[Prediction on the cardio-cerebrovascular death and probability of premature death caused by common risk factors in China in 2030].

Objective: Predictive models were used to evaluate the impact of common risk factors on the number of cardio-cerebrovascular deaths and the probability of premature death. Methods: Using the data for China estimated by the Global Burden of Disease study 2015 (GBD 2015), we calculated the population attribution fraction (PAF) of risk factors. The proportional change model was used to estimate the number of unattributable deaths by 2030, and to predict the number of deaths, mortality, standardized mortality and probability of premature death by 2030. Results: According to the natural change trend of risk factors from 1990 to 2015, the number of deaths and mortality would reach 6.12 million and 428.53/100 000 by 2030, with an increase of 59.92% and 52.87%. By 2030, the probability of premature death from cardio-cerebrovascular diseases among Chinese aged 30-70 years old would continue to decline, from 11.43% to 11.28% for men, and from 5.79% to 4.43% for women. If the goals of all included risk factors were reached by 2030, 2 289 200 cardio-cerebrovascular deaths would be avoided. If only the exposure to a single risk factor was achieved by 2030, blood pressure, total cholesterol, and fine particulate matter exposure were the three most important factors affecting cardio-cerebrovascular deaths, which would reduce 1 332 800, 609 100 and 306 800 deaths, respectively. Among the involved risk factors, the control of blood pressure would mostly decrease the number of deaths due to ischemic heart disease and hemorrhagic stroke, about 677 300 and 391 100 deaths, accordingly. Conclusion: The control of risk factors is of great significance in reducing deaths and probability of premature death due to cardio-cerebrovascular diseases. If the control targets of all risk factors could be achieved by 2030, the burden of cardio-cerebrovascular diseases would be reduced greatly.

[Feasibility and safety of minimally invasive cardiac coronary artery bypass grafting surgery for patients with multivessel coronary artery disease: Early outcome and short-mid-term follow up results].

OBJECTIVE: To explore the feasibility, safety and mid-term outcome of minimally invasive cardiac surgery coronary artery bypass grafting (MICS CABG) surgery. METHODS: Data of patients who underwent MICS CABG between November 2015 and November 2017 in Peking University Third Hospital were retrospectively analyzed. Results were compared with the patients who underwent off-pump coronary aortic bypass grafting (OPCABG) surgery over the same period. The two groups were matched in propensity score matching method according to age, gender, left ventricular ejection fraction, body mass index, severity of coronary artery disease, smoking, diabetes mellitus, hypertension, hyperlipidemia, renal insufficiency, history of cerebrovascular accident, and history of chronic obstructive pulmonary disease (COPD). RESULTS: There were 85 patients in MICS CABG group, including 68 males (80.0%) and 17 females (20%), with an average age of (63.8±8.7) years; 451 patients were enrolled in OPCABG group, and 85 patients were matched by propensity score as control group (OPCABG group). There was no significant difference in general clinical characteristics (P>0.05). The average grafts of MICS CABG and OPCABG were 2.35±0.83 and 2.48±0.72 respectively (P=0.284). No conversion to thoracotomy in MICS CABG group or cardiopulmonary bypass in neither group occurred. There was no significant difference in the major adverse cardiovascular events (MACCEs, 1.17% vs. 3.52%), reoperation (2.34 vs. 3.52%), new-onset atrial fibrillation rate (4.70% vs. 3.52%) or new-onset renal insufficiency rate (1.17% vs. 0%) between MICS CABG group and OPCABG group (P>0.05). The operation time in MICS CABG group was longer than that in OPCABG group [(282.8±55.8) min vs. (246.8±56.9) min, P < 0.05], while the time of ventilator supporting(16.9 h vs. 29.6 h), hospitalization in ICU [(29.3±20.8) h vs. (51.5±48.3) h] and total hospitalization [(18.3±3.2) d vs. (25.7±4.2) d] in MICS CABG group were shorter than those in OPCABG group (P < 0.05). The total patency rate (A+B levels) of MICS CABG was 96.5% after surgery. There was no significant difference in MACCEs rate between the two groups [1.18%(1/85) vs. 3.61%(3/83), P>0.05] in 1-year follow up. CONCLUSION: The MICS CABG surgery is a safe and feasible procedure with good clinical results in early and mid-term follow-up.

