5.32(4) and 4.42(6), respectively. The Al-O value is in accordance with the results from solid-state 27Al nuclear magnetic resonance spectroscopy, which show the presence of six-coordinated aluminum species that are absent in the uncompressed material. These findings explain the appearance of distinct pressure-dependent structural transformation regimes in the preparation of permanently densified magnesium aluminosilicate glasses. They also indicate an anomalous minimum in the pressure dependence of the bulk modulus with an onset that suggests a pressure-dependent threshold for transitioning between scratch-resistant and crack-resistant material properties.

Fluorine in Complex Alumino-Boro-Silicate Glasses: Insight into Chemical Environment and Structure.

Fluorine incorporation into silicate glasses is important for technical fields as diverse as geophysics, extractive metallurgy, reconstructive dentistry, optical devices, and radioactive waste management. In this study, we explored the structural role of fluorine in alkaline alumino-borosilicate glass, with increasing amounts of fluorine up to 25 mol % F while maintaining the glass composition. Glasses were characterized by X-ray diffraction (XRD), 27Al and 19F magic angle spinning nuclear magnetic resonance (MAS NMR) spectroscopy, and electron probe microanalysis. Results showed that essentially all F was retained; however, between 12 and 15 mol % F (∼3.6 and 4.5 wt % F), excess fluorine partitions to CaF2 and then NaF and Na-Al-F crystalline phases. Even prior to crystallization, there exist five distinct F sites, three of which evolve into crystalline phases. The two persistent glassy sites likely involve [4]Al-F-Ca/Na local structures. We propose a general understanding of the expected chemical shift of 19F NMR in systems containing Al, Ca, and Na.

Tryptophan intake and pancreatic cancer: findings from a case-control study.

BACKGROUND: Pancreatic cancer is a leading cause of cancer-related death worldwide. Tryptophan plays a vital role in cell growth and maintenance as a building block of protein and coordination of organismal responses to environmental and dietary cues. Animal model study showed that dietary tryptophan improved treatment response in those who received chemotherapy or immune checkpoint inhibitors. Limited data are available assessing the association between tryptophan intake and risk of pancreatic cancer. We aimed to evaluate this association in a case-control study in Vietnam. METHODS: We analyzed data from a case-control study, including 3759 cancer cases and 2995 control subjects of whom 37 with pancreatic cancer cases. Tryptophan intake was derived from food frequency questionnaire. Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for different levels of tryptophan intake with pancreatic cancer risk. RESULTS: Overall, tryptophan intake was inversely associated with pancreatic cancer risk in a dose-dependent manner. The ORs and 95% CIs of pancreatic cancer were 0.51 (0.29-0.92) for continuous scale, 0.27 (0.10-0.73) for tertile 2 and 0.34 (0.11-1.06) for tertile 3, compared with tertile 1 (the lowest intake) ( Ptrend = 0.02). In stratified analysis, this inverse association pattern was present among those with BMI < 23 kg/m 2 and ever drinkers. CONCLUSION: A diet with a higher intake of tryptophan was significantly associated with a lower incidence of pancreatic cancer among Vietnamese population. These suggest that dietary modification may be an effective strategy for primary prevention of pancreatic cancer development.

CLINICAL FINDINGS OF DENTAL DISEASE AND POTENTIAL CONTRIBUTING FACTORS IN PYGMY SLOW LORISES (NYCTICEBUS PYGMAEUS) UNDER HUMAN CARE.

Dental disease is a common finding in pygmy slow lorises (Nycticebus pygmaeus) under human care, but the etiology is not fully understood. The small oral cavity in this species can make diagnosis of dental disease difficult. This retrospective study evaluated medical records and diet and husbandry protocols from 18 participating institutions with the objective of describing the signalment, clinical signs, physical exam findings, tooth type, tooth location, diagnostics used, and treatments performed to help guide care for dental disease. In addition, the study aimed to identify potential contributing factors to dental disease in this species. Of 59 animals with medical records evaluated, 42 (71.2%) had dental disease: 19 (44.2%) males, 20 (46.5%) females, and 3 (9.3%) without gender documented. Average age at onset of dental disease was 7.6 yr in males and 9 yr in females. Multiple lorises with dental disease (n = 12; 28.6%) had no premonitory clinical signs, and dental disease was found incidentally on examination. On dental examination, 30 lorises (71.4%) had evidence of gingivitis. In 13 cases skull radiographs were taken, but the majority of images (n = 8; 61.5%) were nondiagnostic for pathologic dental changes. A small proportion of cases with dental abnormalities (n = 4; 9.5%) were diagnosed using computed tomography. In total, 175 teeth were extracted from 31 patients; molars were the most frequently extracted tooth (n = 55; 31.4%). No substantial differences in diets were noted among many of the participating institutions, and not all slow lorises evaluated developed dental disease (n = 17; 28.8%). This retrospective study provides clinical findings on slow loris dental disease and guidance for the veterinary care and management of slow lorises under human care.

