Teaching practice recommendations: prevention and screening

The aim of this article is to provide guidance to family doctors on how to tutor students about effective screening and primary prevention. Family doctors know their patients and adapt national and international guidelines to their specific context, risk profile, sex and age as well as to the prevalence of the disorders under consideration. Three cases are presented to illustrate guideline use according to the level of evidence (for a 19-year-old man, a 60-year-old woman, and an 80-year-old man). A particular strength of family medicine is that doctors see their patients over the years. Thus they can progressively go through the various prevention strategies, screening, counselling and immunisation, accompanying their patients with precious advice for their health throughout their lifetime.

Low statin use in adults hospitalized with acute coronary syndrome.

OBJECTIVE To assess recommended and actual use of statins in primary prevention of cardiovascular disease (CVD) based on clinical prediction scores in adults who develop their first acute coronary syndrome (ACS). METHOD Cross-sectional study of 3172 adults without previous CVD hospitalized with ACS at 4 university centers in Switzerland. The number of participants eligible for statins before hospitalization was estimated based on the European Society of Cardiology (ESC) guidelines and compared to the observed number of participants on statins at hospital entry. RESULTS Overall, 1171 (37%) participants were classified as high-risk (10-year risk of cardiovascular mortality ≥5% or diabetes); 1025 (32%) as intermediate risk (10-year risk <5% but ≥1%); and 976 (31%) as low risk (10-year risk <1%). Before hospitalization, 516 (16%) were on statins; among high-risk participants, only 236 of 1171 (20%) were on statins. If ESC primary prevention guidelines had been fully implemented, an additional 845 high-risk adults (27% of the whole sample) would have been eligible for statins before hospitalization. CONCLUSION Although statins are recommended for primary prevention in high-risk adults, only one-fifth of them are on statins when hospitalized for a first ACS.

Prophylactic antibiotics or G(M)-CSF for the prevention of infections and improvement of survival in cancer patients receiving myelotoxic chemotherapy.

BACKGROUND Febrile neutropenia (FN) and other infectious complications are some of the most serious treatment-related toxicities of chemotherapy for cancer, with a mortality rate of 2% to 21%. The two main types of prophylactic regimens are granulocyte (macrophage) colony-stimulating factors (G(M)-CSF) and antibiotics, frequently quinolones or cotrimoxazole. Current guidelines recommend the use of colony-stimulating factors when the risk of febrile neutropenia is above 20%, but they do not mention the use of antibiotics. However, both regimens have been shown to reduce the incidence of infections. Since no systematic review has compared the two regimens, a systematic review was undertaken. OBJECTIVES To compare the efficacy and safety of G(M)-CSF compared to antibiotics in cancer patients receiving myelotoxic chemotherapy. SEARCH METHODS We searched The Cochrane Library, MEDLINE, EMBASE, databases of ongoing trials, and conference proceedings of the American Society of Clinical Oncology and the American Society of Hematology (1980 to December 2015). We planned to include both full-text and abstract publications. Two review authors independently screened search results. SELECTION CRITERIA We included randomised controlled trials (RCTs) comparing prophylaxis with G(M)-CSF versus antibiotics for the prevention of infection in cancer patients of all ages receiving chemotherapy. All study arms had to receive identical chemotherapy regimes and other supportive care. We included full-text, abstracts, and unpublished data if sufficient information on study design, participant characteristics, interventions and outcomes was available. We excluded cross-over trials, quasi-randomised trials and post-hoc retrospective trials. DATA COLLECTION AND ANALYSIS Two review authors independently screened the results of the search strategies, extracted data, assessed risk of bias, and analysed data according to standard Cochrane methods. We did final interpretation together with an experienced clinician. MAIN RESULTS In this updated review, we included no new randomised controlled trials. We included two trials in the review, one with 40 breast cancer patients receiving high-dose chemotherapy and G-CSF compared to antibiotics, a second one evaluating 155 patients with small-cell lung cancer receiving GM-CSF or antibiotics.We judge the overall risk of bias as high in the G-CSF trial, as neither patients nor physicians were blinded and not all included patients were analysed as randomised (7 out of 40 patients). We considered the overall risk of bias in the GM-CSF to be moderate, because of the risk of performance bias (neither patients nor personnel were blinded), but low risk of selection and attrition bias.For the trial comparing G-CSF to antibiotics, all cause mortality was not reported. There was no evidence of a difference for infection-related mortality, with zero events in each arm. Microbiologically or clinically documented infections, severe infections, quality of life, and adverse events were not reported. There was no evidence of a difference in frequency of febrile neutropenia (risk ratio (RR) 1.22; 95% confidence interval (CI) 0.53 to 2.84). The quality of the evidence for the two reported outcomes, infection-related mortality and frequency of febrile neutropenia, was very low, due to the low number of patients evaluated (high imprecision) and the high risk of bias.There was no evidence of a difference in terms of median survival time in the trial comparing GM-CSF and antibiotics. Two-year survival times were 6% (0 to 12%) in both arms (high imprecision, low quality of evidence). There were four toxic deaths in the GM-CSF arm and three in the antibiotics arm (3.8%), without evidence of a difference (RR 1.32; 95% CI 0.30 to 5.69; P = 0.71; low quality of evidence). There were 28% grade III or IV infections in the GM-CSF arm and 18% in the antibiotics arm, without any evidence of a difference (RR 1.55; 95% CI 0.86 to 2.80; P = 0.15, low quality of evidence). There were 5 episodes out of 360 cycles of grade IV infections in the GM-CSF arm and 3 episodes out of 334 cycles in the cotrimoxazole arm (0.8%), with no evidence of a difference (RR 1.55; 95% CI 0.37 to 6.42; P = 0.55; low quality of evidence). There was no significant difference between the two arms for non-haematological toxicities like diarrhoea, stomatitis, infections, neurologic, respiratory, or cardiac adverse events. Grade III and IV thrombopenia occurred significantly more frequently in the GM-CSF arm (60.8%) compared to the antibiotics arm (28.9%); (RR 2.10; 95% CI 1.41 to 3.12; P = 0.0002; low quality of evidence). Neither infection-related mortality, incidence of febrile neutropenia, nor quality of life were reported in this trial. AUTHORS' CONCLUSIONS As we only found two small trials with 195 patients altogether, no conclusion for clinical practice is possible. More trials are necessary to assess the benefits and harms of G(M)-CSF compared to antibiotics for infection prevention in cancer patients receiving chemotherapy.

