Научная статья на тему 'Internet-based automated individualized inferential statistical chronobiologic self-surveillance offers universal preventive vascular care: Conference report'

Internet-based automated individualized inferential statistical chronobiologic self-surveillance offers universal preventive vascular care: Conference report Текст научной статьи по специальности «Медицинские технологии»

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Аннотация научной статьи по медицинским технологиям, автор научной работы — Halberg Franz, Chibisov S. M., Agarval Radzhesh

We monitor our streets to prevent assault and rodents to develop drugs, but not those for whom the drugs are intended. It took over half a century to begin to monitor blood sugar values in patients with insulindependent diabetes. For stroke prevention for many more people, monitoring blood pressure is equally timely and technically feasible. Such chronobiologic homeand website-based personalised care also serves basic science and someday perhaps the management of societal illnesses.

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Похожие темы научных работ по медицинским технологиям , автор научной работы — Halberg Franz, Chibisov S. M., Agarval Radzhesh

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Текст научной работы на тему «Internet-based automated individualized inferential statistical chronobiologic self-surveillance offers universal preventive vascular care: Conference report»

INTERNET-BASED AUTOMATED INDIVIDUALIZED INFERENTIAL STATISTICAL CHRONOBIOLOGIC SELF-SURVEILLANCE OFFERS UNIVERSAL PREVENTIVE VASCULAR CARE: CONFERENCE REPORT

Halberg Franz1 Chibisov S.M.2, AgarvalRadzhesh3

1. Helabergcenter of chronobiology & chronomedicine USA

2. -3. Russian People’s friendship university Russia

We monitor our streets to prevent assault and rodents to develop drugs, but not those for whom the drugs are intended. It took over half a century to begin to monitor blood sugar values in patients with insulindependent diabetes. For stroke prevention for many more people, monitoring blood pressure is equally timely and technically feasible. Such chronobiologic home- and website-based personalised care also serves basic science and someday perhaps the management of societal illnesses.

Abstract

No report of results of research is acceptable today unless it contains probabilities (P-values) from hypothesis testing and a measure of the uncertainties of estimated endpoints (confidence intervals). The same requirements can be implemented automatically in the care of an individual's blood pressure (BP) and heart rate (HR). Broad-based screening leading to the early diagnosis of alterations occurring within the physiological range, overlooked in today's medicine, aims at the prevention of severe and costly heart and brain attacks and other related debilitating life-threatening conditions. Information gained from the monitoring further helps optimizing the treatment when needed and for preventing iatrogenic harm. The approach presented herein targeted to cardiovascular diseases can also serve as a model for other variables and eventually for health care generally. Evidence prompting the immediate use in practice of a scientific time-series-based approach is here illustratively summarized as offering much more than current health care, including the conventionally not feasible detection of both new and long-anticipated vascular and metabolic conditions detected by a preventive as well as curative self-surveillance.

Scientific chronobiologic care:

• seems complicated, but the necessary involved computations are done automatically;

• is less expensive since it is largely based on self-help at home and via the Internet;

• is safer since by self-surveillance it detects early conditions that are not recognized conventionally, such as a drug-induced symptomless blood pressure overswing. Both its preventive as well as its curative aspects apply to diseases of populations as well as of individuals, including sudden cardiac death, suicide and terrorism. Scientific chronobiologic care replacing the spotcheck-based approach has already been modeled and implemented for the case of blood pressure and heart rate in several locations on several continents. It could become universally available by cost-free teaching in primary and secondary schools and by adult education in home- and Internet-based self-help via an automated website. A chronobiologic data collection and analysis system revolving around the e-mail exchange, usually within 24 hours, of analyses for the data (the equivalent of what a website could do automatically), is already functional on a limited scale with human hands-on since a quarter century ago. The BP monitor can be rendered unobtrusive and affordable. With a minimal investment into staff for maintenance and research, a fully automatic website, accessible by cell phone, could function, as it currently does by hands-on e-mail, without involving a care provider as long as the screening does not detect consistent abnormality.

