Robert J. Petrella

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.

The 2009 Canadian Hypertension Education Program recommendations for the management of hypertension: Part 2 – therapy

OBJECTIVE To update the evidence-based recommendations for the prevention and management of hypertension in adults for 2009. OPTIONS AND OUTCOMES For lifestyle and pharmacological interventions, evidence from randomized controlled trials and systematic reviews of trials was preferentially reviewed. Changes in cardiovascular morbidity and mortality were the primary outcomes of interest. However, for lifestyle interventions, blood pressure lowering was accepted as a primary outcome given the lack of long-term morbidity and mortality data in this field. Progression of kidney dysfunction was also accepted as a clinically relevant primary outcome among patients with chronic kidney disease. EVIDENCE A Cochrane collaboration librarian conducted an independent MEDLINE search from 2007 to August 2008 to update the 2008 recommendations. To identify additional published studies, reference lists were reviewed and experts were contacted. All relevant articles were reviewed and appraised independently by both content and methodological experts using prespecified levels of evidence. RECOMMENDATIONS For lifestyle modifications to prevent and treat hypertension, restrict dietary sodium to less than 2300 mg (100 mmol)/day (and 1500 mg to 2300 mg [65 mmol to 100 mmol]/day in hypertensive patients); perform 30 min to 60 min of aerobic exercise four to seven days per week; maintain a healthy body weight (body mass index 18.5 kg/m(2) to 24.9 kg/m(2)) and waist circumference (smaller than 102 cm for men and smaller than 88 cm for women); limit alcohol consumption to no more than 14 units per week in men or nine units per week in women; follow a diet that is reduced in saturated fat and cholesterol, and that emphasizes fruits, vegetables and low-fat dairy products, dietary and soluble fibre, whole grains and protein from plant sources; and consider stress management in selected individuals with hypertension. For the pharmacological management of hypertension, treatment thresholds and targets should be predicated on by the patients global atherosclerotic risk, target organ damage and comorbid conditions. Blood pressure should be decreased to lower than 140/90 mmHg in all patients, and to lower than 130/80 mmHg in those with diabetes mellitus or chronic kidney disease. Most patients will require more than one agent to achieve these target blood pressures. Antihypertensive therapy should be considered in all adult patients regardless of age (caution should be exercised in elderly patients who are frail). For adults without compelling indications for other agents, initial therapy should include thiazide diuretics. Other agents appropriate for first-line therapy for diastolic and/or systolic hypertension include angiotensin- converting enzyme (ACE) inhibitors (in patients who are not black), long-acting calcium channel blockers (CCBs), angiotensin receptor antagonists (ARBs) or beta-blockers (in those younger than 60 years of age). A combination of two first-line agents may also be considered as the initial treatment of hypertension if the systolic blood pressure is 20 mmHg above the target or if the diastolic blood pressure is 10 mmHg above the target. The combination of ACE inhibitors and ARBs should not be used. Other agents appropriate for first-line therapy for isolated systolic hypertension include long- acting dihydropyridine CCBs or ARBs. In patients with angina, recent myocardial infarction or heart failure, beta-blockers and ACE inhibitors are recommended as first-line therapy; in patients with cerebrovascular disease, an ACE inhibitor/diuretic combination is preferred; in patients with proteinuric nondiabetic chronic kidney disease, ACE inhibitors or ARBs (if intolerant to ACE inhibitors) are recommended; and in patients with diabetes mellitus, ACE inhibitors or ARBs (or, in patients without albuminuria, thiazides or dihydropyridine CCBs) are appropriate first-line therapies. All hypertensive patients with dyslipidemia should be treated using the thresholds, targets and agents outlined in the Canadian Cardiovascular Society position statement (recommendations for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease). Selected high-risk patients with hypertension who do not achieve thresholds for statin therapy according to the position paper should nonetheless receive statin therapy. Once blood pressure is controlled, acetylsalicylic acid therapy should be considered. VALIDATION All recommendations were graded according to strength of the evidence and voted on by the 57 members of the Canadian Hypertension Education Program Evidence-Based Recommendations Task Force. All recommendations reported here achieved at least 95% consensus. These guidelines will continue to be updated annually.