A critical evaluation of the clinical evidence for pomegranate preparations in the prevention and treatment of cardiovascular diseases

This study attempts a critical evaluation of the clinical evidence behind the use of dietary pomegranate preparations in the prevention and treatment of cardiovascular diseases. A search of PubMed on August 10, 2014 identified 228 references, which yielded extractable data from 24 clinical studies of pomegranate preparations. Hand searching identified two further studies. The quality of the studies and evidence of effectiveness of pomegranate were assessed by an established set of conventional criteria. Overall, the study quality was poor. Even in the best studies, indications of benefit did not reach the conventional levels of statistical significance. The only study with a definitive design had a biochemical rather than a clinical endpoint: it showed the expected difference in blood concentrations of myeloperoxidase after a single dose of either pomegranate or placebo. Only 10 of the 26 studies provided HPLC data on the amounts of co-active ingredients in the preparations that were consumed by the subjects. If pomegranate has a role in the prevention and treatment of cardiovascular diseases, there is a pressing need for dose-finding and long-term confirmatory studies. The ultimate endpoint for definitive studies would be mortality, but reductions in blood pressure or demonstrable decreases in atherosclerotic plaques would be useful surrogates. Sample sizes for various assumptions are provided. Future studies need to prove the clinical benefit.

Cohort Study on the Association Between Helmet Use and Traumatic Brain Injury in Snowboarders From a Swiss Tertiary Trauma Center.

