Malpractice Trends Involving Active Surveillance Across Cancers.

OBJECTIVE: To characterize malpractice trends related to active surveillance (AS) as a treatment strategy across cancers. BACKGROUND: Active surveillance is increasingly considered a viable management strategy for low-risk cancers. Since a subset of AS cases will progress, metastasize, or exhibit cancer-related mortality, a significant barrier to implementation is the perceived risk of litigation from missing the window for cure. Data on malpractice trends across cancers are lacking. METHODS: Westlaw Edge and LexisNexis Advance databases were searched from 1990 to 2022 for malpractice cases involving active surveillance in conjunction with thyroid cancer, prostate cancer, kidney cancer, breast cancer, or lymphoma. Queries included unpublished cases, trial orders, jury verdicts, and administrative decisions. Data were compiled on legal allegations, procedures performed, and verdicts or settlements rendered. RESULTS: Five prostate cancer cases were identified that pertained to active surveillance. Two cases involved alleged deliberate indifference from AS as a management strategy but were ruled as following the appropriate standard of care. In contrast, 3 cases involved alleged physician negligence for not explicitly recommending AS as a treatment option after complications from surgery occurred. All cases showed documented informed consent for AS, leading to defense verdicts in favor of the physicians. No cases of AS-related malpractice were identified for other cancer types. CONCLUSIONS: To date, no evidence of successful malpractice litigation for active surveillance in cancer has been identified. Given the legal precedent detailed in the identified cases and increasing support across national guidelines, active surveillance represents a sound management option in appropriate low-risk cancers, with no increased risk of medicolegal exposure.

Allele-Specific Reprogramming of Cancer Metabolism by the Long Non-coding RNA CCAT2.

Altered energy metabolism is a cancer hallmark as malignant cells tailor their metabolic pathways to meet their energy requirements. Glucose and glutamine are the major nutrients that fuel cellular metabolism, and the pathways utilizing these nutrients are often altered in cancer. Here, we show that the long ncRNA CCAT2, located at the 8q24 amplicon on cancer risk-associated rs6983267 SNP, regulates cancer metabolism in vitro and in vivo in an allele-specific manner by binding the Cleavage Factor I (CFIm) complex with distinct affinities for the two subunits (CFIm25 and CFIm68). The CCAT2 interaction with the CFIm complex fine-tunes the alternative splicing of Glutaminase (GLS) by selecting the poly(A) site in intron 14 of the precursor mRNA. These findings uncover a complex, allele-specific regulatory mechanism of cancer metabolism orchestrated by the two alleles of a long ncRNA.

Prospective study of quantitative liver MRI in cystic fibrosis: feasibility and comparison to PUSH cohort ultrasound.

BACKGROUND: Pediatric radiologists can identify a liver ultrasound (US) pattern predictive of progression to advanced liver disease. However, reliably discriminating these US patterns remains difficult. Quantitative magnetic resonance imaging (MRI) may provide an objective measure of liver disease in cystic fibrosis (CF). OBJECTIVE: The purpose of this study was to determine if quantitative MRI, including MR elastography, is feasible in children with CF and to determine how quantitative MRI-derived metrics compared to a research US. MATERIALS AND METHODS: A prospective, multi-institutional trial was performed evaluating CF participants who underwent a standardized MRI. At central review, liver stiffness, fat fraction, liver volume, and spleen volume were obtained. Participants whose MRI was performed within 1 year of US were classified by US pattern as normal, homogeneous hyperechoic, heterogeneous, or nodular. Each MRI measure was compared among US grade groups using the Kruskal-Wallis test. RESULTS: Ninety-three participants (51 females [54.8%]; mean 15.6 years [range 8.1-21.7 years]) underwent MRI. MR elastography was feasible in 87 participants (93.5%). Fifty-eight participants had an US within 1 year of MRI. In these participants, a nodular liver had significantly higher stiffness (P<0.01) than normal or homogeneous hyperechoic livers. Participants with a homogeneous hyperechoic liver had a higher fat fraction (P<0.005) than others. CONCLUSION: MR elastography is feasible in children with CF. Participants with a nodular pattern had higher liver stiffness supporting the US determination of advanced liver disease. Participants with a homogeneous hyperechoic pattern had higher fat fractions supporting the diagnosis of steatosis.

