Gaussian Process-based prediction of memory performance and biomarker status in ageing and Alzheimer's disease-A systematic model evaluation.

Neuroimaging markers based on Magnetic Resonance Imaging (MRI) combined with various other measures (such as genetic covariates, biomarkers, vascular risk factors, neuropsychological tests etc.) might provide useful predictions of clinical outcomes during the progression towards Alzheimer's disease (AD). The use of multiple features in predictive frameworks for clinical outcomes has become increasingly prevalent in AD research. However, many studies do not focus on systematically and accurately evaluating combinations of multiple input features. Hence, the aim of the present work is to explore and assess optimal combinations of various features for MR-based prediction of (1) cognitive status and (2) biomarker positivity with a multi-kernel learning Gaussian process framework. The explored features and parameters included (A) combinations of brain tissues, modulation, smoothing, and image resolution; (B) incorporating demographics & clinical covariates; (C) the impact of the size of the training data set; (D) the influence of dimensionality reduction and the choice of kernel types. The approach was tested in a large German cohort including 959 subjects from the multicentric longitudinal study of cognitive impairment and dementia (DELCODE). Our evaluation suggests the best prediction of memory performance was obtained for a combination of neuroimaging markers, demographics, genetic information (ApoE4) and CSF biomarkers explaining 57% of outcome variance in out-of-sample predictions. The highest performance for Aß42/40 status classification was achieved for a combination of demographics, ApoE4, and a memory score while usage of structural MRI further improved the classification of individual patient's pTau status.

Smoking associated with reduced odds of Sjögren's syndrome among rheumatoid arthritis patients.

OBJECTIVE: The objective of this medical record review study is to define the association between smoking and SjÓ§gren's syndrome (SS) in a large rheumatoid arthritis (RA) cohort. METHODS: Electronic health records from a population-based cohort were screened for RA eligibility between 2005 and 2018. Inclusion criteria were age ≥ 18 years, two or more RA diagnoses, including two diagnoses by a rheumatologist, or positive rheumatoid factor or anti-cyclic citrullinated peptide (anti-CCP) antibody. The independent variable, smoking status, was defined as never, current, or past. The outcome, SS, was defined by two or more ICD-9 codes. Multivariable logistic regression was performed to determine odds ratios (ORs) of SS adjusted for age, sex, and race. RESULTS: Among 1861 patients with RA identified for cohort inclusion, 1296 had a reported smoking status. Current smokers were younger and less likely to be female than never smokers. The adjusted OR of current compared to never smokers was negatively associated with SS [OR 0.20, 95% confidence interval (CI) 0.06-0.65]. Female sex and age were associated with SS (OR 2.70, 95% CI 1.18-6.14; OR 3.75, 95% CI 1.23-11.4). CONCLUSION: We report that RA patients who currently smoke had 80% lower odds of SS. Age had a 3.7-fold association and female sex a 2.7-fold association with SS among RA patients. Our data suggest a negative correlation between current smoking and prevalent SS among RA patients. Prospective studies examining pack-year relationships or smoking cessation could further examine risk reduction and causality to follow-up our cross-sectional observational study.

A 390 million-year-old hyper-compound eye in Devonian phacopid trilobites.

Trilobites, extinct arthropods that dominated the faunas of the Palaeozoic, since their appearance c 523 million years ago, were equipped with elaborate compound eyes. While most of them possessed apposition compound eyes (in trilobites called holochroal eyes), comparable to the compound eyes of many diurnal crustaceans and insects living today, trilobites of the suborder Phacopina developed atypical large eyes with wide lenses and wide interspaces in between (schizochroal eyes). Here, we show that these compound eyes are highly sophisticated systems-hyper-compound eyes hiding an individual compound eye below each of the big lenses. Thus, each of the phacopid compound eyes comprises several tens, in cases even hundreds of small compound eye systems composing a single visual surface. We discuss their development, phylogenetic position of this hyper-compound eye, and its neuronal infrastructure. A hyper-compound eye in this form is unique in the animal realm.

Short-term testosterone use in female mice does not impair fertilizability of eggs: implications for the fertility care of transgender males.