BACKGROUND Since the introduction of helmets in winter sports there is on-going debate on whether they decrease traumatic brain injuries (TBI). METHODS This cohort study included 117 adult (≥ 16 years) snowboarders with TBI admitted to a level I alpine trauma center in Switzerland between 2000/2001 and 2010/2011. The primary objective was to examine the association between helmet use and moderate-to-severe TBI. Secondary objectives were to describe the epidemiology of TBI during the past decade in relation to increased helmet use. RESULTS Of 691 injured snowboarders evaluated, 117 (17%) suffered TBI. Sixty-six percent were men (median age, 23 years). Two percent of accidents were fatal. Ninety-two percent of patients sustained minor, 1% moderate, and 7% severe TBI according to the Glasgow coma scale. Pathologic computed tomography findings were present in 16% of patients, 26% of which required surgery. Eighty-three percent of TBIs occurred while riding on-slope. There was no trend in the TBI rate during the studied period, although helmet use increased from 10% to 69%. Comparing patients with and without a helmet showed no significant difference in odds ratios for the severity of TBI. However, of the 5 patients requiring surgery only 1 was wearing a helmet. Off-piste compared with on-slope snowboarders showed an odds ratio of 26.5 (P = 0.003) for sustaining a moderate-to-severe TBI. CONCLUSIONS Despite increased helmet use we found no decrease in TBI among snowboarders. The possibility of TBI despite helmet use and the dangers of riding off-piste should be a focus of future prevention programs.

Prevention of ischemic complications during aneurysm surgery

Ischemic complications during aneurysm surgery are a frequent cause of postoperative infarctions and new neurological deficits. In this article, we discuss imaging and neurophysiological tools that may help the surgeon to detect intraoperative ischemia. The strength of intraoperative digital subtraction angiography (DSA) is the full view of the arterial and venous vessel. DSA is the gold standard in complex and giant aneurysms, but due to certain disadvantages, it cannot be considered standard of care. Microvascular Doppler sonography is probably the fastest diagnostic tool and can quickly aid diagnosis of large vessel occlusions. Intraoperative indocyanine green videoangiography is the best tool to assess flow in perforating and larger arteries, as well as occlusion of the aneurysm sac. Intraoperative neurophysiological monitoring with somatosensory and motor evoked potentials indirectly measures blood flow by recording neuronal function. It covers all causes of intraoperative ischemia, provided that ischemia occurs in the brain areas under surveillance. However, every method has advantages and disadvantages. No single method is superior to the others in every aspect. Therefore, it is very important for the neurosurgeon to know the strengths and weaknesses of each tool in order to have them available, to know how to use them for each individual situation, and to be ready to apply them within the time window for reversible cerebral ischemia.

Clinical Practice Recommendations For The Management And Prevention Of Cisplatin-Induced Hearing Loss Using Pharmacogenetic Markers

Currently no pharmacogenomics-based criteria exist to guide clinicians in identifying individuals who are at risk of hearing loss from cisplatin-based chemotherapy. This review summarizes findings from pharmacogenomic studies that report genetic polymorphisms associated with cisplatin-induced hearing loss and aims to (1) provide up-to-date information on new developments in the field; (2) provide recommendations for the use of pharmacogenetic testing in the prevention, assessment and management of cisplatin-induced hearing loss in children and adults; and (3) identify knowledge gaps to direct and prioritize future research. These practice recommendations for pharmacogenetic testing in the context of cisplatin-induced hearing loss reflect a review and evaluation of recent literature and are designed to assist clinicians in providing optimal clinical care for patients receiving cisplatin based chemotherapy.

Childhood sexual victimization: Risk factor for drug use and sexual risk behaviors

The purpose of this dissertation was to survey men in the Harris County Jail (HCJ) to establish a more valid estimate of childhood sexual abuse (CSA) prevalence in a jailed-based population; to assess whether inmates with a history of CSA were at greater risk for use of drugs and alcohol and engaging in high-risk sexual behaviors than those without histories of childhood sexual abuse. ^ The first study determined the prevalence of childhood sexual abuse among incarcerated males in a county jail. In this study, sixty-three percent of the subjects reported having been sexually abused. Sixty-one percent reported abuse pre-puberty and 10% reported abuse post puberty. In pre-puberty abuse the initiation of first abuse occurred at a mean age of 5.6 years (SD 5.096, range: 2–13 years). ^ The second study explored the association between inmates with histories of CSA as a risk factor for sexual risk behaviors. A history of sexual abuse did not appear to be associated with an elevated risk of sexual risk behaviors. ^ The third study explored a history of drug use and a history of CSA among the inmates. A chi-square test showed that the inmates who reported a history of CSA, was significantly greater for the following drugs: Marijuana (02), Crack (03), Heroin/Morphine (.03), Amphetamines/Speed (01), Downers/Barbiturates (.001), Methamphetamine/Crystal Meth (.001), Valium .02), LSD/Acid (.001), and Inhalants (.001), p < .05). Significance was not found in alcohol, tobacco, cocaine, Quaaludes and methadone. ^ The research from this study provides empirical data supporting previous research. The current data shows that incarcerated inmates have a high prevalence of childhood sexual abuse and drug use. Sexual victimization as a child does not appear to be associated with an elevated risk of unsafe sexual behaviors. However, men who used drugs were twice as likely to have engaged in unprotected sex with casual and regular partners, and rarely used condoms with paid sex. Although our study methods do not permit a causal explanation for this association, we believe it is of concern. Finally, data in this study shows that sexually abused children are likely candidates for adult criminal behavior. ^