Expansion of the composition library for chemodiversity of hardwood extractives at molecular level by ultrahigh-resolution mass spectrometry.

To enhance the characterization of wood extractives at molecular level, a detailed ultrahigh-resolution mass spectrometry (UHRMS)-based analytical methodology was developed in this work. The analytical strategies, including selection of compatible solvent for extraction, evaluation of ionization solvent for effective electrospray ionization, and multi-dimensional data analysis, were established to ensure a comprehensive characterization of complex compositions in wood extractives. Extraction capability of seven solvents with varied polarities was examined by a standard reference material of hardwood biomass and evaluated based on thousands of compounds which were much more than those discovered before. With a variety of data-processing approaches, including compound type distribution, double bond equivalent versus carbon number plot, and van Krevelen diagram, the chemodiversity of the extractives was fully explored from different perspectives. This work greatly expanded the compound library of wood extractives and could also provide guidance for the integrated composition analysis of other biomass materials.

Comprehensive Composition, Structure, and Size Characterization for Thiophene Compounds in Petroleum Using Ultrahigh-Resolution Mass Spectrometry and Trapped Ion Mobility Spectrometry.

Thiophene compounds are the main concern of petroleum desulfurization, and their chemical composition and molecular configuration have critical impacts on thermodynamic and kinetic processes. In this work, atmospheric pressure chemical ionization (APCI) was employed for effective ionization of thiophene compounds in petroleum with complex matrix, in which carbon disulfide was used for generating predominant [M]+• ions without the need of derivatization as for electrospray ionization. APCI coupled with ultrahigh-resolution mass spectrometry (UHRMS) was successfully applied to the composition characterization of thiophene compounds in both a low boiling petroleum fraction and a whole crude oil. APCI coupled with trapped ion mobility spectrometry (TIMS) was developed to determine the shape and size of thiophene compounds, providing configuration information that affects the steric hindrance and diffusion behavior of reactants in the desulfurization reaction, which has not been previously reported. Moreover, the comprehensive experimental structural data, expressed as the collision cross section (CCS) of the ions as surrogates of molecules, provided clues to the factors affecting the desulfurization reactivity of thiophene compounds. Further exploration showed that not only qualitative analysis of thiophene compounds can be achieved from the correlation between m/z and CCS, but also molecular size was found to be correlated with CCS that can be used as structural analysis. Overall, the molecular composition and dimension analysis together can provide substantial information for the desulfurization activity of thiophene compounds, facilitating the desulfurization process studies and catalyst design.

Mental health literacy in primary care: Canadian Research and Education for the Advancement of Child Health (CanREACH).

The effectiveness of a continuing education programme in paediatric psychopharmacology designed for primary healthcare providers was objectively measured based on the assumption that training would lead to measurable changes in referral patterns and established clinical measures of referred patients. Using established, valid and reliable measures of clinical urgency embedded in to a regional healthcare system since 2002, the referrals to child and adolescent psychiatric services of physicians who participated in the training (n=99) were compared pretraining and post-training, and to non-participating/untrained referring physicians (n=7753) making referrals over the same time period. Referrals were analysed for evidence of change based on frequencies and measures of clinical urgency. Participants of the training programme also completed standardised baseline and outcome self-evaluations. Congruent with participants self-reported evaluative reports of improved knowledge and practice, analysis of referral frequency and the clinical urgency of referrals to paediatric psychiatric services over the study period indicated that trained physicians made more appropriate referrals (clinically more severe) and reduced referrals to emergency services. Quantitative clinical differences as completed by intake clinicians blind to referrals from the study group designations were observed within the trained physician group pretraining and post-training, and between the trained physician group and the unexposed physician group. The results illustrate a novel model for objectively measuring change among physicians based on training in paediatric mental health management.

Changes in Total Lesion Glycolysis Evaluated by Repeated F-18 FDG PET/CT as Prognostic Factor in Locally Advanced Esophageal Cancer Patients Treated with Preoperative Chemoradiotherapy.