[Clinical experience of minimal invasive coronary surgery-coronary artery bypass grafting: a series of 244 cases].

Objective: To examine the safety and efficacy of minimally invasive coronary surgery-coronary artery bypass grafting (MICS-CABG). Methods: From the first case in November 2015 to November 2019, a total of 244 cases of MICS-CABG were performed in Department of Cardiovascular Surgery, Peking University Third Hospital. There were 197 males and 47 females, aging (62.3±8.7)years (range: 36 to 88 years). The operations were performed via the 5(th) intercostal space of left thoracic lateral incision (length: 4 to 5 cm extended for 8 to 10 cm), and were performed under off-pump, with the help of the chest wall suspension device and cardiac fixator. The proximal anastomosis on ascending aorta and the distal anastomosis of left anterior descending branch, circumflex branch and right coronary system were completed according to procedure. In all 244 cases, the proportion of 2 grafts was 53.7% (131 cases), 3 grafts was 36.1% (88 cases), 4 grafts was 9.8% (24 cases) and 5 grafts was 0.4% (1 case). The average of grafts was 2.6±0.7 (range: 2 to 5). The proportion of hybrid was 14.3% (35 cases), sequential bypass procedure was 43.0% (105 cases) and multiple artery grafts was 25.4% (62 cases). The perioperative complications of the patients were collected, the patency rate of the grafts was evaluated by coronary angiography or CT within 7 days after the operation, and main adverse cardiovascular and cerebrovascular events (MACCE) were followed up. The survival curve was drawn by Kaplan-Meier method, and the 1-year MACCE rate was calculated by survival analysis. Results: All cases had no transition to thoracotomy and cardiopulmonary bypass procedure, and no cases needed intra aortic balloon pumping and extracorporeal membrane oxygenation during the operation.There were 2 cases of poor incision healing, and reoperation was performed in 10 cases (6 cases of postoperative bleeding, 2 cases of incision debridement, and 2 cases of grafts problems). The rate of MACCE in 30 days was 2.6% (10 cases), which contained 3 cases of death (2 cases of grafts occlusion, 1 case of serious hemorrhage after thoracic puncture drainage), 3 cases of stroke and 5 cases of non-fatal myocardial infarction. By the re-examination of angiography in 7 days after operation, the overall patency of the grafts was 96.1%, and the patency of the left anterior descending was 98.6%. Kaplan-Meier survival analysis was conducted for 235 patients (96.3%) with 1 to 36 months follow-up results, and the 1-year MACCE rate was 5.6% (95%CI: 4.2% to 7.0%) . There was no significant difference among the incidences of MACCE at each stage of learning curve. Surgeon could reduce the operation time and complete more anastomosis with the accumulation of experience after the early 30 cases. Conclusions: MICS-CABG can safely achieve completed revascularization, which has good operative effects in short and medium-long term. There is no significant risk in the early cases of learning curve.

[Early clinical outcomes of minimally invasive coronary surgery-total arterial coronary revascularization].

Objective: To summarize the early experience and clinical value of minimally invasive coronary surgery-total arterial coronary revascularization (MICS-TACR) through the left anterior small incision. Methods: Between May 2015 and June 2018, a total of 31 consecutive cases [21 males and 10 females, aged (63.2±9.3) years] in Peking University Third Hospital who were performed MICS-TACR with bilateral internal mammary artery and radial artery were enrolled. Meanwhile, 1 489 cases of conventional median sternal incision off-pump coronary artery bypass grafting (OPCABG) were matched as control group. According to exclusion criteria and matching score, 90 cases [55 males and 35 females, aged (63.8±9.5) years] were selected as the control group, and the perioperative data of the two groups were compared. All patients in MICS-TACR group underwent postoperative angiography and the graft patency was evaluated. Results: There were no statistically significant differences in baseline data between the two groups. The perioperative blood transfusion of MICS-TACR group was less than control group [0(0,0) U vs 0(0,4) U, P=0.003]. There were no statistically significant differences in operative mortality, intraoperative and postoperative intra-aortic balloon pump (IABP) and extracorporeal membrane oxygenation (ECMO) use, re-operation rate, perioperative major adverse cardiac and cerebrovascular events (MACCE), new-onset renal failure, atrial fibrillation, and multiple organ failure between the two groups. Postoperative angiography showed that there was no significant difference in the patency rate between the MICS-TACR group and control group(all P>0.05). Conclusion: Total arterial coronary revascularization can be successfully accomplished under the left anterior small incision, and the early clinical outcome is satisfied.