Social and behavioral determinants of consistent condom use among female commercial sex workers (FCSWs) in Ghana

This study aims at investigating the social and behavioral predictors of consistent condom use among female commercial sex workers (FCSWs) in Ghana. Street commercial sex workers were interviewed in Accra, Kumasi and Techiman. Whereas respondents had attained certain accurate knowledge about HIV transmission routes, misconceptions were still commonly reported. The level of condom education was very low (14%), however consistent condom use (all the time) with clients was relatively high (49.6%), 38.89% reported using condom sometimes and 11.56% reported never using condoms. ^ 277 of the respondent ants did not use condoms all the time. 163 of them reported not using condoms due to refusal by their clients, the remaining 64 respondents did not even request their clients to use condom due to cultural perception of power, lack of authority and the fear of loosing clients. ^ Significant predictive factors associated with consistency of condom use among FCSWs in a multivariate analysis were; age, level of education, religion, and number of customers. Some of the major obstacles to condom use by the FCSWs were refusal by clients, availability of free condoms, trying to communicate trust to their clients, and the lack of empowerment to negotiate safer sex with clients. Some of the respondents may have developed a false sense of safety by subjectively assessing whether their clients were well and do not look sick, but they were unaware that HIV carriers may show no obvious symptoms of illness at all. ^ In summary, this study points to an urgent need for reestablishing effective prevention intervention and some insights of what is required of such program in Ghana. ^

Internet use, exposure to Internet pornography, and sexual behavior among middle school youth

The purpose of this study is to examine associations between adolescents’ Internet use, exposure to pornography online, and sexual behavior. This cross-sectional study examines data collected from an HIV, sexually transmitted infection, and pregnancy prevention program being evaluated in inner-city middle schools. Chi-squares were used to examine differences in Internet use and exposure to Internet pornography by gender, race/ethnicity, and sexual behavior. Univariate and multivariate logistic regression were used to examine associations between Internet use, exposure to Internet pornography, and sexual behavior. Ninety-four percent of students have used the Internet. Sixty-two percent of students had accidentally seen pornography on the Internet and 35% had purposefully viewed pornography online. Students who experienced sexual solicitation and who purposefully viewed pornography online were more likely to report lifetime and current sexual behavior. Additional research is needed to understand the impact of Internet use and exposure to Internet pornography on adolescents’ sexual behavior.^

Does parental monitoring influence the use of alcohol and drugs among inner city 7th grade students?

Objective. To examine associations between parental monitoring and adolescent alcohol/drug use. ^ Methods. 981 7th grade students from 10 inner-city middle schools were surveyed at the 3 month follow-up of an HIV, STD, and pregnancy prevention program. Data from 549 control subjects were used for analyses. Multinomial logistic regression was used to examine associations between five parental monitoring variables and substance use, coded as: low risk [never drank alcohol or used drugs (0)], moderate risk [drank alcohol, no drug use (1)], and high risk [both drank alcohol and used drugs or just used drugs (2)]. ^ Results. Participants were 58.3% female, 39.6% African American, 43.8% Hispanic, mean age 13.3 years. Lifetime alcohol use was 47.9%. Lifetime drug use was 14.9%. Adjusted for gender, age, race, and family structure, each individual parental monitoring variable (perceived parental monitoring, less permissive parental monitoring, greater supervision (public places), greater supervision (teen clubs), and less time spent with older teens) was significant and protective for the moderate and high risk groups. When all 5 variables were entered into a single model, only perceived parental monitoring was significantly associated (OR=0.40, 95% CI 0.29-0.55) for the moderate risk group. For the high risk group, 3 variables were significantly protective (perceived parental monitoring OR=0.28, CI 0.18-0.42, less time spent with older teens OR=0.75, CI 0.60-0.93, and greater supervision (public places) OR=0.79, CI 0.64-0.99). ^ Conclusion. The association between parental monitoring and substance abuse is complex and varied for different risk levels. Implications for intervention development are addressed. ^