AIMS: The present study was aimed to investigate whether volumetric parameters measured by sequential F-18 fluoro-D-glucose (F-18 FDG) positron emission tomography/computed tomography (PET/CT) could be used as prognostic factors in patients with locally advanced esophageal cancer (LAEC) who received preoperative chemoradiotherapy (CRT). METHODS: A total of 61 patients with LAEC were included in the current study. All patients were evaluated by F-18 FDG PET/CT before and after 46 Gy of radiotherapy with a concurrent cisplatin-based chemotherapy. Initial, second, and percent changes (Δ, %) of semiquantitative and volumetric parameters were used to calculate recurrence-free survival (RFS) and overall survival (OS). The median values of each parameter were used as cutoff values. The prognostic significance was assessed using univariate and multivariate Cox proportional hazard regression analyses. RESULTS: Cox proportional hazard regression analyses revealed that change in total lesion glycolysis (ΔTLG) was a potent predictor of RFS and OS. Kaplan-Meier survival curves showed better prognosis in higher ΔTLG. CONCLUSION: Our data suggest that ΔTLG measured by sequential F-18 FDG PET/CT after preoperative CRT could provide prognostic information in LAEC patients.

The efficacy of (177)Lu-labelled peptide receptor radionuclide therapy in patients with neuroendocrine tumours: a meta-analysis.

PURPOSE: This study was performed to evaluate the efficacy of (177)Lu-labelled peptide receptor radionuclide therapy (PRRT) in patients with inoperable or metastatic neuroendocrine tumours (NETs). METHODS: Systematic searches of MEDLINE and EMBASE databases were performed using the keywords of "neuroendocrine", "(177)Lu" and "prognosis". All published studies of neuroendocrine tumours treated with (177)Lu-labelled radiopharmaceuticals and evaluated with either Response Evaluation Criteria in Solid Tumours (RECIST) 1.0 or Southwest Oncology Group (SWOG) criteria or both were included. If there was more than one published study from the same institution, only one report with the information most relevant to this study was included. Each response criteria group was analysed for disease response rates and disease control rates, defined as the percentages of patients with complete response (CR) + partial response (PR), and CR + PR + stable disease (SD), respectively, to a therapeutic intervention in clinical trials of anticancer agents. The pooled proportions are presented with both a fixed-effects model and random-effects model. RESULTS: Six studies with 473 patients (4 in RECIST criteria group with 356 patients, 3 in SWOG criteria group with 375 patients and 1 in both groups) were included. The RECIST criteria group demonstrated disease response rates ranging between 17.6 and 43.8% with a pooled effect of 29% [95% confidence interval (CI) 24-34%]. Disease control rates ranged from 71.8 to 100%. The random-effects model showed an average disease control rate of 81% (95% CI 71-91%). The SWOG criteria group demonstrated disease response rates ranging between 7.0 and 36.5% with a pooled effect of 23% (95% CI 11-38%). Disease control rates ranged from 73.9 to 89.1%. The random-effects model showed an average disease control rate of 82% (95% CI 71-91%). CONCLUSION: (177)Lu-labelled PRRT is an effective treatment option for patients with inoperable or metastatic NETs.

VesiX cetylpyridinium chloride is rapidly bactericidal and reduces uropathogenic Escherichia coli bladder epithelial cell invasion in vitro.

Management of urinary tract infection (UTI) in postmenopausal women can be challenging. The recent rise in resistance to most of the available oral antibiotic options together with high recurrence rate in postmenopausal women has further complicated treatment of UTI. As such, intravesical instillations of antibiotics like gentamicin are being investigated as an alternative to oral antibiotic therapies. This study evaluates the efficacy of the candidate intravesical therapeutic VesiX, a solution containing the cationic detergent Cetylpyridinium chloride, against a broad range of uropathogenic bacterial species clinically isolated from postmenopausal women with recurrent UTI (rUTI). We also evaluate the cytotoxicity of VesiX against cultured bladder epithelial cells and find that low concentrations of 0.0063% and 0.0125% provide significant bactericidal effect toward diverse bacterial species including uropathogenic Escherichia coli (UPEC), Klebsiella pneumoniae, Enterococcus faecalis, Pseudomonas aeruginosa, and Proteus mirabilis while minimizing cytotoxic effects against cultured 5637 bladder epithelial cells. Lastly, to begin to evaluate the potential utility of using VesiX in combination therapy with existing intravesical therapies for rUTI, we investigate the combined effects of VesiX and the intravesical antibiotic gentamicin. We find that VesiX and gentamicin are not antagonistic and are able to reduce levels of intracellular UPEC in cultured bladder epithelial cells. IMPORTANCE: When urinary tract infections (UTIs), which affect over 50% of women, become resistant to available antibiotic therapies dangerous complications like kidney infection and lethal sepsis can occur. New therapeutic paradigms are needed to expand our arsenal against these difficult to manage infections. Our study investigates VesiX, a Cetylpyridinium chloride (CPC)-based therapeutic, as a candidate broad-spectrum antimicrobial agent for use in bladder instillation therapy for antibiotic-resistant UTI. CPC is a cationic surfactant that is FDA-approved for use in mouthwashes and is used as a food additive but has not been extensively evaluated as a UTI therapeutic. Our study is the first to investigate its rapid bactericidal kinetics against diverse uropathogenic bacterial species isolated from postmenopausal women with recurrent UTI and host cytotoxicity. We also report that together with the FDA-approved bladder-instillation agent gentamicin, VesiX was able to significantly reduce intracellular populations of uropathogenic bacteria in cultured bladder epithelial cells.