STUDY QUESTION: Does testosterone use in females affect reproductive potential, particularly with regard to the production of fertilizable gametes? SUMMARY ANSWER: Testosterone (T) injections given to post-pubertal female mice caused virilization and although the ovaries were smaller than controls they were still responsive and produced fertilizable eggs when superovulated. WHAT IS KNOWN ALREADY: Studies to examine the effects of testosterone on reproductive potential in transgender males are lacking. Recently, a model was developed that simulates many aspects of testosterone use in transgender males in order to look at reproductive effects of testosterone in female mice. This study found masculinizing effects on the mice but did not find significant deficits on the number of ovarian follicles; however, effects of testosterone use on ovarian stimulation and fertilizability of oocytes were not investigated. STUDY DESIGN, SIZE, DURATION: A total of 66, 6-week-old Hsd:NSA (CF-1) female mice and six Hsd:ICR (CD-1) male mice were used for this study. Mice were injected s.c. with 400 µg T or sesame oil once a week for 6 weeks and were either killed 1 week after the sixth injection (active exposure group), or 6-7 weeks after the final T injection (washout group). PARTICIPANTS/MATERIALS, SETTING, METHODS: Both active exposure and washout groups were further subdivided into three groups: unstimulated, equine CG (eCG)-stimulated or eCG/hCG-stimulated. eCG-stimulated mice were killed 44-48 h after eCG injection. eCG/hCG-stimulated mice were injected with eCG, followed 48 h later with hCG. Mice were killed ∼13-18 h after the hCG injection. Data collected included daily vaginal cytology, terminal testosterone levels, ovary weights and histology, number of oocytes/eggs collected in each group, and cleavage to the two-cell stage following IVF. MAIN RESULTS AND THE ROLE OF CHANCE: Testosterone-treated mice had testosterone levels elevated to the level of male mice and ceased cycling. Ovaries were significantly smaller in testosterone-treated mice, but they contained normal cohorts of follicles and responded to gonadotrophin stimulation by ovulating similar numbers of eggs as controls, that fertilized and cleaved in vitro. LIMITATIONS, REASONS FOR CAUTION: Mice were treated for only 6 weeks, whereas many transgender men use testosterone for many years before considering biological children, and developmental competence was not assessed. Importantly, a mouse system may not perfectly simulate human reproductive physiology. WIDER IMPLICATIONS OF THE FINDINGS: The current standard of care for transgender men who desire biological children is to cease testosterone therapy prior to ovarian stimulation, but the necessity for stopping testosterone is not known. Our model demonstrates that it is possible for testosterone-suppressed ovaries to respond to gonadotrophic stimulation by producing and ovulating fertilizable eggs, thereby obviating the need for testosterone cessation prior to ovarian stimulation. In time, these results may provide insights for future clinical trials of fertility treatment options for transgender men. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Reproductive Endocrinology and Infertility fellowship program through UConn Health Graduate Medical Education (to C.B.B.). The authors have no competing interests. TRIAL REGISTRATION NUMBER: N/A.

[Quality of life and depression in hearing-impairment : A German survey]. / Lebensqualität und Depression bei Hörminderung : Eine deutsche Bedarfsanalyse.

BACKGROUND: Hearing-impairment can lead to a reduced quality of life and thus represents a vulnerability factor for mental disorders. OBJECTIVE: This study represents the first psychiatric analysis of subjective quality of life and depression in people with hearing-impairment in Germany. MATERIALS AND METHODS: The patient group included 30 hearing-impaired participants (27 women, 3 men) with a current or previous mental disorder and/or psychiatric/psychotherapeutic treatment (age: mean, M = 49.67 years; standard deviation, SD = 13.54 years). The control group consisted of 22 hearing-impaired participants (16 women, 6 men) without mental disorders or treatment (age: M = 52.41 years, SD = 17.30 years). Besides sociodemographic variables, we registered onset/extent of the various hearing-impairments and hearing aid provision. Both groups underwent extensive diagnostic assessment comprising subjective functional impairment (Sheehan Disability Scale, SDS), health-related quality of life (SF-36 Health Survey), and depressive symptoms (Beck Depression Inventory, BDI-II). RESULTS: Groups did not differ significantly in terms of sociodemographic variables such as age, gender, or intelligence. Participants of the patient group had a significantly greater subjective impairment, a lower quality of life, and more pronounced symptoms of depression. The invasiveness of the hearing aid (i. e., cochlear implant) as well as the timepoint of hearing-impairment onset (postlingually) appear to serve as vulnerability factors for mental health problems in this group. CONCLUSION: Our results indicate that besides delivering high-quality acoustic care, practitioners should continuously check patients' requirements for psychosocial treatment due to a loss of quality of life. The development of a specific psychotherapeutic treatment for hearing-impaired clients requires additional research focused on protective and vulnerability factors which may influence the emergence of mental disorders in these patients.