High risks of stroke and of other life-threatening individuals' illnesses, Figures 1A and 1B, usually unassessed in current single office measurements or 24-hour profiles, are detected early for prophylactic action by computer-aided, Internet-supported technology, by means of continued half-hourly chronobiologically-interpreted BP and HR measurements for a week as a start and longer when needed (without involving providers for spotchecks). Guidelines for prevention as well as diagnosis and treatment are provided in a consensus co-signed by a minister of health and a university president, both cardiac

physiologists (1, 2). A handout for the public (3) can also be made universally understandable and available. Treatment administered at the optimal time determined for each patient individually, dubbed prehabilitation, before (as well as after) disease becomes overt and expensive to treat, reduces the suffering and costs of rehabilitation, Figures 2A and 2B (4; cf. 5). Treatment efficacy is validated scientifically for each patient so that silent great harm, a change from a 5% to a near 100% risk of cerebral ischemic event within 6 years is avoided, the number of catastrophic events (strokes, heart attacks and kidney damage) reduced and no harm is unintentionally done. Data and other information transmittal from a monitor by a cell phone to a website is feasible, as is the return of analyses, Figure 3. A minimal investment into developing and operating automatic unobtrusive recorders and a website on a national, or preferably multilingual international scale could yield a maximal return from self-surveillance in a preventive and curative home-based health care involving providers only when abnormality occurs, Figure 4 (1-3).

Information gathered within this scope could also serve to address societal diseases, like aggression, and to detect effects of space weather on conditions such as sudden cardiac death, suicide and terrorism, Figure 5, diseases that urgently need countermeasures.

A consensus at a meeting on "Noninvasive methods in cardiology" in Brno in 2008 (1, 2) advocated adoption of the foregoing for the following reasons:

1. Safety. First do no harm. Figures 2A and 2B show how Hyzaar, a popular antihypertensive medication when tested for a month at a time, at each of six different circadian stages, can be harmful at one time and beneficial at others for some patients. No conventional health plan can discover such cases with unintentional harm done at different clock hours for different individuals. For the time being, in this context, "the blind [providers] lead the blind [care recipients]". This load of blindness can be cured by chronobiologically-interpreted monitoring and concerns about 70 million people in the USA alone who are said to be treated for high BP. Some may make a bad trade, acquiring a higher risk of stroke in exchange for an acceptable blood pressure (1-3).

2. Universal availability. The computer/home/Internet loop for prevention could be made universally available to any circle of family and friends that owns a computer and has a computer-savvy member, or it could be made available in public-minded stores that now provide immunizations. This monitoring is immediately available, of interest to some of the 70 or more million Americans who are currently being treated for high blood pressure, some misdiagnosed, recognized as false positives and false negatives, under the labels of "white-coat" and "masked" hypertension, respectively. The current opinion that a 24-hour profile can clarify the diagnosis ignores the facts that such profiles are neither consistent from day to day nor do they reveal vascular variability disorders without replication and, what seems critical, without a chronobiological analysis and its interpretation (1-3).

3. Prehabilitation. Preventive as well as curative chronobiologic cybercare detects conditions long suspected (6) but never recognized as measurable entities with minimal week-long sampling requirements. The prevention of the risk of having a cerebral ischemic event within 6 years, that increased from 5% to 100% in a completed study on 297 people is confirmed with proxy outcomes in over 1,000 and awaits a large clinical trial. Figure 4 suggests that estimated millions of people have vascular variability disorders that cannot be assessed by a spotcheck or by a chronobiologically uninterpreted 24-hour profile.

4. Science. Chronobiologic cybercare becomes scientific. For the first time, the P-values for the statistical significance of a change are applied to individuals as soon as they are diagnosed and treated. For instance, an increase in a parameter such as the average or the extent of swing is assessed longitudinally in the given person for diagnosis and/or a decrease as an effect of treatment is tested, with uncertainty estimates that are requisites for any publication on groups.

5. Cost. As compared to conventional care, once a monitor has been acquired and automatic data analyses are provided by a website (maintained by a few scientist-researchers for everyman and everywoman), cost-free chronobiologic cyber-self-help-based preventive care of topics related to BP and HR is MUCH cheaper, as is computer-implemented essential self-surveillance during treatment.