Downstaging disease in patients with hepatocellular carcinoma outside of Milan criteria: strategies using drug-eluting bead chemoembolization.

PURPOSE: To assess downstaging rates in patients with United Network for Organ Sharing stage T3N0M0 hepatocellular carcinoma (HCC) treated with doxorubicin-eluting bead transarterial chemoembolization to meet Milan criteria for transplantation. MATERIALS AND METHODS: A single-center retrospective review of 239 patients treated with doxorubicin-eluting bead (DEB) chemoembolization between September 2008 and December 2011 was undertaken. Baseline and follow-up computed tomography or magnetic resonance imaging was assessed for response based on the longest enhancing axial dimension of each tumor (ie, modified Response Evaluation Criteria In Solid Tumors measurements), and medical records were reviewed. Fisher exact tests and exact logistic regression were used to test the association of patient and disease characteristics with downstaging. RESULTS: After exclusions, 22 patients remained in the analysis, 17 of whom (77%) had their HCC downstaged to meet Milan criteria. Among those whose disease was downstaged, seven underwent transplantation, one remained listed for transplantation, six had disease progression beyond Milan criteria, two underwent conventional transarterial chemoembolization, and one underwent radiofrequency ablation. The seven patients who received transplants were still living, but recurrent HCC developed in two. Baseline age (P = .25), Model for End-stage Liver Disease score (P = .77), and α-fetoprotein (AFP) level (P = 1.00) were similar between patients with and without downstaged HCC. No associations were observed between the odds of downstaging and sex (P = .21), Child-Pugh class (P = .14), Child-Pugh class controlling for baseline tumor multiplicity (P = .15), Eastern Cooperative Oncology Group performance status (P = 1.00), tumor burden (P = .31), multiple tumors (P = .31), or hepatitis C virus infection (P = 1.00). Fifteen patients who did not receive transplants were alive at 1 year, with two progression-free. Baseline AFP levels differed between those who survived 1 year and those who did not (P = .02), but did not differ by progression-free survival status (P = .62). CONCLUSIONS: T3N0M0 HCC treatment with DEB chemoembolization has a high likelihood (77%) of downstaging the disease to meet Milan criteria.

Observation of CO2 and solvent adduct ions during negative mode electrospray ionization Fourier transform ion cyclotron resonance mass spectrometric analysis of monohydric alcohols.

RATIONALE: Monohydric alcohols are common in natural products, bio-oils, and medicine. We have found that monohydric alcohols can form O3 (ions containing three oxygen atoms) and O4 adduct ions in negative electrospray ionization (ESI) Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS), which would significantly affect the composition analysis of alcohols, especially in a complex mixture. It is necessary to study the reaction pathways and the method to eliminate or reduce the 'artifact' adducts. METHODS: Octadecanol, cholesterol, squalanol and two complex monohydric alcohol mixtures were selected as model compounds. These samples were subjected to negative ion ESI FT-ICR MS analysis. The composition and formation mechanism of adducts were studied by the ultrahigh-resolution accurate mass measurement for elemental composition, along with the MS(2) isolation and collision-induced dissociation (CID) experiments for structural determination. RESULTS: The reaction pathway of O3 adduct formation is the coupling of a monohydric alcohol ion with a CO2 to form a stable O3 ionic species by likely a covalent bond (source of CO2 is not clear). The O4 species are formed by O3 ionic species adducted with an alcohol molecule of the solvent, such as methanol or ethanol, by likely a hydrogen bond. These adduct ions could be eliminated or reduced by increasing collision energy. However, excessive collision energy would fragment monohydric alcohol ions. CONCLUSIONS: The formation mechanisms of O3 and O4 adducts from monohydric alcohols in negative ion ESI FT-ICR MS were proposed. The solvent adduction effects can be eliminated or reduced by optimizing the collision energy of CID in FT-ICR MS.