[Robustness of Hospital Benchmarking with the Hospital Standardized Mortality Ratio (HSMR): An Analysis of Secondary Data from 37 German Hospitals]. / Robustheit eines Krankenhausvergleichs mit der Hospital Standardized Mortality Ratio (HSMR): eine Sekundärdatenanalyse von 37 deutschen Krankenhäusern.

Introduction: Internationally, the hospital standardized mortality ratio is increasingly used as a risk-adjusted simple measure for quality control. Goodness of fit of different risk models in Germany and robustness of hospital comparisons were evaluated with a secondary data analysis. Methods: Anonymized routine data from the year 2012 of 37 hospitals of the association Quality Indicators for Ecclesiastical Hospitals were used. 2 independent risk models and the observed mortality were compared, the risk models considered both the original and the adapted forms. Results: The risk models showed an area under curve between 0.906 [95% CI 0.904-0.908] and 0.920 [0.918-0.922]. There was a significant correlation between the risk models and the observed mortality with a correlation coefficient between 0.388 (p<0.05) and 0.936 (p<0.01). 26 hospitals had an identical assessment in all risk models comparing their HSMR with the group. 2 hospitals achieved a positive and a negative assessment taking into account the observed mortality. Conclusion: The quality of the risk models is high and the hospital comparison with the HSMR remained stable. However, it is unclear whether the differences are caused by quality-related issues or by different structures and case-mix. Therefore, the HSMR is primarily intended for quality management purposes within German hospitals.

Risk factors for infection with Foot-and-Mouth Disease virus in a cattle population vaccinated with a non-purified vaccine in Iran.

In this study, we estimated the level of Foot-and-Mouth (FMD) virus infection in a cattle-dense north-western province of Islamic Republic of Iran and analyzed putative risk factors for FMD infection. Calves (6-24 months of age) from all 17 districts of West Azerbaijan were tested for antibodies against non-structural proteins (NSP-Ab) of FMD virus. A proportional stratification with a minimum of 30 epi-units was applied for 3 different husbandry systems: villages, dairy and mixed farms. Within an epi-unit, 30 calves were sampled. For the interpretation of ELISA test results, we used the 50% inhibition (50PI) cut-off as per producer's instructions and created one at 75% inhibition (75PI) based on the lowest point of the histogram of PI results. This approach resulted in three categories of outcomes; negative (N), low-positive (LP) and high-positive (HP). A generalized mixed-effect model for binary outcomes was used for analysing putative risk factors and was run for both cut-off values. A total of 8378 calves from 202 villages, 51 dairy farms and 28 mixed farms were eligible for analysis. The percentage of calves testing positive (LP+HP) was 53.7% (95% Confidence interval (CI): 52.6%-54.8%), with 39.6% (95% CI: 38.6-40.7%) testing HP (n=3309) while 14.1% (95% CI: 13.5-15.0%) of calves tested LP (n=1188). Of 281 epi-units sampled, all calves sampled tested negative in only 2 epi-units (0.7% (95% CI: 0.1-2.5%)) and more than 25 calves tested positive in 29 epi-units (10.3% (95% CI: 7.0-14.5%)). Outcomes of regression modelling using the 50 PI cut-off indicated that, for each month increase in age, the odds of testing positive increased 1.01 times (95% CI: 1.00-1.03). The odds of calves testing NSP-positive increased 1.46 times (95% CI: 1.22-1.77) for calves residing in epi-units that had experienced clinical FMD in the 12 months preceding this study. The odds of calves owned by livestock owners who traded livestock testing positive were 1.4-1.6 times higher than those owned by persons not engaged in trading while the odds for calves testing positive in dairy herds was 1.62 (95% CI: 1.10-2.35) times higher compared with calves in villages. The results of the model using the 75 PI cut-off value resulted in comparable estimates, with the age-effect becoming more evident. These results have confirmed widespread FMD infection and were used in developing a risk-based control strategy on FMD, in line with Stage 1 of the Progressive Control Pathway for FMD (PCP-FMD).