What Are the Differences in Hospital Cost Associated With the Use of Cemented Versus Cementless Femoral Stems in Hemiarthroplasty and Total Hip Arthroplasty for the Treatment of Femoral Neck Fracture?

BACKGROUND: The purpose of this study was to determine if there is a difference in hospital costs associated with the use of cemented versus cementless femoral stems in hemiarthroplasty (HA) and total hip arthroplasty (THA) for the treatment of femoral neck fracture (FNF). METHODS: This retrospective cohort study utilizes the 2019 Medicare Provider Analysis and Review Limited Data Set. Patients undergoing arthroplasty for the treatment of FNF were identified. Patients were grouped by cemented or cementless femoral stem fixation. There were 16,148 patients who underwent arthroplasty for FNF available: 4,913 THAs (3,705 patients who had cementless femoral stems and 1,208 patients who had cemented femoral stems) and 11,235 HAs (6,099 patients who had cementless femoral stems and 5,136 who had cemented femoral stems). Index hospital costs were estimated by multiplying total charges by cost-to-charge ratios. Costs were analyzed using univariable and multivariable generalized linear models. RESULTS: Cemented femoral stem THA generated 1.080 times (95% confidence interval, 1.06 to 1.10; P < .001), or 8.0%, greater index hospital costs than cementless femoral stem THA, and cemented femoral stem HA generated 1.042 times (95% confidence interval, 1.03 to 1.05; P < .001), or 4.2%, greater index hospital costs than cementless femoral stem HA. CONCLUSIONS: Cemented femoral stems for FNF treated with either THA or HA are associated with only a small portion of increased cost compared to cementless femoral stems. Providers may choose the method of arthroplasty stem fixation for the treatment of FNF based on what they deem most appropriate for the specific patient.

Low-Cost, Compact Quadrupole Mass Filters with Unity Mass Resolution via Ceramic Resin Vat Photopolymerization.

This study reports novel, compact, and additively manufactured quadrupole mass filters (QMFs) with adequate filtering performance for practical mass spectrometry applications. The QMFs are monolithically fabricated via vat photopolymerization of glass-ceramic resin using 57 µm × 57 µm × 100 µm voxels, and selective electroless plating of nickel-boron. Experimental characterization of QMF prototypes at 1.74 MHz using FC-43 yields 131 Da peaks with 0.50 Da full width at half maximum (260 resolution), surpassing the resolution of reported miniaturized counterparts under similar conditions, and being on par with commercial, non-miniaturized, heavier devices. The sensitivity of the 3D-printed devices is estimated at 0.13 mA Torr-1 (comparable to that of optimized, commercial counterparts), while the devices attained up to 250 Da of mass range (limited by the driving electronics). The work is of interest to low-cost, capable mass spectrometry, 3D-printed instruments, and in-space manufacturing of complex instrumentation.

Elective THA for Indications Other Than Osteoarthritis Is Associated With Increased Cost and Resource Use: A Medicare Database Study of 135,194 Claims.