[Progress in cohort studies related to injury].

Objective: To summarize the progress of injury cohort studies over the world. Methods: Relevant information of injury cohort publications published before December 2017 were retrieved from PubMed, WanFang and China National Knowledge Infrastructure (CNKI) databases, consisting of the starting year, category of injury, study population, sample size, countries, follow-up duration, main exposure variables, outcome variables and method of data collection, and statistical methods. Results: A total of 295 studies were included in the analysis. The overall number of injury cohort studies increased with a peak in 2000, and then decreased. The top three countries that most frequently published cohort studies were the United States (52), Sweden (46) and the United Kingdom (37). A total of 29 published injury cohorts were identified in China, about 3, 23 and 3 cohort studies from the mainland of China, Taiwan Province, and Hong Kong Specific Administrative Region, respectively. The majority of cohort studies involved a single injury cause (93.6%); the most common injury causes included suicide/self-harm (46.1%), falls (17.3%) and road traffic injuries (14.6%). For the published cohort studies, exposure variables and outcome events varied with injury causes, primarily being collected through data registration system, national survey data, questionnaire survey, telephone interviews, and other means. Conclusion: A number of injury cohorts have been established worldwide, and few in the mainland of China. The existed cohort studies could offer important references for the design of large-scale, multi-center and high-quality injury cohort in China in the future.

Topical application of epidermal growth factor with no scaffold material on the healing of human traumatic tympanic membrane perforations.

OBJECTIVE: We evaluated the effects of conservative treatment and topical application of epidermal growth factor (EGF) with no scaffold material on the healing of human traumatic tympanic membrane perforations (TMPs). STUDY DESIGN: Prospective, randomised clinical trial. METHODS: A prospective analysis was performed between January 2015 and March 2015 for the treatment of human traumatic TMPs. The closure rate, closure time, hearing gain and rate of purulent otorrhoea were compared between the topical application of EGF and conservative treatment. RESULT: In total, 97 patients were analysed. The total closure rates did not significantly differ between the observation and EGF groups (83.0% versus 92.0%, P = 0.182). The total average closure time in the observation group was significantly longer than in the EGF group (25.1 ± 10.5 versus 11.7 ± 5.2 days, P = 0.001). When the closure rate was evaluated according to perforation size, no significant difference was seen for medium or large perforations (P = 0.18 and 0.21, respectively). When closure time was evaluated according to perforation size, a significant difference was seen for medium and large perforations (P = 0.001). CONCLUSIONS: This study suggests that topical application of EGF with no scaffold material may significantly shorten the closure time of human traumatic TMPs. Such a shorter recovery time may lead to reduced healthcare costs. This alternative technique to a classic myringoplasty is particularly beneficial and suitable for the closure of large human traumatic TMPs.

Changes in the expression of Fox O1 and death ligand genes during follicular atresia in porcine ovary.

Follicular atresia, a key phenomenon in follicle development, eliminates most of the follicles in mammalian ovaries. To investigate the molecular mechanism of follicular atresia in porcine ovaries, we investigated the mRNA expression of three important cell death ligand-receptor systems and Fox O1 in follicles with a diameter of 3-5 mm. The phosphorylation and subcellular localization of Fox O1 during granulosa cell apoptosis was also determined. TRAIL and Fas L played an important role in follicular atresia at this stage. Fox O1 expression was upregulated during atresia, and was confined to the nucleus of granulosa cells; however, phosphorylated Fox O1 was localized to the cytoplasm. These results suggest Fox O1 involvement in the regulation of TRAIL and Fas L expression during follicular atresia in pigs.

[Forecasting the burden of disease from diabetes under the scenarios of specific risk factors control in China in 2030].

