The impact of mammography screening programmes on incidence of advanced breast cancer in Europe: a literature review.

BACKGROUND: Observational studies have reported conflicting results on the impact of mammography service screening programmes on the advanced breast cancer rate (ABCR), a correlation that was firmly established in randomized controlled trials. We reviewed and summarized studies of the effect of service screening programmes in the European Union on ABCR and discussed their limitations. METHODS: The PubMed database was searched for English language studies published between 01-01-2000 and 01-06-2018. After inspection of titles and abstracts, 220 of the 8644 potentially eligible papers were considered relevant. Their abstracts were reviewed by groups of two authors using predefined criteria. Fifty studies were selected for full paper review, and 22 of these were eligible. A theoretical framework for their review was developed. Review was performed using a ten-point checklist of the methodological caveats in the analysis of studies of ABCR and a standardised assessment form designed to extract quantitative and qualitative information. RESULTS: Most of the evaluable studies support a reduction in ABCR following the introduction of screening. However, all studies were challenged by issues of design and analysis which could at least potentially cause bias, and showed considerable variation in the estimated effect. Problems were observed in duration of follow-up time, availability of reliable reference ABCR, definition of advanced stage, temporal variation in the proportion of unknown-stage cancers, and statistical approach. CONCLUSIONS: We conclude that much of the current controversy on the impact of service screening programmes on ABCR is due to observational data that were gathered and/or analysed with methodological approaches which could not capture stage effects in full. Future research on this important early indicator of screening effectiveness should focus on establishing consensus in the correct methodology.

Association of exposure to benzene and smoking with oxidative damage to nucleic acids by means of biological monitoring of general population volunteers.

In this study, the validation of liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) isotopic dilution method for the determination of benzene and nicotine metabolites in urine was carried out. Limit of detection are 0.026 µg/L for S-phenylmercapturic acid (SPMA), 0.55 µg/L for t,t-muconic acid (t,t-MA), and 12.41 µg/L for the cotinine, and the relative combined uncertainty was also calculated. The study involves 446 healthy volunteer residents since at least 10 years in an area of central Italy. SPMA resulted to be strongly correlated with cotinine (p = 0.75), its concentration in smokers (93) being about ten times than in non/ex-smokers (197/156), while the t,t-MA of smokers is about twice the non/ex-smokers value. A cutoff value for the definition of smoker is set at 100 µg/g creat. Oxidative stress was studied in smokers and non- and ex-smokers by means of the determination of the biomarkers 8-Oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo), 8-Oxo-7,8-dihydroguanosine (8-oxoGuo), and 8-Oxo-7,8-dihydroguanine (8-oxoGua): no significant differences were found between smokers and non/ex-smokers, but when subjects are classified according to the cotinine cutoff value, a correlation in smokers' urinary 8-oxodGuo is found with SPMA and cotinine (p = 0.60 and p = 0.57). Results were confirmed by chemometric analysis that also identified the experimental variables most contributing the discrimination as cotinine and t,t-MA.

Effectiveness of HPV vaccination in women reaching screening age in Italy.

BACKGROUND AND OBJECTIVES: A randomized trial was conducted in Tuscany, Italy, to evaluate the effectiveness of HPV vaccination for 25year old (yo) women who attend at the first time cervical cancer screening. The trial also evaluated immune response after vaccination, reductions of cytological abnormalities and the impact of vaccination on screening activity. STUDY DESIGN: During 2010-2011, all 25 yo women who were invited to the Florence cervical cancer screening programme were also asked to participate in the trial. Enrolled women were randomized into study and control groups. Those in the study group were offered HPV vaccination after the usual Pap test. The cytology distribution and prevalence for any high risk (hr) HPV type were compared at the subsequent screening round in an intention-to-treat analysis. The impact of HPV vaccination was evaluated per protocol comparing vaccinated women with the control group. RESULTS: Our results showed a reduction in HPV prevalence at recall for any hr-HPV type but it was not statistically significant, being 17.1% vs 21.4%, p=0.20 in the study and control groups, respectively. If we restricted the analysis to vaccinated women, strong reductions of the HPV 16,18,31,33,45 and HPV 31,33,45 infections were observed, being 5.3% vs 12.8%, p<0.01 and 2.1% vs 6.5%, p=0.02, respectively. Significant reductions for any hr-HPV infection and for HPV 16 infection were also observed in women HPV 16/18 negative at enrolment, being 12% vs 21.4%, p<0.01 and 0.6% vs 6.7%, p-value<0.01, respectively. In women hr-HPV negative at enrolment no infections due to HPV 16 or HPV 18 were observed and there was a big reduction for any hr-HPV infection (7.1% vs 21.4% p<0.01). A strong antibody response was observed not only for HPV 16 & 18 but also for their related types. CONCLUSIONS: Our findings suggest that HPV vaccination at the age 25 is beneficial if it is offered to hr-HPV negative women. Our data will assist in developing a cost effectiveness model for choosing the best strategy to integrate screening and vaccination for the coming years. Clinical trial registration number is NCT02296255.