6. Quality. For all the foregoing personalized reasons, for avoiding false diagnoses (to avoid treating people for a lifetime who do not need treatment and to avoid not treating those who need treatment) and as compared to those not determining the right treatment time and possibly doing unintentional harm, chronobiologic cyber care is better.

7. Societal health. The data from individuals' monitoring have been used for understanding the cycles in seemingly desirable (e.g., motivation reflected by religious proselytism) and undesirable behavior (e.g., criminality and terrorism) triggered by space weather. This research constitutes a step toward dealing with human aggression, including terrorism. It already rests on published documentary evidence on this and all of the other points. Illustrative examples as case reports have now appeared (2, cf. 1, 3).

8. Primary, secondary and adult education. Feasibility studies have already demonstrated practicability. A book (7) published with the (U.S.) National Science Teachers Association introduces chronobiology in early education (8) (a task in need of updating in an also educational as well as automatically analyzing website).

9. Hurdles:

a. Obtrusiveness of arm-cuff-worn monitors to be eliminated by automated improved wrist monitors, available as prototypes (9).

b. Cost of monitors, shown to be amenable to lowering by the Phoenix group (9).

c. Cost of maintaining a data acquisition, analysis and monitoring service now provided by personal funds.

d. The greatest obstacle is the mindset of providers (taught to rely on the fiction of "the true" blood pressure) and of the population at large to be remedied by education upstream of medical students and in early secondary and adult classes, and a multilingual website, the equivalent of which has been functional on a small scale for a quarter century locally and since 2000 internationally.

Volunteers of the Phoenix Project (Twin Cities chapter of the Institute of Electrical and Electronics Engineers, http://www.phoenix.tc-ieee.org), in association with the Halberg Chronobiology Center at the University of Minnesota (http://www.msi.umn.edu/~halberg/), have already succeeded in matching BP-pulse monitors that sell for USD $1600 by monitors that would retail for an estimated $75 when mass-produced (9). A few permanently appointed individuals could utilize the website's data flow for epidemiologic and other transdisciplinary research. Let us monitor individuals who may need treatment, as is done internationally (1-3), as Janeway (6) insisted in 1904:

"... it is essential that a record of the pressure be made at frequent intervals at some time previous [presumably to an examination], to establish the normal level and the extent of the periodic variations [...] to demonstrate changes [which] would be considered within the limits of normal variation".

This step toward home- and Internet-based medicine in 2010 goes beyond aims noted for 2028 (10). It is scientific, using inferential statistical criteria applied to the individual, as done in Urausu, Japan (11); Brno, Czech Republic; Moradabad, India; and elsewhere since 2000 (1-3). The same data flow (1-3) is used for medical and transdisciplinary (12) research into society's ills (13).

Franz Halberg (halbe001@umn.edu), Germaine Cornelissen (corne001@umn.edu) and Othild Schwartzkopff (schwa115@umn.edu)

University of Minnesota, Minneapolis, Minnesota, USA Rajesh Agarwal (somvoz@live.ru)

Network of Young Doctors and Health Administrators, Moscow, Russia Sergei M. Chibisov (kalcna@mail.ru)

People's Friendship University of Russia, Moscow, Russia

1. Halberg F, Cornelissen G, Otsuka K, Siegelova J, Fiser B, Dusek J, Homolka P, Sanchez de la Pena S, Singh RB, BIOCOS project. Extended consensus on means and need to detect vascular variability disorders (VVDs) and vascular variability syndromes (VVSs). Leibniz-Online Nr. 5, 2009 (http://www.leibniz-sozietaet.de/journal). 35 pp.