Objective: To forecast mortality, age-standardized mortality, and probability of premature mortality from diabetes, and to simulate the impact of controlling risk factors by 2030 in China. Methods: We simulated the burden of disease from diabetes in six scenarios according to the development goals of risk factors control by the WHO and Chinese government. Based on the theory of comparative risk assessment and the estimates of the burden of disease for China from the Global Burden of Disease Study 2015, we used the proportional change model to project the number of deaths, age-standardized mortality, and probability of premature mortality from diabetes under different scenarios of risk factors control in 2030. Results: If the trends in exposures to risk factors from 1990 to 2015 continued. Mortality, age-standardized mortality, and probability of premature mortality from diabetes would increase to 32.57/100 000, 17.32/100 000, and 0.84% by 2030, respectively. During that time, mortality, age-standardized mortality and probability of premature mortality for males would all be higher than for females. If the goals of controlling risk factors were all achieved, the number of deaths from diabetes in 2030 would decrease by 62.10% compared to the predicted numbers based on the historical trends in exposure to risk factors, and the probability of premature mortality would drop to 0.29%. If only the exposure to a single risk factor were achieved by 2030, high fasting plasma glucose control would have the greatest impact on diabetes, resulting in a 56.00% reduction in deaths compared to the predicted numbers based on the historical trends, followed by high BMI (4.92%), smoking (0.65%), and low physical activity (0.53%). Conclusions: Risk factors control plays an important role in reducing the number of deaths, age-standardized mortality rate, and probability of premature mortality from diabetes. We suggest taking comprehensive measures to control relevant risk factors for certain populations and regions, to achieve the goal of reducing the burden of disease from diabetes as expected.

Predictive model for deep venous thrombosis caused by closed lower limb fracture after thromboprophylactic treatment.

OBJECTIVE: Currently, there are still no convincing clinical models predicting closed lower extremity fracture-associated deep vein thrombosis in patients treated through thromboprophylactic methods. We aimed at using two retrospective cohorts to develop and externally verify a clinical prediction model for deep vein thrombosis in patients treated with anticoagulants after suffering closed lower extremity fractures. PATIENTS AND METHODS: We evaluated the patients' pre- and post-operatively, to accurately determine the predictive power of the biomarkers and clinical risk factors. Two retrospective cohorts were used for the development and external verification of a pre-operative clinical prediction model (development: n = 2,253; verification: n = 833) and post-operative clinical prediction model (development: n = 1,422; verification: n = 449), respectively. RESULTS: The C-indices were used to show the predicted incidence of objective thrombosis at the pre- and post-operative stage, which were then compared with the observed incidence of thrombosis in both cohorts. Biomarkers and clinical indicators were included in pre- and post-operative nomograms, which were adequately calibrated in both cohorts. The cross-validated C-indices of the pre- and post-operative clinical prediction models in the verification cohort were 0.706 (95% Cl, 0.67-0.74) and 0.875 (95% Cl, 0.84-0.91), respectively. CONCLUSIONS: We present our findings of novel pre- and post-operative nomograms for the prediction of deep venous thrombosis in patients who received thromboprophylaxis after suffering closed lower extremity fractures.

[Prediction on the burden of disease of chronic obstructive pulmonary disease and simulation of the effectiveness of controlling risk factors in China by 2030].

Objective: To forecast the burden of chronic obstructive pulmonary disease (COPD) in China by 2030 and evaluate the effectiveness of controlling risk factors based on the predictive model. Methods: Based on the relationship between the death of COPD and exposure to risk factors and the theory of comparative risk assessment, we used the estimates of the Global Burden of Disease Study 2015 (GBD2015) for China, targets for controlling risk factors, and proportion change model to project the number of deaths, standardized mortality rate, and probability of premature mortality from chronic respiratory diseases by 2030 in different scenarios and to evaluate the impact of controlling the included risk factors to the disease burden of COPD in 2030. Results: If the trends in exposure to risk factors from 1990 to 2015 continued, the number of deaths and the mortality for COPD would be 1.06 million and 73.85 per 100 000 population in China by 2030, respectively, with an increase of 15.81% and 10.69% compared to those in 2015. Compared to 2015, the age-standardized mortality rate would decrease by 38.88%, and the premature mortality would reduce by 52.73% by 2030. If the smoking rate and fine particulate matter (PM2.5) concentration separately achieve their control targets by 2030, there would be 0.34 and 0.27 million deaths that could be avoided compared to the predicted numbers based on the natural trends in exposure to risk factors and the probability of premature death would reduce to 0.59% and 0.52%, respectively. If the control targets of all included risk factors were achieved by 2030, a total of 0.53 million deaths would be averted, and the probability of premature death would decrease to 0.44%. Conclusions: If the exposures to risk factors continued as showed from 1990 to 2015, the number of deaths and mortality for COPD would increase by 2030 compared to 2015, and the standardized mortality and the probability of premature death would decrease significantly, which would achieve the targets of preventing and controlling COPD. If the exposure to the included risk factors all achieved the targets by 2030, the burden of COPD would be reduced, suggesting that the control of tobacco use and air pollution should be enhanced to prevent and control COPD.