Oxidative stress biomarkers and otoacoustic emissions in humans exposed to styrene and noise.

OBJECTIVE: Evaluating the correlation between otoacoustic emission levels, styrene exposure, and oxidative stress biomarkers concentration in styrene-exposed subjects, to investigate the role of oxidative stress in outer hair cell damage. DESIGN: Distortion product otoacoustic emissions were measured in the exposed workers and in a control group. Separation between the distortion and reflection otoacoustic components was performed by time-frequency-domain filtering. The urinary concentration of the DNA and RNA oxidation products, namely 8-oxo-7,8-dihydroguanine (oxoGua), 8-oxo-7,8-dihydro-2'-deoxyguanosine (oxodGuo), and 8-oxo-7,8-dihydroguanosine (oxoGuo), were evaluated. STUDY SAMPLE: Nine subjects exposed to styrene in a fiberglass factory, eight control subjects. The two groups were statistically equivalent in mean age. RESULTS: Statistically significant differences were found in the distortion component levels between the exposed and the control group. High levels of the oxidative damage biomarkers were found in the workers exposed to high levels of styrene. Significant negative correlation was found between the otoacoustic emission distortion component levels and the concentration of the oxoGuo biomarker. CONCLUSIONS: Exposure-induced damage of the cochlear amplifier is shown in the mid-frequency range, confirming animal experiments, in which hair cells in the cochlear middle turn were damaged. Hearing damage is consistent with the outer hair cell apoptosis pathway associated with oxidative stress.

Sex differences in the outcome of juvenile social isolation on HPA axis function in rats.

Women are more likely than men to suffer from anxiety disorders and major depression. These disorders share hyperresponsiveness to stress as an etiological factor. Thus, sex differences in brain arousal systems and their regulation by chronic stress may account for the increased vulnerability to these disorders in women. Social isolation is a model of early life stress that results in neurobiological alterations leading to increased anxiety-like and depressive-like behaviors. Here we investigated the sex difference in the effects of post-weaning social isolation on acute stress sensitivity and behavior in rats. In both sexes, social isolation at weaning reduced basal levels of the neuroactive steroid allopregnanolone in the brain and of corticosterone in plasma. Moreover, acute stress increased plasma corticosterone levels in both group-housed and socially isolated male and female rats; however this effect was greater in male than female rats subjected to social isolation. Intriguingly, group-housed female rats showed no change in plasma and brain levels of allopregnanolone after acute foot-shock stress. The absence of stress-induced effects on allopregnanolone synthesis might be due to the physiologically higher levels of this hormone in females vs. males. Accordingly, increasing allopregnanolone levels in male rats blunted the response to foot-shock stress in these animals. Socially isolated male, but not female, rats also display depressive-like behavior and increased hippocampal brain-derived neurotrophic factor (BDNF). The ovarian steroids could "buffer" the effect of this adverse experience in females on these parameters. Finally, the dexamethasone (DEX) suppression test indicated that the chronic stress associated with social isolation impairs feedback inhibition in both sexes in which an increase in the abundance of glucocorticoid receptors (GRs) in the hippocampus was found. Altogether, these results demonstrate that social isolation affects neuroendocrine reactivity to stress, plasticity and emotionality in a sexually dimorphic manner.

Careful monitoring of the use of sedative drugs at the end of life: the role of Epidemiology. The ITAELD study.