A model for use by local public health departments to evaluate pandemic influenza plans

The events of the 1990's and early 2000's demonstrated the need for effective planning and response to natural and man-made disasters. One of those potential natural disasters is pandemic flu. Once defined, the CDC stated that program, or plan, effectiveness is improved through the process of program evaluation. (Centers for Disease Control and Prevention, 1999) Program evaluation should be accomplished not only periodically, but in the course of routine administration of the program. (Centers for Disease Control and Prevention, 1999) Accomplishing this task for a "rare, but significant event" is challenging. (Herbold, John R., PhD., 2008) To address this challenge, the RAND Corporation (under contract to the CDC) developed the "Facilitated Look-Backs" approach that was tested and validated at the state level. (Aledort et al., 2006).^ Nevertheless, no comprehensive and generally applicable pandemic influenza program evaluation tool or model is readily found for use at the local public health department level. This project developed such a model based on the "Facilitated Look-Backs" approach developed by RAND Corporation. (Aledort et al., 2006) Modifications to the RAND model included stakeholder additions, inclusion of all six CDC program evaluation steps, and suggestions for incorporating pandemic flu response plans in seasonal flu management implementation. Feedback on the model was then obtained from three LPHD's—one rural, one suburban, and one urban. These recommendations were incorporated into the final model. Feedback from the sites also supported the assumption that this model promotes the effective and efficient evaluation of both pandemic flu and seasonal flu response by reducing redundant evaluations of pandemic flu plans, seasonal flu plans, and funding requirement accountability. Site feedback also demonstrated that the model is comprehensive and flexible, so it can be adapted and applied to different LPHD needs and settings. It also stimulates evaluation of the major issues associated with pandemic flu planning. ^ The next phase in evaluating this model should be to apply it in a program evaluation of one or more LPHD's seasonal flu response that incorporates pandemic flu response plans.^

The association between maternal use of spermicides, condoms, intra-uterine devices or progesterone and major structural birth defects

Birth defects occur in 1 of every 33 babies born in the United States, and are the leading cause of infant death. Mothers using contraceptives that become pregnant may continue to use their contraceptives after their first missed menstrual period, thus exposing their baby in utero to the contraceptive product. Progesterone is also sometimes prescribed during the first trimester of pregnancy to mothers with a history of miscarriages or infertility problems. To ensure the safety of these products, it is important to investigate whether there is an increased occurrence of babies born with birth defects to mothers using various contraceptive methods or progesterone in early pregnancy. Using data from the National Birth Defects Prevention Study (NBDPS), an ongoing multi-state, population based case-control study, this study assessed maternal exposures to IUDs, spermicides, condoms and progesterone in early pregnancy. ^ Progesterone used for threatened miscarriage during the first three months of pregnancy was associated with an increased occurrence of hypoplastic left heart (adjusted odds ratios (OR) 2.24, 95% CI 1.13-4.21), perimembranous ventricular septal defects (OR 1.64, 95% CI 1.10-2.41), septal associations (OR 2.52, 95% CI 1.45-4.24), esophageal atresia (OR 1.82, 95% CI 1.04-3.08), and hypospadias (OR 2.12, 95% CI 1.41-3.18). Mothers using progesterone for injectable contraception had increased (OR > 2.5), but insignificant odds ratios for anencephaly, septal associations, small intestinal atresias and omphalocel. Progesterone used for fertility was not associated with an increased occurrence of any birth defects examined. ^ Mothers using progesterone for fertility assistance and threatened miscarriage were very similar with respect to their demographics and pregnancy history. They also both reported similar types of progesterone. Thus, if progesterone was a causal risk factor for birth defects we would have expected to observe similar increases in risk among mothers using progesterone for both indications. Because we predominantly observed increased associations among mothers using progesterone for threatened miscarriage but not fertility assistance, it is possible the increased associations we observed were confounded by indication (i.e. progesterone was administered for vaginal bleeding which occurred as a sequelae to the formation of a congenital anomaly. ^ No significant increased associations were observed between maternal spermicide use during pregnancy and 26 of 27 types of structural malformations. While multiple statistical tests were performed we observed first trimester maternal spermicide use to be associated with a significant increased occurrence of perimembranous ventricular septal defects (OR 2.21, 95% CI 1.16-4.21). A decreased occurrence (OR < 1.0) was observed for several categories of birth defects among mothers who conceived in the first cycle after discontinuing the use of spermicides (22 of 28) or male condoms (23 of 33). ^ Overall the percent of IUD use was similar between mothers of controls and mothers of all cases in aggregate (crude OR 1.05, 95% CI 0.61-1.84). Power was limited to detect significant associations between IUD use and birth defects, however mothers using an IUD in the month immediately prior to conception or during pregnancy were not associated with an increase of birth defects. Limb defects and amniotic band sequence previously reported to be associated with IUD use during pregnancy were not found to occur among any mothers reporting the use of an IUD during pregnancy.^