[Prediction of disease burden caused by malignant cancer in the context of risk factor control in China, 2030].

Objective: To predict the number of deaths, standardized mortality and probability of premature mortality caused by malignant cancer in the context of risk factor control at different levels in China in 2030, and assess the possibility of achieving the target of reducing the probability of premature mortality of malignant cancer. Methods: According to the risk factor control standard for malignant cancer used both at home and abroad, the results of China from Global Burden of Disease Study 2015 were used to calculate the population attributable fraction of the risk factors. Based on the comparative risk assessment theory, the deaths of malignant cancer were classified as attributable deaths and un-attributable deaths. Proportional change model was used to predict risk factor exposure and un-attributable deaths of malignant cancer in the future, then the number of deaths, standardized mortality rate and probability of premature mortality of malignant cancer in 2030 was estimated. Data analyses were performed by using software R 3.6.1. Results: If the risk factor exposure level during 1990-2015 remains, the number of deaths, standardized mortality rate, and probability of premature mortality of malignant cancer would increase to 3.62 million, 153.96/100 000 and 8.92% by 2030, respectively. If the risk factor exposure control level meets the requirement, the probability of premature mortality from cancer in people aged 30-70 years would drop to 7.57% by 2030. Conclusions: The control of risk factor exposure will play an important role in reducing deaths, standardized mortality rate and probability of premature mortality of malignant cancer. But more efforts are needed to achieve the goals of Health China Action.

Pure angular momentum generator using a ring resonator.

This paper reports a pure angular momentum generator using a ring resonator surrounded by a group of nano-rods. The evanescent waves of the circulating light in the ring are scattered by the nano-rods and generate a rotating electromagnetic field, which has only angular momentum but no linear momentum along the axis of rotation. The angular order is determined by the difference between the order of Whispering Gallery mode and the number of the rods, the rotating frequency is equal to the light frequency divided by the angular order. The maximum amplitude of the rotating electromagnetic fields can be 10 times higher than the amplitude of the input field when there are 36 rods (R(rod) = 120 nm, nr = 1.6). The pure angular momentum generator provides a new platform for trapping and rotation of small particles.

Sumatriptan alleviates nitroglycerin-induced mechanical and thermal allodynia in mice.

The association between the clinical use of nitroglycerin (NTG) and headache has led to the examination of NTG as a model trigger for migraine and related headache disorders, both in humans and laboratory animals. In this study in mice, we hypothesized that NTG could trigger behavioural and physiological responses that resemble a common manifestation of migraine in humans. We report that animals exhibit a dose-dependent and prolonged NTG-induced thermal and mechanical allodynia, starting 30-60 min after intraperitoneal injection of NTG at 5-10 mg/kg. NTG administration also induced Fos expression, an anatomical marker of neuronal activity in neurons of the trigeminal nucleus caudalis and cervical spinal cord dorsal horn, suggesting that enhanced nociceptive processing within the spinal cord contributes to the increased nociceptive behaviour. Moreover, sumatriptan, a drug with relative specificity for migraine, alleviated the NTG-induced allodynia. We also tested whether NTG reduces the threshold for cortical spreading depression (CSD), an event considered to be the physiological substrate of the migraine aura. We found that the threshold of CSD was unaffected by NTG, suggesting that NTG stimulates migraine mechanisms that are independent of the regulation of cortical excitability.

Comparison of approaches for efficient gene silencing induced by microRNA-based short hairpin RNA and indicator gene expression.