BACKGROUND: Sedative drugs are often used at the end of life for different clinical indications, and sometimes sedation is not interrupted until the patient dies. The aim of this study was to estimate the prevalence of patients who died while deeply sedated in Italy in 2007. METHODS: Cross-sectional survey which asked physicians about the last death that occurred among their assisted patients during the last year, and about their attitudes towards end-of-life decisions. All general practitioners (N=5,710) and a random sample of hospital physicians (N=8,950) from 14 Italian provinces were invited to participate. RESULTS: The response rate was 20%. Among 1855 reported deaths, 1466 (79.2%) were classified by physicians as expected or non-sudden; 18.2% of these expected or non-sudden deaths occurred while the patient was deeply sedated. GPs were the least likely to report deep sedation, whereas anesthetists were the most likely. In 8% of cases, sedation occurred along with an abrupt increase in the dosage of opioids during the last day of life, reaching a dosage considered higher than necessary by the doctor. No association with positive attitudes of the physician towards physician assisted death was found, whereas reporting sedation was associated with a positive attitude towards respecting the choice of relatives to forgo life-sustaining treatment in the case of an incompetent patient. CONCLUSION: Our study confirms the high prevalence of patients in Italy who die while being deeply sedated and shows that different practices may converge under the same label. Careful descriptive language is needed.

Otoacoustic emission sensitivity to exposure to styrene and noise.

The ototoxic effect of the exposure to styrene is evaluated, also in the presence of simultaneous exposure to noise, using otoacoustic emissions as biomarkers of mild cochlear damage. Transient-evoked and distortion product otoacoustic emissions were recorded and analyzed in a sample of workers (15 subjects) exposed to styrene and noise in a fiberglass manufacturing facility and in a control group of 13 non-exposed subjects. Individual exposure monitoring of the airborne styrene concentrations was performed, as well as biological monitoring, based on the urinary concentration of two styrene metabolites, the Mandelic and Phenylglyoxylic acids. Noise exposure was evaluated using wearable phonometers, and hearing loss with pure tone audiometry. Due to their different job tasks, one group of workers was exposed to high noise and low styrene levels, another group to higher styrene levels, close to the limit of 20 ppm, and to low noise levels. A significant negative correlation was found between the otoacoustic emission levels and the concentration of the styrene urinary metabolites. Otoacoustic emissions, and particularly distortion products, were able to discriminate the exposed workers from the controls, providing also a rough estimate of the slope of the dose-response relation between otoacoustic levels and styrene exposure.

Trends in colorectal incidence by anatomic subsite from 1985 to 2005: a population-based study.

BACKGROUND: Conflicting results on the shift of right-left ratio in colon cancer incidence have been reported. We examine incidence trends by subsite in a population-based study. MATERIALS AND METHODS: Colorectal cancer cases diagnosed in the 1985-2005 period were identified through the Tuscany Cancer Registry. Colon subsite was defined as proximal and distal; gender, age at diagnosis, histology, and stage were analyzed. Average annual incidence and age-specific rates according to subsite were calculated. RESULTS: A total of 21,160 colorectal cancer cases were extracted; in 18,311 cases, the subsite was identified: 6,916 rectal, 5,239 proximal, and 6,156 distal. A larger proportion of distal colon cancers presented as early stage when compared with proximal. Incidence of rectal and distal colon cancer remained stable, while proximal colon cancer incidence increased. CONCLUSIONS: Proximal colon cancer incidence rate increased through the period. Temporal variations in the incidence rate by subsite could suggest different carcinogenic pathways of right- and left-sided colon cancer.

Invasive breast cancer: a significant correlation between histological types and molecular subgroups.

INTRODUCTION: The special types of breast cancer seem to have not only distinct morphological features but also distinct biological features. MATERIALS AND METHODS: Women diagnosed with a first primary invasive breast cancer in the 2004-2005 period were identified through Tuscan Cancer Registry. Information on age, tumor size, lymph node status, histological type and grade, hormonal receptors, HER2 immunohistochemical expression were collected. Five subtypes were defined: luminal A, luminal B HER2+, luminal B HER2-, triple negative, and HER2 positive. The association between the histological type and molecular subgroups was assessed by a Fisher's exact test, and a multinomial logistic regression model was used. RESULTS: Out of 1,487 patients, 34 % were luminal A subtype, 25 % luminal B HER2-, 11 % luminal B HER2+, 19 % triple negative, and 10.2 % HER2+; 58.5 % of cancers were ductal NOS types. With luminal A as reference, histological types distribution was significantly different between the subgroups. Mucinous, tubular, and cribriform histotypes were found among luminal A cancers more than in other subgroups; all medullary carcinomas were triple negative cancers. Pathological stage at diagnosis was more advanced, and histological grade was lower among subgroups other than luminal A. CONCLUSIONS: Significant association between breast cancer histotypes and molecular subgroups was found.