Valgus femoral osteotomy for noncontainable Perthes hips: prognostic factors of remodeling.

BACKGROUND: The authors have performed valgus femoral osteotomy (VFO) with rotational and sagittal components for Legg-Calvé-Perthes disease hips with hinge abduction. We analyzed skeletally mature patients to determine: (1) whether VFO improved hip function; (2) whether favorable radiographic remodeling of the hip occurred; and (3) whether any clinical or radiographic factors were associated with remodeling of femoral head deformity. METHODS: Thirty-one patients (31 hips, 25 boys and 6 girls) who underwent VFO between 1986 and 2007, and subsequently followed until skeletal maturity constituted the study cohort. The mean age at surgery was 9.4 years (range, 3.5 to 15 y) and the mean age at the most recent follow-up was 20.2 years (range, 14.6 to 28.3 y). Clinical outcomes were evaluated using Iowa Hip Scores and ranges of hip motion. Radiographic outcomes were assessed with respect to the radiographic indices for femoral head deformity and subluxation. Clinical and radiographic parameters were analyzed to find correlations with the femoral head remodeling (preoperative to final follow-up changes in deformity index). RESULTS: Iowa Hip Score improved from 71 (30 to 91) to 92 (76 to 100). Ranges of hip abduction, internal rotation, and external rotation increased. At last follow-up evaluations, mean Mose sphericity index of the femoral head was 4.2 mm (range, 0 to 13 mm) and femoral heads had 4 Stulberg type II, 21 type III, and 6 type IV deformity. Overall radiographic indices for femoral head deformity and subluxation did not change during follow-up period except decreased medial joint space, but greater amount of preoperative to final follow-up changes in deformity index was associated with younger age (<10 y) and earlier disease stages (fragmentation and early reossification stage) at time of surgery. CONCLUSIONS: VFO modified to accommodate the various hinging patterns of Legg-Calvé-Perthes disease hips was found to beneficially improve hip function at skeletal maturity. Although overall radiographic remodeling was not definite, favorable remodeling of the femoral head can be expected when younger patients undergo this procedure at the fragmentation or early reossification stage.

ChatGPT failed Taiwan's Family Medicine Board Exam.

BACKGROUND: Chat Generative Pre-trained Transformer (ChatGPT), OpenAI Limited Partnership, San Francisco, CA, USA is an artificial intelligence language model gaining popularity because of its large database and ability to interpret and respond to various queries. Although it has been tested by researchers in different fields, its performance varies depending on the domain. We aimed to further test its ability in the medical field. METHODS: We used questions from Taiwan's 2022 Family Medicine Board Exam, which combined both Chinese and English and covered various question types, including reverse questions and multiple-choice questions, and mainly focused on general medical knowledge. We pasted each question into ChatGPT and recorded its response, comparing it to the correct answer provided by the exam board. We used SAS 9.4 (Cary, North Carolina, USA) and Excel to calculate the accuracy rates for each question type. RESULTS: ChatGPT answered 52 questions out of 125 correctly, with an accuracy rate of 41.6%. The questions' length did not affect the accuracy rates. These were 45.5%, 33.3%, 58.3%, 50.0%, and 43.5% for negative-phrase questions, multiple-choice questions, mutually exclusive options, case scenario questions, and Taiwan's local policy-related questions, with no statistical difference observed. CONCLUSION: ChatGPT's accuracy rate was not good enough for Taiwan's Family Medicine Board Exam. Possible reasons include the difficulty level of the specialist exam and the relatively weak database of traditional Chinese language resources. However, ChatGPT performed acceptably in negative-phrase questions, mutually exclusive questions, and case scenario questions, and it can be a helpful tool for learning and exam preparation. Future research can explore ways to improve ChatGPT's accuracy rate for specialized exams and other domains.

Knowledge, attitudes, and perceptions of hidradenitis suppurativa among young adults in Singapore.