2. Sánchez de la Peña S (Ed.) Geronto-Geriatrics: Int J Gerontology-ChronomeGeriatrics 2008; 11 (14): 110-185.

3. Cornélissen G, Delmore P, Halberg F. Health Watch 3: Dedicated, on his 80th birthday, to Earl E. Bakken, the developer of the implantable cardiac pacemaker for long-term use (and founder of Medtronic Inc., the company manufacturing many devices for rehabilitation) to be better-known in the future for /rehabilitation. Minneapolis: Halberg Chronobiology Center, University of Minnesota/Department of Communications, Medtronic, Inc.; 2004. 31 pp. www.phoenix.tc-ieee.org/Phoenix Bibliography.htm. See also Cornélissen G et al. 100 or 30 years after Janeway or Bartter, Healthwatch helps avoid "flying blind". Biomed & Pharmacother 2004; 58 (Suppl 1): S69-S86.

4. Watanabe Y, Cornélissen G, Halberg F, Beaty L, Siegelova J, Otsuka K, Bakken EE. Harm vs. benefit from losartan with hydrochlorothiazide at different circadian times in MESOR-hypertension or CHAT. In: Halberg F, Kenner T, Fiser B, Siegelova J (Eds.) Proceedings, Noninvasive Methods in Cardiology, Brno, Czech Republic, October 4-7, 2008. p. 149-167. http://web.fnusa.cz/files/kfdr2008/sbornik 2008.pdf

5. Halberg F, Cornélissen G, Katinas G, Tvildiani L, Gigolashvili M, Janashia K, Toba T, Revilla M, Regal P, Sothern RB, Wendt HW, Wang ZR, Zeman M, Jozsa R, Singh RB, Mitsutake G, Chibisov SM, Lee J, Holley D, Holte JE, Sonkowsky RP, Schwartzkopff O, Delmore P, Otsuka K, Bakken EE, Czaplicki J, International BIOCOS Group. Chronobiology's progress: Part II, chronomics for an immediately applicable biomedicine. J Applied Biomedicine 2006; 4: 73-86. http://www.zsf.jcu.cz/vyzkum/jab/4 2Zhalberg2.pdf

6. Janeway TC. The clinical study of blood pressure. New York: D. Appleton & Co.; 1904. 300 pp.

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7. Ahlgren A, Halberg F. Cycles of Nature: An Introduction to Biological Rhythms. Washington, DC: National Science Teachers Association; 1990. 87 pp. (Library of Congress Catalog Card #89-063723; ISBN #0-87355-089-7. National Science Teachers Association, 1742 Connecticut Ave. N.W., Washington, DC 20009, www.nsta.org)

8. Halberg F, Smith HN, Cornélissen G, Delmore P, Schwartzkopff O, International BIOCOS Group. Hurdles to asepsis, universal literacy, and chronobiology—all to be overcome. Neuroendocrinol Lett 2000; 21: 145-160.

9. Beaty L, Cornélissen G. Towards inexpensive ambulatory blood pressure variability monitors for home use: A first experiment using off-the-shelf devices as the basis for ABPMs. Available from Larry A. Beaty, labeaty@bitstream.net

10. Koop CE, Mosher R, Kun L, Geiling J, Grigg E, Long S, Macedonia C, Merrell RC, Satava R, Rosen JM. Future delivery of health care: cybercare. A distributed network-based health-care system. IEEE Engineering in Medicine and Biology Mag 2008; 29-38. doi 10.1109/MEMB.2008.929888

11. Yamanaka G, Otsuka K, Hotta N, Murakami S, Kubo Y, Matsuoka O, Takasugi E, Yamanaka T, Shinagawa M, Nunoda S, Nishimura Y, Shibata K, Saitoh H, Nishinaga M, Ishine M, Wada T, Okumiya K, Matsubayashi K, Yano S, Ishizuka S, Ichihara K, Cornélissen G, Halberg F. Depressive mood is independently related to stroke and cardiovascular events in a community. Biomed & Pharmacother 2005; 59 (Suppl 1): S31-S39. Cf. also Biomed & Pharmacother 2005; 59 (Suppl 1): S40-S44, S45-S48, S49-S53 and S54-S57.

12. Halberg F, Cornélissen G, Sothern RB, Katinas GS, Schwartzkopff O, Otsuka K. Cycles tipping the scale between death and survival (= "life"). Progress of Theoretical Physics 2008; Suppl. 173: 153-181.