The 2013 Canadian Hypertension Education Program recommendations for blood pressure measurement, diagnosis, assessment of risk, prevention, and treatment of hypertension.

We updated the evidence-based recommendations for the diagnosis, assessment, prevention, and treatment of hypertension in adults for 2013. This years update includes 2 new recommendations. First, among nonhypertensive or stage 1 hypertensive individuals, the use of resistance or weight training exercise does not adversely influence blood pressure (BP) (Grade D). Thus, such patients need not avoid this type of exercise for fear of increasing BP. Second, and separately, for very elderly patients with isolated systolic hypertension (age 80 years or older), the target for systolic BP should be < 150 mm Hg (Grade C) rather than < 140 mm Hg as recommended for younger patients. We also discuss 2 additional topics at length (the pharmacological treatment of mild hypertension and the possibility of a diastolic J curve in hypertensive patients with coronary artery disease). In light of several methodological limitations, a recent systematic review of 4 trials in patients with stage 1 uncomplicated hypertension did not lead to changes in management recommendations. In addition, because of a lack of prospective randomized data assessing diastolic BP thresholds in patients with coronary artery disease and hypertension, no recommendation to set a selective diastolic cut point for such patients could be affirmed. However, both of these issues will be examined on an ongoing basis, in particular as new evidence emerges.

Association of temporal trends in risk factors and treatment uptake with coronary heart disease mortality, 1994-2005.

CONTEXT Coronary heart disease (CHD) mortality has declined substantially in Canada since 1994. OBJECTIVE To determine what proportion of this decline was associated with temporal trends in CHD risk factors and advancements in medical treatments. DESIGN, SETTING, AND PATIENTS Prospective analytic study of the Ontario, Canada, population aged 25 to 84 years between 1994 and 2005, using an updated version of the validated IMPACT model, which integrates data on population size, CHD mortality, risk factors, and treatment uptake changes. Relative risks and regression coefficients from the published literature quantified the relationship between CHD mortality and (1) evidence-based therapies in 8 distinct CHD subpopulations (acute myocardial infarction [AMI], acute coronary syndromes, secondary prevention post-AMI, chronic coronary artery disease, heart failure in the hospital vs in the community, and primary prevention for hyperlipidemia or hypertension) and (2) population trends in 6 risk factors (smoking, diabetes mellitus, systolic blood pressure, plasma cholesterol level, exercise, and obesity). MAIN OUTCOME MEASURES The number of deaths prevented or delayed in 2005; secondary outcome measures were improvements in medical treatments and trends in risk factors. RESULTS Between 1994 and 2005, the age-adjusted CHD mortality rate in Ontario decreased by 35% from 191 to 125 deaths per 100,000 inhabitants, translating to an estimated 7585 fewer CHD deaths in 2005. Improvements in medical and surgical treatments were associated with 43% (range, 11% to 124%) of the total mortality decrease, most notably in AMI (8%; range, -5% to 40%), chronic stable coronary artery disease (17%; range, 7% to 35%), and heart failure occurring while in the community (10%; range, 6% to 31%). Trends in risk factors accounted for 3660 fewer CHD deaths prevented or delayed (48% of total; range, 28% to 64%), specifically, reductions in total cholesterol (23%; range, 10% to 33%) and systolic blood pressure (20%; range, 13% to 26%). Increasing diabetes prevalence and body mass index had an inverse relationship associated with higher CHD mortality of 6% (range, 4% to 8%) and 2% (range, 1% to 4%), respectively. CONCLUSION Between 1994 and 2005, there was a decrease in CHD mortality rates in Ontario that was associated primarily with trends in risk factors and improvements in medical treatments, each explaining about half of the decrease.