Biological characteristics of interval cancers: a role for biomarkers in the breast cancer screening.

INTRODUCTION: In a population-based screening program, a percentage of tumors remain undetected; these tumors comprise a heterogeneous group, and they are more likely to have adverse prognostic features. The aim of this study was to identify differences in biological characteristics of screen-detected versus interval breast cancers in a population-based screening program according to molecular subtypes. MATERIALS AND METHODS: We analyzed the population-based data from a long-running screening program in the area of Florence. Data on screening history and on age, T and N status, grade, histotype, hormonal status and Ki-67 and HER2 expression were retrieved. Subtypes of breast cancer were defined on the expression of ER, PR, Ki-67 and HER2: luminal A if ER/PR+, HER2- and Ki67 <14 %, luminal B (HER2 negative) if ER/PR+, HER2- and Ki67 ≥14 %, luminal B (HER2 positive) if ER/PR+ and HER2+, triple negative if ER/PR-and HER2-, HER2 positive if ER/PR- and HER2+. Association between molecular subtypes and mode of detection will be evaluated by a logistic regression model adjusted for the potential confounding variables. RESULTS: Information about biomarkers was known for 277 cases, 211 screening-detected and 66 interval cancers. Among interval cases, the triple-negative cancers were more represented than luminal A (OR = 3.52; CI, 1.112-11.13; p = 0.0319), while the proportion of HER2+ was quite similar (OR = 1.57; p = 0.4709). CONCLUSION: Although made on a small number of cases, our results suggest a difference in distribution of molecular subtypes according to mode detection, confirming the results of earlier studies.

Occupational exposure to styrene in the fibreglass reinforced plastic industry: comparison between two different manufacturing processes.

BACKGROUND: Styrene is used in manufacturing fiberglass reinforced plastics: and occupational exposure was related to neurotoxicology and genotoxicity. The sum of the metabolites mandelic and phenylglyoxylic acids is the ACGIH biomarker for occupational exposure with a BEI of 400 mg/g of creatinine in end shift urine corresponding to a airborne styrene concentration of 85 mg/m3. There are two main molding processes, open and closed, the last more effective at controlling worker's styrene exposure. OBJECTIVES: To compare the open molding process to the compression of fiber reinforced resin foils, a kind of closed molding, monitoring the styrene exposure of workers in two production sites (A and B). METHODS: Environmental Monitoring was carried out by Radiello samplers and Biological Monitoring by means of the determination of MA and PGA with HPLC/MS/MS in 10 workers at Site A and 14 at Site B. RESULTS: The median values for styrene exposure resulted 31.1 mg/m3 for Site A and 24.4 mg/m for Site B, while the medians for the sum of the two metabolites in the end shift urine were 86.7 e 33.8 mg/g creatinine respectively. There is a significant linear correlation between personal styrene exposure and the excretion of styrene metabolites (R = 0.74). CONCLUSIONS: As expected the exposure markers of the workers of the two production sites resulted higher in the open process. The analytical results of both environmental and biological monitoring were all below the occupational exposure limits, confirming the efficacy of the protective devices.

The impact of mammographic screening on breast cancer mortality in Europe: a review of trend studies.

OBJECTIVE: Analysing trends in population breast cancer mortality statistics appears a simple method of estimating the effectiveness of mammographic screening programmes. We reviewed such studies of population-based screening in Europe to assess their value. METHODS: A literature review identified 17 papers, of which 12 provided quantitative estimates of the impact of screening. Due to differences in comparisons and outcome measures, no pooled estimate of effectiveness was calculated. RESULTS: Comparisons included breast cancer mortality before and after the introduction of screening, trends in early and late starting areas and trends in age groups affected and unaffected by screening. Studies that calculated the percentage annual change after the start of screening found reductions of 1-9% per year (1%, 2.3-2.8% and 9% for those with adequate follow-up). Of studies that compared mortality in time periods before and after introduction of screening, three single country studies all had adequate follow-up and estimated mortality reductions ranging from 28% to 36%. Limitations of studies of population mortality rates include the inability to exclude deaths in women with breast cancer diagnosed before invitation to screening, diluting any observable impact of screening, and the gradual implementation of screening in a country or region. CONCLUSIONS: Although analysing population breast cancer mortality rates over time can be a first step in examining changes following the introduction of screening, this method is of limited value for assessment of screening impact. Other methods and individual data are necessary to properly quantify the effect.