13. Halberg F, Cornélissen G, Wilson D, Singh RB, De Meester F, Watanabe Y, Otsuka K, Khalilov E. Chronobiology and chronomics: detecting and applying the cycles of nature. Biologist 2009; 56: in press.

Epilogue

"Your model which focuses on individual care in the home setting is particularly relevant today as the nation once again tackles the prohibitive rise in health care costs. Your use of the internet to report the collected data provides a cost effective model for prevention and monitoring of chronic conditions and provides an effective example of the use of information technology in health care, another of our national priorities. This is medicine of the future -- patient centered care enhanced through the use of technical tools." (Deborah E.

Powell, Associate Vice-President, Academic Health Center, University of Minnesota, personal communication to Germaine Cornelissen, May 1, 2009)

Figure 1A. Circadian vascular variability disorders (VVDs) in abstract form. Screening based on ~half-hourly or hourly 24-hour/7-day monitoring of blood pressure and heart rate as a minimum. Once the analysis of the first 7 days as a whole shows alterations, repeated 24/7 monitoring is indicated for a positive diagnosis of a VVD. When a VVD is thus confirmed by the second around-the-clock 24/7 surveillance, continued monitoring for the duration of any ongoing treatment is recommended so that, e.g., the risk of ‘a’ is not replaced by the greater risk of ‘b’ or, what is worse, is not complicated by other VVDs.*

• VVDs, computed, in the case of ‘a-c’, by cosinor, diagnosed by reference to prediction limits of peers of the same gender and age, can be systolic (S-MH), diastolic (D-MH), both (SD-MH), and/or mean arterial (MA-MH), and are complemented non-parametrically, after stacking with also-stacked reference standards from gender- and age-associated peers for MESOR-hypertension, MH (where M = MESOR, midline-estimating statistic of rhythm). VVDs, diagnosed based on at least two profiles of hourly or denser 7-day around-the-clock monitoring, are:

‘a’ (above left). MH: M above the upper 95% PI (prediction limit);

‘b’ (above middle). Circadian Hyper-Amplitude-Tension (CHAT). The circadian amplitude is above the upper corresponding 95% PI.

‘c’ (above right). Ecphasia (odd timing of the circadian rhythm of BP but not of that in HR); circadian acrophase outside its PI.

‘d’ (below middle vs. left). Excessive pulse pressure (EPP), when the difference in the MESORs of SBP and DBP for adults exceeds 60 mmHg.

‘e’ (lower row, upper right). A deficient HR variability (DHRV), defined as a standard deviation of HR less than 7.5 beats/minute. Thresholds for ‘d’ and ‘e’ remain to be replaced by reference values from clinically healthy peers, eventually with disease free long-life outcomes specified further by gender, age, ethnicity and geography.

VVDs can combine to form vascular variability syndromes (VVSs), Figure 10. © Halberg.

Figure 1B. Chronomics detects nocturnal escape from treatment (I), risk of stroke and nephropathy (IIA-B), even in MESOR-normotension (IIIC), and monitors transient and/or lasting success of treatment (IIIA-C), Illustrative results supporting the need for continued surveillance, above, and for a chronomic analysis of blood pressure series.

I: Nocturnal hypertension: data stacked from 11 days of around-the-clock monitoring. Office spotchecks cannot detect nocturnal pathology. II A: Among risk factors, an excessive circadian blood pressure (BP) amplitude (A) raises the risk of ischemic stroke most. II B: Among risk factors, an excessive circadian blood pressure (BP) amplitude (A) raises the risk of nephropathy most. II C: An excessive circadian BP-A is a risk factor for ischemic stroke independent from the 24-hour mean (MESOR). III A: Individualized assessment (by CUSUM) of a patient’s initial response and subsequent failure to respond to autogenic training (AT) (EO, F, 59 y). III B: Individualized BP chronotherapy. Lower circadian double A (2A) and MESOR (M) after switching treatment time from 08:30 (left) to 04:30 (right)*. III C - Control chart assesses efficacy of individualized anti-MESOR-hypertensive chronotherapy.