The 2011 Canadian Hypertension Education Program Recommendations for the Management of Hypertension: Blood Pressure Measurement, Diagnosis, Assessment of Risk, and Therapy

We updated the evidence-based recommendations for the diagnosis, assessment, prevention, and treatment of hypertension in adults for 2011. The major guideline changes this year are: (1) a recommendation was made for using comparative risk analogies when communicating a patients cardiovascular risk; (2) diagnostic testing issues for renal artery stenosis were discussed; (3) recommendations were added for the management of hypertension during the acute phase of stroke; (4) people with hypertension and diabetes are now considered high risk for cardiovascular events if they have elevated urinary albumin excretion, overt kidney disease, cardiovascular disease, or the presence of other cardiovascular risk factors; (5) the combination of an angiotensin-converting enzyme (ACE) inhibitor and a dihydropyridine calcium channel blocker (CCB) is preferred over the combination of an ACE inhibitor and a thiazide diuretic in persons with diabetes and hypertension; and (6) a recommendation was made to coordinate with pharmacists to improve antihypertensive medication adherence. We also discussed the recent analyses that examined the association between angiotensin II receptor blockers (ARBs) and cancer.

Effects of Exercise on Cardiovascular Risk Factors in Type 2 Diabetes A meta-analysis

OBJECTIVE Exercise is a cornerstone of diabetes management and the prevention of incident diabetes. However, the impact of the mode of exercise on cardiovascular (CV) risk factors in type 2 diabetes is unclear. RESEARCH DESIGN AND METHODS We conducted a systematic review of the literature between 1970 and October 2009 in representative databases for the effect of aerobic or resistance exercise training on clinical markers of CV risk, including glycemic control, dyslipidemia, blood pressure, and body composition in patients with type 2 diabetes. RESULTS Of 645 articles retrieved, 34 met our inclusion criteria; most investigated aerobic exercise alone, and 10 reported combined exercise training. Aerobic alone or combined with resistance training (RT) significantly improved HbA1c −0.6 and −0.67%, respectively (95% CI −0.98 to −0.27 and −0.93 to −0.40, respectively), systolic blood pressure (SBP) −6.08 and −3.59 mmHg, respectively (95% CI −10.79 to −1.36 and −6.93 to −0.24, respectively), and triglycerides −0.3 mmol/L (95% CI −0.48 to −0.11 and −0.57 to −0.02, respectively). Waist circumference was significantly improved −3.1 cm (95% CI −10.3 to −1.2) with combined aerobic and resistance exercise, although fewer studies and more heterogeneity of the responses were observed in the latter two markers. Resistance exercise alone or combined with any other form of exercise was not found to have any significant effect on CV markers. CONCLUSIONS Aerobic exercise alone or combined with RT improves glycemic control, SBP, triglycerides, and waist circumference. The impact of resistance exercise alone on CV risk markers in type 2 diabetes remains unclear.

Can primary care doctors prescribe exercise to improve fitness?: The step test exercise prescription (STEP) project