Evaluation of an integrated care program for schizophrenia: concept and study design.

Concept and design of an independent scientific evaluation of different pathways of care for schizophrenia patients in Germany with respect to effectiveness and efficiency are presented. In this prospective, observational study, schizophrenia patients receiving an integrated care treatment, the intervention group (IG), are compared with patients under routine care conditions treated by the same physician (first control group, CG 1). A second control group (CG 2) of patients treated by office-based psychiatrists not participating in the integrated care program will be recruited and their data compared with the two other groups. The total amount of psychiatric hospital days after 12 months is defined as primary outcome parameter. Secondary outcome parameters comprise the frequency of psychiatric inpatient readmissions, severity of schizophrenia symptoms, remission rates and quality of life. Patients undergo assessments at baseline, month 6 and 12 using standardized and experimental questionnaires. Routine data of a regional German social health insurance fund complement information on included patients. Additionally, a cost-effectiveness and cost-utility analysis will be performed. Until now, 137 psychiatrists included 980 patients in the integrated care project in Lower Saxony, Germany, and 47 psychiatrists (IG and both CGs) are willing to participate in the independent evaluation. For the first time, a prospective observational controlled evaluation study of a countrywide integrated care project planning to recruit 500 schizophrenia patients has started using comprehensive assessments as well as routine data of a social health insurance fund.

Clinical and laboratory evaluation of a real-time PCR for Clostridium difficile toxin A and B genes.

Many laboratories use enzyme immunoassays (EIAs) for the diagnosis of Clostridium difficile infection (CDI). More recently, polymerase chain reaction (PCR)-based diagnosis has been described as a sensitive test. Real-time PCR for the detection of C. difficile toxin A and B genes was evaluated. A prospective evaluation was performed on stool samples from 150 hospitalized adult patients and 141 healthy volunteers. PCR was compared to toxigenic culture (TC), direct cytotoxicity test (CTT), ImmunoCard® Toxin A and B (Meridian Bioscience), and enzyme-linked immunosorbent assay (ELISA) (Vidas). The results were correlated with clinical data using a standardized questionnaire. The diagnostic yield of the PCR was further evaluated after implementation. Using toxigenic culture as the gold standard, the sensitivity and specificity of PCR were 100 and 99.2%, respectively. Patients were categorized as follows: TC/PCR-positive (n = 17) and negative TC (n = 133). The differences in these groups were more frequent use of antibiotics and leukocytosis (p < 0.05). The diagnostic yield of PCR was evaluated during a period of 6 months and showed an increase of positive patients by 50%. PCR for the detection of toxigenic C. difficile has a high sensitivity and can rule out CDI, but cannot differentiate CDI from asymptomatic carriage. Clinicians should be aware of this in order to prevent inappropriate treatment and delay of other diagnostics.

A survey of the prevalence of smoking and smoking cessation advice received by inpatients in a large teaching hospital in Ireland.

BACKGROUND: The adverse effects of smoking are well documented and it is crucial that this modifiable risk factor is addressed routinely. Professional advice can be effective at reducing smoking amongst patients, yet it is not clear if all hospital in-patient smokers receive advice to quit. AIMS: To explore smoking prevalence amongst hospital in-patients and smoking cessation advice given by health professionals in a large university teaching hospital. METHODS: Interviews were carried out over 2 weeks in February 2011 with all eligible in-patients in Beaumont Hospital. RESULTS: Of the 205 patients who completed the survey, 61% stated they had been asked about smoking by a healthcare professional in the past year. Only 44% of current/recent smokers stated they had received smoking cessation advice from a health professional within the same timeframe. CONCLUSIONS: Interventions to increase rates of healthcare professional-provided smoking cessation advice are urgently needed.

Curative effect of topical treatment of digital dermatitis with a gel containing activated copper and zinc chelate.