Chronomics detects nocturnal escape from hypotensive treatment taken in the morning (I above); a circadian overswing, CHAT; a risk of stroke and nephropathy, greater than hypertension (IIA-B), even in MESOR-normotension (IIC) and monitors transient and/or lasting success of treatment (IIIA-C).

Merits are:

• Detection of abnormality during the night when the dose of medication taken in the morning may no longer be effective in certain patients, facts not seen during office visits in the afternoon but revealed as consistent abnormality by around-the-clock monitoring;

• Detection of abnormal circadian pattern of blood pressure (CHAT, “overswinging”) associated with a risk of cerebral ischemia and nephropathy larger than other risks (including “hypertension”) assessed concomitantly (IIA and B);

• Finding that CHAT carries a very high risk, even among MESOR-normotensives who do not need antihypertensive medication (IIC);

• Availability of statistical procedures such as a self-starting cumulative sum (CUSUM) applicable to the individual patient to determine whether an intervention such as autogenic training is effective and if so for how long it remains effective (IIIA);

• N-of-1 designs for the optimization of treatment timing: the same dose of the same medication can further lower the same subject's blood pressure MESOR and circadian amplitude when the timing of daily administration is changed (IIIB and C), as ascertained by as-one-goes (sequential) testing and parameter tests, procedures applicable to the given individual. © Halberg.

Figure 2A. This figure is pertinent to large numbers of people worldwide, who are currently treated for high blood pressure. They must realize that a popular drug, if prescribed without personalized surveillance, can harm by inducing a VVD such as a circadian overswing or CHAT, brief for circadian hyper-amplitude-tension. As this figure shows, a change in the time when the drug is taken can make the same dose of the same drug in the same person beneficial rather than harmful or vice versa (4). The drug can eliminate CHAT, a risk of stroke and other hard events greater than a high blood pressure, or induce it, depending on timing.

Figure 2B. This figure reveals that at one administration time (before noon), Hyzaar induces CHAT in diastolic blood pressure and exacerbates a preexisting CHAT in systolic blood pressure (red). At another time of administration, Hyzaar eliminates a pre-existing VVD. These opposite effects of the same drug in the same dose in the same person were found in tests at 6 medication times, each of about a month, with half-hourly surveillance of blood pressure during the last week of each about monthly treatment time. These differences occur as a function of the timing of the drug's use along the scale of 24 hours. Without surveillance, we leave it up to chance and ignore whether we do harm at one time, shown in red, while we can be beneficial at another time, shown in green (top and middle, for systolic and diastolic blood pressure, respectively). If timing is not tested, the blind (care providers) lead the blind (care recipients) (bottom, showing the status quo). Original study by Dr. Yoshihiko Watanabe: this result followed-up on a study wherein immediately following the diagnosis of MESOR-hypertension the time when a hypotensive drug was taken was systematically varied at about 17-day intervals with continuous half-hour monitoring of blood pressure (5). That procedure used at the time of diagnosis of each new case seems warranted by selfsurveillance with analyses currently provided within the BIOCOS project cost-free, in exchange for the data (corne001@umn.edu), and eventually available from a multilingual international website.

At the bottom, Pieter Brueghel’s painting "The Parable of the Blind Leading the Blind" is reproduced by kind permission of the Fototeca della Soprintendenza of the BAS PSAE and of the Polo Museale of the City of Naples, in order to emphasize that CHAT is silent to both the caregiver acting on the basis of a conventionally interpreted (chronobiologically uninterpreted) 24-hour blood pressure as well as to the majority of providers treating on the basis of single measurements in their office. © Halberg.