Malaria prevention in Kenyan women of childbearing age

The objective of this program is to reduce malaria incidence in Kenya. Malaria poses a large public health challenge in Kenya, and although public health efforts have traditionally been focused on treatment of infected patients, due to increased drug resistance and lack of drug-adherence, prevention strategies are needed. This program targets Kenyan women, the likely caretakers in the home, and promotes malaria prevention behaviors through health education. ^ A planning group will be assembled and a needs assessment will be performed, verifying risk factors and conditions associated with malaria, as well as personal and external determinants. Behavioral and environmental outcomes will be determined, and performance objectives for each outcome will be established. Matrices of change objectives will be created, and detailed methods and strategies will be linked to each change objective. Program elements include media, education, and incentives. All materials used in this program will be subjected to pre-test to ensure cultural relevance and fidelity. Matrices of change objectives will be created for program adopters and implementers, as well as correlating methods and strategies associated with each change objective. Performance objectives will also be compiled for program maintainers. A program evaluation plan will follow "Pre-Post Comparison Group" design. Outcome evaluation and process evaluation will be conducted. The sample population will be screened based on age and gender so as to maintain comparability to the target population. Measurements will be taken before the program to establish baseline, directly following the program to determine short-term effects, and three months after the program is completed to determine long-term effects. ^ One limitation of this program is selection bias, due to the nature of quasi-experimental studies. Thorough screening prior to sample selection will minimize selection bias and ensure group homogeneity. Another limitation is attrition, and this will be minimized where possible through the use of incentives. In cases where loss to follow-up is not avoidable, such as death or natural disasters, the attrition effect will be estimated using structural equation modeling after reviewing the sample size, differential attrition and total attrition. ^ This intervention is based heavily on health promotion theories, but it is important to remember that in the field, the program plan will likely include only the necessary practical strategies. The target population, Kenyan women of childbearing age, will be significant in decreasing the malaria disease burden in Kenya.^

Physical activity, body composition, exogenous estrogen use and their association with insulin-like growth factors

Obesity and physical inactivity are modifiable risk factors that are associated with several health issues; they are major factors in up to 30% of major cancers. Elevated levels of circulating insulin-like growth factor-I (IGF-I) have been associated with high body composition measurements and high cancer risk; exogenous estrogen use is associated with low circulating IGF-I levels and high cancer risk. The relationship between physical activity and circulating IGF levels is complex and findings of previous studies of their relationship remain inconsistent; however, these studies included vague definitions of physical activity. In this study, we used cross-sectional data from the Women's Health Initiative to determine the relationship between specific measures of physical activity (e.g., intensity, duration, and frequency) and circulating IGF-I levels, accounting for exogenous estrogen use and body composition. These data were collected from women enrolled at Women's Health Initiative clinical centers at Baylor College of Medicine and Wake Forest University School of Medicine. Multivariate linear regression analysis showed that circulating IGF-I and IGF-binding protein (BP) 3 levels were positively associated with frequency, duration, and intensity of physical activity. Circulating IGF-I levels and the molar IGF-I:IGF-BP3 ratio were significantly associated with frequency of walking, whereas circulating IGF-BP3 levels were significantly associated with strenuous physical activity, suggesting that different aspects of physical activity and their effects on fitness affect members of the IGF family differently. The results from our study support the recommendation of a regular exercise routine, particularly that of strenuous intensity, for postmenopausal women as a means to prevention of cancer.^