BACKGROUND Sedentary lifestyle is associated with adverse health outcomes. Available evidence suggests that, despite positive attitudes toward regular exercise in promoting a healthy lifestyle, few physicians actually prescribe exercise for their patients. Barriers include lack of skills and standard office instruments. Because primary care physicians have regular contact with a large proportion of the population, the impact of preventive health interventions may be great. OBJECTIVES To determine the effect of an exercise prescription instrument (i.e., Step Test Exercise Prescription [STEP]), compared to usual-care exercise counseling delivered by primary care doctors on fitness and exercise self-efficacy among elderly community-dwelling patients. DESIGN Randomized controlled trial; baseline assessment and intervention delivery with postintervention follow-up at 3, 6, and 12 months. SETTING Four large (>5000 active patient files) academic, primary care practices: three in urban settings and one in a rural setting, each with four primary care physicians; two clinics provided the STEP intervention and two provided usual care control. PARTICIPANTS A total of 284 healthy community-dwelling patients (72 per clinic) aged >65 years were recruited in 1998-1999. INTERVENTION STEP included exercise counseling and prescription of an exercise training heart rate. MAIN OUTCOME MEASURES The primary outcome measure was aerobic fitness (VO(2max)). Secondary outcomes included predicted VO(2max) from the STEP test, exercise self-efficacy (ESE), and clinical anthropometric parameters. RESULTS A total of 241 subjects (131 intervention, 110 control) completed the trial. VO(2max) was significantly increased in the STEP intervention group (11%; 21.3 to 24ml/kg/min) compared to the control group (4%; 22 to 23ml/kg/min) over 6 months (p <0.001), and 14% (21.3 to 24.9ml/kg/min) and 3% (22.1 to 22.8ml/kg/min), respectively, at 12 months (p <0.001). A similar significant increase in ESE (32%; 4.6 vs 6.8) was observed for the STEP group compared to the control group (22%; 4.2 vs 5.4) at 12 months (p < 0.001). Systolic blood pressure decreased 7.3% and body mass index decreased 7.4% in the STEP group, with no significant change in the control group (p <0.05). Exercise counseling time was significantly (p <0.02) longer in the STEP (11.7+/-3.0 min) compared to the control group (7.1+/-7.0 min), but more (p <0.05) subjects completed > or =80% of available exercise opportunities in the STEP group. CONCLUSIONS Primary care physicians can improve fitness and exercise confidence of their elderly patients using a tailored exercise prescription (e.g., STEP). Further, STEP appears to maintain benefits to 12 months and may improve exercise adherence. Future study should determine the impact of combining cognitive/behavior change strategies with STEP.

Systematic Review of Hip Fracture Rehabilitation Practices in the Elderly

OBJECTIVE To address the need for a research synthesis on the effectiveness of the full range of hip fracture rehabilitation interventions for older adults and make evidence based conclusions. DATA SOURCES Medline, PubMed, EMBASE, CINAHL, and the Cochrane Central Register of Controlled Trials were searched from 1980 to 2007 for studies published in English. The terms rehabilitation and hip fracture were exploded in order to obtain related search terms and categories. STUDY SELECTION In the initial search of the databases, a combined total of 1031 articles was identified. Studies that did not focus on hip fracture rehabilitation, did not include persons over the age of 50 years, and/or did not include measures of physical outcome were excluded. DATA EXTRACTION Only studies with an Oxford Center for Evidence-Based Medicine Levels of Evidence level of I (randomized controlled trial, RCT) or II (cohort) were reviewed. The methodologic quality of both types of studies was assessed using a modified version of the Downs and Black checklist. DATA SYNTHESIS There were 55 studies that met our selection criteria: 30 RCTs and 25 nonrandomized trials. They were distributed across 6 categories for rehabilitation intervention (care pathways, early rehabilitation, interdisciplinary care, occupational and physical therapy, exercise, intervention not specified) and 3 settings (acute care hospital, postacute care/rehabilitation, postrehabilitation). CONCLUSIONS When looking across all of the intervention types, the most frequently reported positive outcomes were associated with measures of ambulatory ability. Eleven intervention categories across 3 settings were associated with improved ambulatory outcomes. Seven intervention approaches were related to improved functional recovery, while 6 intervention approaches were related to improved strength and balance recovery. Decreased length of stay and increased falls self-efficacy were associated with 2 interventions, while 1 intervention had a positive effect on lower-extremity power generation.

The 2006 Canadian Hypertension Education Program recommendations for the management of hypertension: Part II - Therapy