Does an organised screening programme reduce the inequalities in breast cancer survival?

BACKGROUND: The aim of the present study was to examine whether the implementation of an organised mammographic screening programme in Florence has been successful in reducing socioeconomic inequalities in breast cancer survival. PATIENTS AND METHODS: All invasive breast cancer cases diagnosed in women resident in the city of Florence in a prescreening period and in the first 10 years of the screening programme were selected. Their socioeconomic status (SES) was determined by using the national census 2001 data. All breast cancers were followed up to 10 years after the diagnosis. RESULTS: In the prescreening period, the survival of deprived women was 12 percentage points lower than the reference class, both in the younger age class (<50 years old) and in the age class target of the screening programme (50-69 years old). This difference progressively decreases until disappearing completely during the first 10 years of the screening programme for the age class invited to screening, whereas it remains stable in the younger age class. Participation in breast cancer screening and diagnostic accuracy were similar by SES. CONCLUSION: The organised breast cancer screening implemented in the Florentine area achieved the goal of reducing inequalities in breast cancer survival.

Dose exposure in the ITALUNG trial of lung cancer screening with low-dose CT.

Few data are available on the effective dose received by participants in lung cancer screening programmes with low-dose CT (LDCT). We report the collective effective dose delivered to 1406 current or former smokers enrolled in the ITALUNG trial who completed 4 annual LDCT examinations and related further investigations including follow-up LDCT, 2-[(18)F]flu-2-deoxy-d-glucose positron emission tomography (FDG-PET) or CT-guided fine needle aspiration biopsy (FNAB). Using the air CT dose index and Monte Carlo simulations on an anthropomorphic phantom, the whole-body effective dose associated with LDCT was determined for the eight CT scanners used in the trial. A value of 7 mSv was assigned to FDG-PET while the measured mean effective dose of CT-guided FNAB was 1.5 mSv. The mean collective effective dose in the 1406 subjects ranged between 8.75 and 9.36 Sv and the mean effective dose to the single subject over 4 years was between 6.2 and 6.8 mSv (range 1.7-21.5 mSv) according to the cranial-caudal length of the LDCT volume. 77.4% of the dose was owing to annual LDCT and 22.6% to further investigations. Considering the nominal risk coefficients for stochastic effects after exposure to low-dose radiation according to the National Radiological Protection Board, International Commission on Radiological Protection (ICRP) 60, ICRP103 and Biological Effects of Ionizing Radiation VII, the mean number of radiation-induced cancers ranged between 0.12 and 0.33 per 1000 subjects. The individual effective dose to participants in a 4-year lung cancer screening programme with annual LDCT is very low and about one-third of the effective dose that is associated with natural background radiation and diagnostic radiology in the same time period.

Breast cancer screening case-control study design: impact on breast cancer mortality.

BACKGROUND: Recent case-control studies on the effectiveness of population-based breast cancer screening show differences in the magnitude of breast cancer mortality reduction. We investigated the role played by aspects of the case-control study design on these differences, e.g. the definition of cases and exposure to screening. MATERIAL AND METHODS: We investigated six case-control studies conducted in East Anglia (UK), Wales, Iceland, central and northern Italy, South Australia and The Netherlands. RESULTS: The breast cancer mortality reduction in the different case-control studies ranged from 38% to 70% in the screened versus the nonscreened women. We identified differences in design, e.g. the inclusion or exclusion of the first years of screening, and the correction factor for self-selection bias. CONCLUSIONS: Overall, the design of the case-control studies was similar. The differences in the magnitude of breast cancer mortality reductions are therefore unlikely to be caused by variations in the design of the case-control studies. These differences must be due to other factors, like the organisation of the service screening programme and the attendance rate. The reduction in breast cancer mortality estimated in these case-control studies indicates that the impact of current mammographic screening is at least consistent with the effect reported by the former randomised screening trials.

[Biological monitoring of the PAH exposure in the hardening of metals]. / Monitoraggio biologico dell'esposizione ad IPA nella tempra dei metalli.