Background: The prevalence of hidradenitis suppurativa (HS) is 0.00033% to 4.10% globally. Few epidemiological studies derive from Asia, with social stigmatization postulated to result in under-diagnosis. Objective: This study aimed to assess the self-reported prevalence of HS, and the knowledge, attitudes, and perceptions towards HS among Singaporean young-adults. Methods: A cross-sectional study (n = 158) was conducted by anonymous online questionnaire. The association between demographic factors and risk of potentially undiagnosed HS was evaluated using multivariable logistic regression. Differences between attitude-perception scores by demographic factors and knowledge of HS were tested using two-sample t-tests. Results: The prevalence of diagnosed and potentially undiagnosed HS was 0.63% and 8.9%, respectively. Non-Chinese had significantly higher social attitude-perception scores than Chinese (P = .029). Females had significantly higher social (P = .048) as well as economic and work (P = .037) attitude-perception scores than males. Those with knowledge of HS had significantly higher attitude-perception scores for interpersonal (P = .031) and social (P = .0052) subsections. Limitations: Small sample size, low frequency of HS cases, and self-reported prevalence may not generalize to the broader population in Singapore. Conclusion: Our results suggest a potential underdiagnosis of HS. Non-Chinese stigmatize HS less than Chinese, and females less than males. Individuals with knowledge of HS might be more open to interpersonal and social interactions with HS sufferers.

Sustained Increases in Cardiomyocyte Protein O-Linked ß-N-Acetylglucosamine Levels Lead to Cardiac Hypertrophy and Reduced Mitochondrial Function Without Systolic Contractile Impairment.

Background Lifestyle and metabolic diseases influence the severity and pathogenesis of cardiovascular disease through numerous mechanisms, including regulation via posttranslational modifications. A specific posttranslational modification, the addition of O-linked ß-N acetylglucosamine (O-GlcNAcylation), has been implicated in molecular mechanisms of both physiological and pathologic adaptations. The current study aimed to test the hypothesis that in cardiomyocytes, sustained protein O-GlcNAcylation contributes to cardiac adaptations, and its progression to pathophysiology. Methods and Results Using a naturally occurring dominant-negative O-GlcNAcase (dnOGA) inducible cardiomyocyte-specific overexpression transgenic mouse model, we induced dnOGA in 8- to 10-week-old mouse hearts. We examined the effects of 2-week and 24-week dnOGA overexpression, which progressed to a 1.8-fold increase in protein O-GlcNAcylation. Two-week increases in protein O-GlcNAc levels did not alter heart weight or function; however, 24-week increases in protein O-GlcNAcylation led to cardiac hypertrophy, mitochondrial dysfunction, fibrosis, and diastolic dysfunction. Interestingly, systolic function was maintained in 24-week dnOGA overexpression, despite several changes in gene expression associated with cardiovascular disease. Specifically, mRNA-sequencing analysis revealed several gene signatures, including reduction of mitochondrial oxidative phosphorylation, fatty acid, and glucose metabolism pathways, and antioxidant response pathways after 24-week dnOGA overexpression. Conclusions This study indicates that moderate increases in cardiomyocyte protein O-GlcNAcylation leads to a differential response with an initial reduction of metabolic pathways (2-week), which leads to cardiac remodeling (24-week). Moreover, the mouse model showed evidence of diastolic dysfunction consistent with a heart failure with preserved ejection fraction. These findings provide insight into the adaptive versus maladaptive responses to increased O-GlcNAcylation in heart.

Compositional space boundaries for organic compounds.

An upper elemental compositional boundary for fossil hydrocarbons has previously been established as double-bond equivalents (i.e., DBE = rings plus double bonds) not exceeding 90% of the number of carbons. For heteroatom-containing fossil compounds, the 90% rule still applies if each N atom is counted as a C atom. The 90% rule eliminates more than 10% of the possible elemental compositions at a given mass for fossil database molecules. However, some synthetic compounds can fall outside the upper boundary defined for naturally occurring compounds. Their inclusion defines an "absolute" upper boundary as DBE (rings plus double bonds to carbon) equal to carbon number plus one, and applies to all organic compounds including fullerenes and other molecules containing no hydrogen. Finally, the DBE definition can fail for molecules with particular atomic valences. Therefore, we also present a generalized DBE definition that includes atomic valence to enable calculation of the correct total number of rings, double bonds, and triple bonds for heteroatom-containing compounds.