Figure 3. Currently, a project on The BIOsphere and the COSmos provides analyses multilingually, in English, French and German to all comers worldwide, in exchange for the data (at corne001@umn.edu when need be). These analyses serve multiple purposes transdisciplinarily: for the person monitored, the analyses determine a VVD and guide treatment via a care provider for lifelong self-help in continuously monitored sphygmochrons. The data in turn also serve eventually (after lifetime records from disease-free subjects) for improving reference standards and in records from individuals with morbid events to look for novel harbingers. Furthermore, the data can be analyzed to monitor solar activity with signatures in blood pressure and heart rate and in archived hard events. The Phoenix Project of volunteering members of the Twin Cities chapter of the Institute of Electrical and Electronics Engineers (http://www.phoenix.tc-ieee.org) is planning on developing an inexpensive, cuffless automatic monitor of BP and on implementing the concept of a website (www.sphygmochron.org) for a service providing automatic analyses in exchange for the data that in turn are to be used for refining methods and for monitoring psychophysiological effects of space weather. © Halberg.

Figure 4. The incidence of VVDs in this graph is assessed in a clinic population of 297 patients. BP and HR of each subject were monitored around the clock for 2 days at 15-minute intervals at the start of study. Each record was analyzed chronobiologically and results interpreted in the light of time-specified reference limits qualified by gender and age. On this basis, MESOR-hypertension, MH (diagnosed in 176 patients), excessive pulse pressure (EPP), CHAT (a circadian overswing), and a deficient heart rate variability (DHRV) were identified and their incidence related to 4 outcomes (cerebral ischemic attack, coronary artery disease, nephropathy, and/or retinopathy). Outcomes, absent at the start of study in these non-diabetic patients, were checked every 6 months for 6 years, to estimate the relative risk associated with each VVD alone (primary diagnosis, PD) or in combination with 1, 2, or 3 additional VVDs, shown in columns. Earlier work showed that CHAT was associated with a risk of cerebral ischemic event and of nephropathy higher than MH, and that the risks of CHAT, EPP, and DHRV were mostly independent and additive. It thus seemed important to determine the incidence of each VVD, present alone or in combination with one or more additional VVDs. The 176 patients with MH were broken down into 103 (34.7% of the population of 297 patients) with uncomplicated MH, 55 (18.5%) with MH complicated by one additional VVD, 15 (5.1%) and 3 (1.0%) with MH complicated by two or three additional VVDs. In the latter group, all 3 patients had a morbid outcome within 6 years of the BP monitoring. Ambulatory BP monitoring over only 48 hours, used for diagnosis, is much better than a diagnosis based on casual clinic measurements, yet its results apply only to groups. With this qualification, of the 176 patients with MH, 73 (42.2%) had additional VVDs that further increase their vascular disease risk, and that are not considered in the treatment plan of these patients since current practice does not assess these VVDs. This proportion may be smaller in a 7-day record (available for CHAT). Results related to EPP (bottom left), CHAT (upper right), and DHRV (bottom right) illustrate that these conditions can be present in the absence of MH in as many as 12 (4.0%) of the 297 subjects. Since they do not have MH, it is unlikely that these subjects would be treated from a conventional viewpoint, even though their vascular disease risk can be as high as or even higher than MH.

Evidence exists to suggest that treatment of these conditions may translate into a reduction in morbidity and/or mortality from vascular disease (1-3). Another lesson from these results is that around-the-clock monitoring of blood pressure and heart rate interpreted chronobiologically is needed, even in the absence of MESOR-hypertension, to detect vascular disease risk associated with VVDs such as CHAT and DHRV, that cannot be assessed on the basis of casual clinic measurements, so that non-pharmacologic and/or pharmacologic intervention can be instituted in a timely fashion before the occurrence of adverse outcomes. Once implemented across the board rather than in selected patient populations, vascular disease could be curbed to a much larger extent at relatively low cost if the monitoring is offered directly to the public and care providers become involved only after detection of a VVD. A website has to be built to interest many people and to provide cost-free analyses in exchange for the data (1-3), as is now provided worldwide by the BIOCOS project on a small scale (corne001@umn.edu). © Halberg.

Figure 5. On the left, this figure shows a lesser prominence of an ~7-day spectral component in the heart rate of 5 men when the solar wind loses its counterpart of corresponding length. Implied, but not shown, is the persistence in the biosphere of an ~7-day component that can be driven (amplified) by a reciprocal component in solar activity.