The efficacy of two topical treatments for painful ulcerative stage (M2) of bovine digital dermatitis (BDD) lesions was compared in a clinical trial conducted on five dairy farms in 2009 to 2010. The first treatment was a water-based gel with active components copper and zinc (Intra Hoof-fit gel [IHF]) and the second treatment was a topical chlortetracycline spray (CTC spray). The experimental unit for this study was the hindleg with the presence of a BDD lesion. Cure was defined as the transition of an M2 lesion into a healed (M0) or a non-painful chronic stage (M4) of BDD at D28. On day 0, cows with M2 BDD lesions were photographed and were treated with either IHF or CTC. Subsequently, feet were photographed and scored on D28. The cure rate of M2 BDD lesions treated with IHF at D28 was 0.92 (CI 0.84 to 0.96) and was significantly better than for M2 BDD lesions treated with CTC, which was 0.58 (CI 0.47 to 0.68).

Prevalence of Coxiella burnetii infection in Dutch dairy herds based on testing bulk tank milk and individual samples by PCR and ELISA.

A study using an ELISA and a real-time PCR assay based on the detection of the repetitive transposon-like gene of Coxiella burnetii revealed that infection with the bacterium was widespread among Dutch dairy herds, with antibodies detected in bulk tank milk (BTM) from 268 of 341 herds (78.6 per cent) and bacterial DNA detected in 193 of 341 herds (56.6 per cent). The BTM samples were taken in November and December 2007. Serological and molecular studies in young and adult cattle selected from 100 herds showed that antibodies were present in the blood of 470 of 2936 (16.0 per cent) lactating cows but only in 19 of 1831 (1.0 per cent) young animals. Bacterial DNA was detected in the milk of 254 of 2925 (8.7 per cent) lactating cows; bacterial DNA was not detected in any of the faecal samples obtained from youngstock. The blood and milk samples were taken from the cattle in the period January to April 2008.

Mortality attributable to bluetongue virus serotype 8 infection in Dutch dairy cows.

In 2007, bluetongue virus serotype 8 (BTV-8) re-emerged in the Netherlands and a large number of farmers notified morbidity and mortality associated with BTV-8 to the authorities. All dead cows in the Netherlands are registered in one of the three age classes: newborn calves <3 days, calves 3 days to 1 year, and cows >1 year. These registrations result in a complete data set of dead cattle per herd per day from 2003 until 2007. In this study, the mortality associated with BTV-8 for the Dutch dairy industry was estimated, based on this census data. Default, mortality associated with BTV-8 was estimated for the confirmed notification herds. Moreover, an additional analysis was performed to determine if mortality associated with BTV-8 infection occurred in non-notification herds located in BTV-8 infected compartments. A multivariable population-averaged model with a log link function was used for analyses. Separate analyses were conducted for the three different age groups. Confirmed notification herds had an increased cow mortality rate ratio (MRR) (1.4 (95% CI: 1.2-1.6)); calf MRR (1.3 (95% CI: 1.1-1.4)); and newborn calf MRR (1.2 (95% CI: 1.1-1.3)). Furthermore, in non-notification herds in BTV-8 infected compartments, mortality significantly increased 1.1 times (95% CI: 1.1-1.1) in cows, 1.2 times (95% CI: 1.2-1.2) in calves and 1.1 times (1.1-1.1) in newborn calves compared with BTV-8 non-infected months. Using objective census data over a 5-year period, the MRRs indicated increased mortality associated with BTV-8 infection not only in herds of which the farmer notified clinical signs but also in non-notification herds in infected compartments.

Recombinant human erythropoietin delays loss of gray matter in chronic schizophrenia.

Neurodevelopmental abnormalities together with neurodegenerative processes contribute to schizophrenia, an etiologically heterogeneous, complex disease phenotype that has been difficult to model in animals. The neurodegenerative component of schizophrenia is best documented by magnetic resonance imaging (MRI), demonstrating progressive cortical gray matter loss over time. No treatment exists to counteract this slowly proceeding atrophy. The hematopoietic growth factor erythropoietin (EPO) is neuroprotective in animals. Here, we show by voxel-based morphometry in 32 human subjects in a placebo-controlled study that weekly high-dose EPO for as little as 3 months halts the progressive atrophy in brain areas typically affected in schizophrenia, including hippocampus, amygdala, nucleus accumbens, and several neocortical areas. Specifically, gray matter protection is highly associated with improvement in attention and memory functions. These findings suggest that a neuroprotective strategy is effective against common pathophysiological features of schizophrenic patients, and strongly encourage follow-up studies to optimize EPO treatment dose and duration.