OBJECTIVE To provide updated, evidence-based recommendations for the management of hypertension in adults. OPTIONS AND OUTCOMES For lifestyle and pharmacological interventions, evidence from randomized, controlled trials and systematic reviews of trials was preferentially reviewed. Changes in cardiovascular morbidity and mortality were the primary outcomes of interest. For lifestyle interventions, blood pressure (BP) lowering was accepted as a primary outcome given the lack of long-term morbidity/mortality data in this field. For treatment of patients with kidney disease, the development of proteinuria or worsening of kidney function was also accepted as a clinically relevant primary outcome. EVIDENCE MEDLINE searches were conducted from November 2004 to October 2005 to update the 2005 recommendations. In addition, reference lists were scanned and experts were contacted to identify additional published studies. All relevant articles were reviewed and appraised independently by content and methodological experts using prespecified levels of evidence. RECOMMENDATIONS Lifestyle modifications to prevent and/or treat hypertension include the following: perform 30 min to 60 min of aerobic exercise four to seven days per week; maintain a healthy body weight (body mass index of 18.5 kg/m2 to 24.9 kg/m2) and waist circumference (less than 102 cm for men and less than 88 cm for women); limit alcohol consumption to no more than 14 standard drinks per week in men or nine standard drinks per week in women; follow a diet that is reduced in saturated fat and cholesterol and that emphasizes fruits, vegetables and low-fat dairy products; restrict salt intake; and consider stress management in selected individuals. Treatment thresholds and targets should take into account each individuals global atherosclerotic risk, target organ damage and comorbid conditions. BP should be lowered to less than 140/90 mmHg in all patients, and to less than 130/80 mmHg in those with diabetes mellitus or chronic kidney disease (regardless of the degree of proteinuria). Most adults with hypertension require more than one agent to achieve these target BPs. For adults without compelling indications for other agents, initial therapy should include thiazide diuretics. Other agents appropriate for first-line therapy for diastolic hypertension with or without systolic hypertension include beta-blockers (in those younger than 60 years), angiotensin-converting enzyme (ACE) inhibitors (in nonblack patients), long-acting calcium channel blockers or angiotensin receptor antagonists. Other agents for first-line therapy for isolated systolic hypertension include long-acting dihydropyridine calcium channel blockers or angiotensin receptor antagonists. Certain comorbid conditions provide compelling indications for first-line use of other agents: in patients with angina, recent myocardial infarction or heart failure, beta-blockers and ACE inhibitors are recommended as first-line therapy; in patients with diabetes mellitus, ACE inhibitors or angiotensin receptor antagonists (or in patients without albuminuria, thiazides or dihydropyridine calcium channel blockers) are appropriate first-line therapies; and in patients with nondiabetic chronic kidney disease, ACE inhibitors are recommended. All hypertensive patients should have their fasting lipids screened, and those with dyslipidemia should be treated using the thresholds, targets and agents recommended by the Canadian Hypertension Education Program Working Group on the management of dyslipidemia and the prevention of cardiovascular disease. Selected patients with hypertension, but without dyslipidemia, should also receive statin therapy and/or acetylsalicylic acid therapy. VALIDATION All recommendations were graded according to strength of the evidence and voted on by the 45 members of the Canadian Hypertension Education Program Evidence-Based Recommendations Task Force. All recommendations reported here achieved at least 95% consensus. These guidelines will continue to be updated annually.

Muscle fiber number in the biceps brachii muscle of young and old men

We have compared the number of muscle fibers in the biceps brachii muscle (BB) of six old men (82.3 ± 4.3 years) and six young men (21.2 ± 1.9 years). Muscle fiber number was estimated by dividing the maximal area of the BB, determined with magnetic resonance imaging, by the mean fiber area of the BB determined in a muscle biopsy. The percentage of type II fibers in the BB (∼60%) and the type I fiber area were not different between the groups. The BB area (−26%), type II fiber area (−24%), mean fiber area (−20%), and maximal voluntary contraction strength (MVC) of the elbow flexor muscles (−27%) were lower in the old than young group. However, the estimated number of muscle fibers was not significantly different between the young (253,000) and old (234,000) men. Consequently, the smaller BB area of the old men could be explained primarily by a smaller type II fiber size. These findings suggest that old age is not associated with a reduced number of muscle fibers in the BB. The relative contribution of a reduction in fiber number to age‐related muscle atrophy may be muscle‐dependent. Muscle Nerve 28: 62–68, 2003