The hardening of metals involves the immersion of hot components in mineral oil with production of aerosols containing PAHs, to wich workers can be exposed. The determination of airborne PAHs and urinary 1-hydroxypyrene (1-OHPy) was performed for a group of workers and the latter resulted within the reference values. However, the average 1-OHPy concentration on metal workers (0.07 microg/g creatinine) was statistically different from the average value obtained for a group of employees (0.03 microg/g creatinine), highlighting the risk of exposure to PAHs. Therefore, being these potentially carcinogenic compounds, interventions were prescribed in order to reduce the risk of occupational exposure.

[Synergistic exposure to noise and styrene and cochlear functionality in a sample of exposed workers: preliminary results]. / Esposizione sinergica a rumore e stirene e funzionalità cocleare in un campione di lavoratori esposti: risultati preliminari.

This study is aimed at testing the cochlear functionality using otoacoustic emissions, analyzing the synergistic effects of simultaneous exposure to noise and organic solvents EBTx on workers of a glass-reinforced plastic products factory. Exposure to organic solvents was assessed using ambiental measurements and evaluation of the salivary concentration. Biological monitoring was performed evaluating the urinary concentration of the styrene metabolites. Statistical analysis shows that otoacoustic tests can discriminate between different exposure groups. Significant differences were found between controls and subjects exposed to high styrene and low noise levels, showing the ototoxic effect (at sub-clinical level) of the styrene exposure.

The major determinant of exendin-4/glucagon-like peptide 1 differential affinity at the rat glucagon-like peptide 1 receptor N-terminal domain is a hydrogen bond from SER-32 of exendin-4.

BACKGROUND AND PURPOSE: Exendin-4 (exenatide, Ex4) is a high-affinity peptide agonist at the glucagon-like peptide-1 receptor (GLP-1R), which has been approved as a treatment for type 2 diabetes. Part of the drug/hormone binding site was described in the crystal structures of both GLP-1 and Ex4 bound to the isolated N-terminal domain (NTD) of GLP-1R. However, these structures do not account for the large difference in affinity between GLP-1 and Ex4 at this isolated domain, or for the published role of the C-terminal extension of Ex4. Our aim was to clarify the pharmacology of GLP-1R in the context of these new structural data. EXPERIMENTAL APPROACH: The affinities of GLP-1, Ex4 and various analogues were measured at human and rat GLP-1R (hGLP-1R and rGLP-1R, respectively) and various receptor variants. Molecular dynamics coupled with in silico mutagenesis were used to model and interpret the data. KEY RESULTS: The membrane-tethered NTD of hGLP-1R displayed similar affinity for GLP-1 and Ex4 in sharp contrast to previous studies using the soluble isolated domain. The selectivity at rGLP-1R for Ex4(9-39) over Ex4(9-30) was due to Ser-32 in the ligand. While this selectivity was not observed at hGLP-1R, it was regained when Glu-68 of hGLP-1R was mutated to Asp. CONCLUSIONS AND IMPLICATIONS: GLP-1 and Ex4 bind to the NTD of hGLP-1R with similar affinity. A hydrogen bond between Ser32 of Ex4 and Asp-68 of rGLP-1R, which is not formed with Glu-68 of hGLP-1R, is responsible for the improved affinity of Ex4 at the rat receptor.

CHARMM: the biomolecular simulation program.

CHARMM (Chemistry at HARvard Molecular Mechanics) is a highly versatile and widely used molecular simulation program. It has been developed over the last three decades with a primary focus on molecules of biological interest, including proteins, peptides, lipids, nucleic acids, carbohydrates, and small molecule ligands, as they occur in solution, crystals, and membrane environments. For the study of such systems, the program provides a large suite of computational tools that include numerous conformational and path sampling methods, free energy estimators, molecular minimization, dynamics, and analysis techniques, and model-building capabilities. The CHARMM program is applicable to problems involving a much broader class of many-particle systems. Calculations with CHARMM can be performed using a number of different energy functions and models, from mixed quantum mechanical-molecular mechanical force fields, to all-atom classical potential energy functions with explicit solvent and various boundary conditions, to implicit solvent and membrane models. The program has been ported to numerous platforms in both serial and parallel architectures. This article provides an overview of the program as it exists today with an emphasis on developments since the publication of the original CHARMM article in 1983.