[Influence of floor disinfection on microbial and particulate burden measured under low turbulance air flow in ophthalmological operation theatres]. / Einfluss der Fußbodendesinfektion auf die mikrobielle und partikuläre Belastung der Raumluft in Augen-OP-Räumen mit Verdrängungslüftungsbereichen.

AIM: The necessity for routine disinfection of floors between two surgical procedures or disinfection only after visible contamination was assessed in two identical ophthalmological operating theatres equipped with laminar air flow ventilation. METHOD: Over a period of four weeks, one of the two tested operating rooms was disinfected after every surgical procedure, and the other only in the case of visible contamination. This regimen was inverted every week. To compare the air quality, particle count and total bacteria count were measured inside and outside the laminar air flow. Additionally, bacteria count was measured in the operating field, consisting of the operating table and the instrument tray. Patients were monitored for surgical site infection over a period of one year after operation. RESULTS: No difference in particle count or number of viable bacteria was found between the two investigated procedures. Also, no wound infections were observed after one year of surveillance for surgical site infection. CONCLUSION: It appears that frequent cleaning disinfection of floors is not necessary if a laminar air flow ventilation system is installed. Under these conditions, targeted disinfection of visibly soiled surfaces appears to be sufficient. Generally, the duration of surgical procedures should be kept as short as possible.

The increase in seroprevalence of bluetongue virus (BTV) serotype 8 infections and associated risk factors in Dutch dairy herds, in 2007.

Bluetongue virus serotype 8 (BTV-8) emerged in the Netherlands in August 2006 for the first time. In the winter of 2006/2007, during the transmission free period, the government decided to establish a sentinel network to monitor the re-emergence of BTV-8 in 2007. Between June and December 2007, a sentinel network of 275 dairy herds with 8901 seronegative cows at start, was in place for BTV-8 testing in milk samples. Besides estimates of the monthly BTV-8 within-herd prevalence per region (south, central and north), this sentinel was used to determine BTV-8 associated risk factors. Information on management and housing practices that were hypothesized to be related to the increase in BTV-8 prevalence (risk factors) were used. Complete information on BTV-8 testing and management was obtained for 234 herds. At herd level, the increase in seroprevalence was defined as the total increase in seroprevalence amongst sentinel cows per herd during the sampling period (in months) divided by the number of sampling months in which the spread of BTV-8 occurred within the particular compartment in which the herd was located. This parameter was used as dependent variable in the linear regression analysis. The final model revealed four risk factors remained in the final model. Herds in the central and southern region of the Netherlands had a higher monthly increase in seroprevalence 6.4% (95% CI: 3.1-9.9) and 10.1% (95% CI: 6.2-14.3), respectively compared to herds in the northern region. Furthermore, there was a strong association with grazing. The monthly increase in seroprevalence in cattle pastured a few hours per day or throughout the day was 5.6% (95% CI: 1.4-10.2) to 11.4% (95% CI: 6.0-17.3) higher, relative to that for cattle kept indoors. For cattle that grazed outdoors throughout the day and the night, the monthly increase in seroprevalence was 13.6% (95% CI: 7.2-20.8). In addition, an association was found between the monthly increase in seroprevalence and some factors relating to stable design. Keeping the stable doors closed during the day was linked to a higher seroprevalence rate compared to that in stables with the door left open (3.6% (95% CI: 0.3-7.1)). Furthermore, a horizontal ventilation opening (>30 cm) along the walls of the stable, and with a windbreak curtain, appeared to offer some protection (-3.0% per month (95% CI: -6.0 to 0.2)) as compared to stables that had no or, only a small, ventilation opening (<30 cm). By the second half of 2007, bluetongue had spread over throughout the Netherlands. Our study indicated that there were some management factors that may help limit exposure to BTV-8 and its consequences.

Calorimetric observation of the melting of free water nanoparticles at cryogenic temperatures.

We present an experimental study of the thermodynamics of free, size-selected water cluster anions consisting of 48 and 118 molecules. The measured caloric curves of the clusters are bulklike at low temperatures but show a well-defined, particle-size specific transition at 93+/-3 K for (H2O)48- and 118+/-3 K for (H2O)118-. At the transition temperature the heat capacity strongly increases, which marks the onset of melting.

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.