MicroRNA-based short hairpin RNAs (shRNAs) are natural inducers of RNA interference and have been increasingly used in shRNA expression strategies. In the present study, we compared the efficiencies of exogenous green fluorescence protein (GFP) and endogenous glyceraldehyde-3-phosphate dehydrogenase (GAPDH) knockdown and red fluorescent protein (RFP) indicator expression mediated by three differently designed plasmids. RFP was introduced either at the 5' end, at the 3' end of the human mir155-based target gene (TG) (e.g., GFP or GAPDH) shRNA expression cassette (EC), or at the 3' end of the chimeric intron-containing TG shRNA EC. Comparisons with the control vector showed an obvious reduction of GFP or GAPDH expression with the various shRNA expression plasmids (P < 0.05). When RFP was located at the 5' end or at the 3' end of the TG shRNA EC, RFP expression was low; whereas when RFP was connected with the chimeric intron-containing TG shRNA EC, RFP expression was high. Taken together, this study demonstrated an efficient plasmid design for both TG silencing induced by microRNA-based shRNA and indicator gene expression in vitro.

[Evidence summary for postoperative hypothermia rewarming in adults with severe burns].

Objective: To retrieve, evaluate, and summarize the best evidence for postoperative hypothermia rewarming in adults with severe burns. Methods: Foreign language databases including Cochrane Library, Joanna Briggs Institute Evidence-Based Health Care Center Database, PubMed, Ovid-Medline, BMJ Best Practice, and Web of Science were retrieved with the search terms of " severe burn/major burn/severe degree burn" , " hypothermia/warming intervention/hypothermia/temperature/body temperature change" , and " postoperative /perioperative/peri-operative/post-operative" and Chinese databases including Chinese Journal Full-Text Database, Wanfang Database, and VIP Database were retrieved with the search terms of "//" , "/" , and "" to obtain all the publicly published evidence for postoperative hypothermia rewarming in adults with severe burns from the establishment of each database to April 2018, including systematic evaluations, guidelines, expert consensus, evidence summary, and original research closely related to the evidence. The literatures were screened and evaluated for their quality, the evidences were extracted from them, evaluated, classified in order to summarize the best evidences. Results: A total of 8 literatures were included, including one systematic evaluation, three guidelines, one expert consensus, and three evidence summaries. Finally, the best evidences in 8 aspects including the body temperature monitoring site, body temperature monitoring frequency, surface heating, in vivo heating, rewarming start, multi-strategy rewarming, equipment, and personnel training were summarized. Conclusions: Based in the evidence-based nursing method, this study retrieves and evaluates the literature, summarizes the evidence analysis and evaluation, and obtains the best evidences of postoperative hypothermia rewarming in adult patients with severe burns, which provides a strong reference for the clinical implementation of rewarming.

Triplet repeat mutations in human disease.

Triplet repeats are the sites of mutation in three human heritable disorders, spinal and bulbar muscular atrophy (SBMA), fragile X syndrome, and myotonic dystrophy (DM). These repeats are GC-rich and highly polymorphic in the normal population. Fragile X syndrome and DM are examples of diseases in which premutation alleles cause little or no disease in the individual, but give rise to significantly amplified repeats in affected progeny. This newly identified mechanism of mutation has, so far, been identified in two of the most common heritable disorders, fragile X syndrome and DM, and one rare disease, SBMA.

An unstable triplet repeat in a gene related to myotonic muscular dystrophy.

Synthetic oligonucleotides containing GC-rich triplet sequences were used in a scanning strategy to identify unstable genetic sequences at the myotonic dystrophy (DM) locus. A highly polymorphic GCT repeat was identified and found to be unstable, with an increased number of repeats occurring in DM patients. In the case of severe congenital DM, the paternal triplet allele was inherited unaltered while the maternal, DM-associated allele was unstable. These studies suggest that the mutational mechanism leading to DM is triplet amplification, similar to that occurring in the fragile X syndrome. The triplet repeat sequence is within a gene (to be referred to as myotonin-protein kinase), which has a sequence similar to protein kinases.

An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome.

Familial advanced sleep phase syndrome (FASPS) is an autosomal dominant circadian rhythm variant; affected individuals are "morning larks" with a 4-hour advance of the sleep, temperature, and melatonin rhythms. Here we report localization of the FASPS gene near the telomere of chromosome 2q. A strong candidate gene (hPer2), a human homolog of the period gene in Drosophila, maps to the same locus. Affected individuals have a serine to glycine mutation within the casein kinase Iepsilon (CKIepsilon) binding region of hPER2, which causes hypophosphorylation by CKIepsilon in vitro. Thus, a variant in human sleep behavior can be attributed to a missense mutation in a clock component, hPER2, which alters the circadian period.