BACKGROUND: Under Medicare's fee-for-service and bundled payment models, the basic unit of hospital payment for inpatient hospitalizations is determined by the Medicare Severity Diagnosis Related Group (MS-DRG) coding system. Primary total joint arthroplasties (hip and knee) are coded under MS-DRG code 469 for hospitalizations with a major complication or comorbidity and MS-DRG code 470 for those without a major complication or comorbidity. However, these codes do not account for the indication for surgery, which may influence the cost of care.Questions/purposes We sought to (1) quantify the differences in hospital costs associated with six of the most common diagnostic indications for THA (osteoarthritis, rheumatoid arthritis, avascular necrosis, hip dysplasia, posttraumatic arthritis, and conversion arthroplasty), (2) assess the primary drivers of cost variation using comparisons of hospital charge data for the diagnostic indications of interest, and (3) analyze the median length of stay, discharge destination, and intensive care unit use associated with these indications. METHODS: This study used the 2019 Medicare Provider Analysis and Review Limited Data Set. Patients undergoing primary elective THA were identified using MS-DRG codes and International Classification of Diseases, Tenth Revision, Procedure Coding System codes. Exclusion criteria included non-fee-for-service hospitalizations, nonelective procedures, patients with missing data, and THAs performed for indications other than the six indications of interest. A total of 713,535 primary THAs and TKAs were identified in the dataset. After exclusions were applied, a total of 135,194 elective THAs were available for analysis. Hospital costs were estimated using cost-to-charge ratios calculated by the Centers for Medicare and Medicaid Services. The primary benefit of using cost-to-charge ratios was that it allowed us to analyze a large national dataset and to mitigate the random cost variation resulting from unique hospitals' practices and patient populations. As an investigation into matters of health policy, we believe that assessing the surgical cost borne by the "average" hospital was most appropriate. To analyze estimated hospital costs, we performed a multivariable generalized linear model controlling for patient demographics (gender, age, and race), preoperative health status, and hospital characteristics (hospital setting [urban versus rural], geography, size, resident-to-bed ratio, and wage index). We assessed the principal drivers of cost variation by analyzing the median hospital charges arising from 30 different hospital revenue centers using descriptive statistics. Length of stay, intensive care use, and discharge to a nonhome location were analyzed using multivariable binomial logistic regression. RESULTS: The cost of THA for avascular necrosis was 1.050 times (95% confidence interval 1.042 to 1.069; p < 0.001), or 5% greater than, the cost of THA for osteoarthritis; the cost of hip dysplasia was 1.132 times (95% CI 1.113 to 1.152; p < 0.001), or 13% greater; the cost of posttraumatic arthritis was 1.220 times (95% CI 1.193 to 1.246; p < 0.001), or 22% greater; and the cost of conversion arthroplasty was 1.403 times (95% CI 1.386 to 1.419; p < 0.001), or 40% greater. Importantly, none of these CIs overlap, indicating a discernable hierarchy of cost associated with these diagnostic indications for surgery. Rheumatoid arthritis was not associated with an increase in cost. Medical or surgical supplies and operating room charges represented the greatest increase in charges for each of the surgical indications examined, suggesting that increased use of medical and surgical supplies and operating room resources were the primary drivers of increased cost. All of the orthopaedic conditions we investigated demonstrated increased odds that a patient would experience a prolonged length of stay and be discharged to a nonhome location compared with patients undergoing THA for osteoarthritis. Avascular necrosis, posttraumatic arthritis, and conversion arthroplasty were also associated with increased intensive care unit use. Posttraumatic arthritis and conversion arthroplasty demonstrated the largest increase in resource use among all the orthopaedic conditions analyzed. CONCLUSION: Compared with THA for osteoarthritis, THA for avascular necrosis, hip dysplasia, posttraumatic arthritis, and conversion arthroplasty is independently associated with stepwise increases in resource use. These cost increases are predominantly driven by greater requirements for medical and surgical supplies and operating room resources. Posttraumatic arthritis and conversion arthroplasty demonstrated substantially increased costs, which can result in financial losses in the setting of fixed prospective payments. These findings underscore the inability of MS-DRG coding to adequately reflect the wide range of surgical complexity and resource use of primary THAs. Hospitals performing a high volume of THAs for indications other than osteoarthritis should budget for an anticipated increase in costs, and orthopaedic surgeons should advocate for improved MS-DRG coding to appropriately reimburse hospitals for the financial and clinical risk of these surgeries. LEVEL OF EVIDENCE: Level IV, economic and decision analysis.

UNSEG: unsupervised segmentation of cells and their nuclei in complex tissue samples.

Multiplexed imaging technologies have made it possible to interrogate complex tumor microenvironments at sub-cellular resolution within their native spatial context. However, proper quantification of this complexity requires the ability to easily and accurately segment cells into their sub-cellular compartments. Within the supervised learning paradigm, deep learning based segmentation methods demonstrating human level performance have emerged. Here we present an unsupervised segmentation (UNSEG) method that achieves deep learning level performance without requiring any training data. UNSEG leverages a Bayesian-like framework and the specificity of nucleus and cell membrane markers to construct an a posteriori probability estimate of each pixel belonging to the nucleus, cell membrane, or background. It uses this estimate to segment each cell into its nuclear and cell-membrane compartments. We show that UNSEG is more internally consistent and better at generalizing to the complexity of tissue samples than current deep learning methods. This allows UNSEG to unambiguously identify the cytoplasmic compartment of a cell, which we employ to demonstrate its use in an example biological scenario. Within the UNSEG framework, we also introduce a new perturbed watershed algorithm capable of stably and accurately segmenting a cell nuclei cluster into individual cell nuclei. Perturbed watershed can also be used as a standalone algorithm that researchers can incorporate within their supervised or unsupervised learning approaches to replace classical watershed. Finally, as part of developing UNSEG, we have generated a high-quality annotated gastrointestinal tissue dataset, which we anticipate will be useful for the broader research community. Segmentation, despite its long antecedents, remains a challenging problem, particularly in the context of tissue samples. UNSEG, an easy-to-use algorithm, provides an unsupervised approach to overcome this bottleneck, and as we discuss, can help improve deep learning based segmentation methods by providing a bridge between unsupervised and supervised learning paradigms.