In the middle of the figure, the top row reveals non-stationary intermittent frequencies in SWS. These, like those in systolic blood pressure (SBP), are dubbed Aeolian (derived, as a personification of the solar wind, as Aeolus, Greek ruler of winds), the use of the term implying, however, that interval as well as point estimates of the periods are provided, at least globally and, whenever desirable, time-varyingly in chronomic serial sections, complementing gliding windows. SWS, like SBP, changes in frequency, smoothly [A] or abruptly [B, C, D], bifurcating [D, F] and rejoining [G], and varies in amplitude [B], up to disappearing [C, E] and reappearing. An abrupt change in SWS is followed in SBP with a lag by changes such as the narrowing (disappearance of part) of a broad band and the damping of the remaining part of the ~1.3-year (1.22- to 1.38-year) far-transyear component in SBP, previously congruent with a counterpart in SWS and by the disappearance of part of a cis-year. This finding suggests that some of FH's cis- and

transyear components were driven by the SW. Note also that part of a far-transyear band disappeared with a lag of about a far-transyear following the disappearance (subtraction) of the same components from the SWS spectrum. The lag in the disappearance from SBP of a cis-year component of ~0.66 year is the same (not shorter) as that for the transyear, suggesting the possibility that it represents a harmonic of a non-sinusoidal far-transyear. Specifically, after the broad band disappears in the SWS, at E, parts of the same broad band in SBP also disappear, with a lag (delay) at E', while other parts, albeit damped, persist. This persistence of a narrower damped band in the spectral domain suggests prior driving of a component with partial endogenicity, i.e., an evolutionary acquisition of biotic transyear oscillations that may reflect solar dynamics for the past billions of years. Post hoc ergo propter hoc reasoning can never be ruled out. N=2,418 daily averages of BP and HR data; total N=55,000, from automatic around-the-clock monitoring for nearly 16 years, mostly at 30-min intervals, with interruptions. Gliding spectra computed with interval = 8 years, resolution low in time but high in frequency, increment = 1 month, trial periods from 2.5 to 0.4 year(s), with harmonic increment = 0.05. Darker shading corresponds to larger amplitude.

In Section C, acrophases, peaks of best fitting cosine curves and parts of chronomic serial sections, show by bracketing the intermittent statistical significance of a far-transyear of an ~1.3 year length in both solar wind speed (top) and in the antipodal geomagnetic index, aa, (middle) followed on each of two occasions with a lag by a statistically significant bout of terrorism which by far outlasts the apparently triggering putative heliogeomagnetic drivers. Noteworthy further, but not shown, is that a transyear replaces the calendar year in a 39-year series of terrorist acts, suggesting the importance of transyears in militarypolitical affairs, with the same finding of a transyear, as a replacement of the seasons, in the popularity of a U.S. president. These and/or other nonphotic signatures pervade human affairs, including military and political activity, economics and health; a transyear and a cis-halfyear pattern are pertinent to sudden cardiac death, a condition wherein magnetic storms may be protective rather than noxious. © Halberg.

Figure 1A

Chronomics Detects Nocturnal Escape from Treatment (I), Risk of Stroke and Nephropathy Greater than Hypertension (IIA-B), even in MESOR-Normotension (IIC) and Monitors Transient and/or Lasting Success of Treatment (IIIA-C)*

Stacked from 11 days of around-the-clock monitoring. Office spotchecks cannot detect nocturnal pathology.

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Figure 2A

Treatment Beneficial at Certain Other Times (9,12 or 15 hours after awakening) can EXACERBATE a Pre-existing CHAT in Systolic Blood Pressure (SBP) and INDUCE CHAT in Diastolic Blood Pressure (DBPJ when Given at the Wrong Time in Patient Su *

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Preventive and curative health care can yield the dividend of biomedical monitoring of space weather by time-structural analyses of ambulatory blood pressure and heart rate series1

Preventive Self-Help-Based Health Care

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Em-evolmg diagnostic tests & improved reference standards

(1) by aligning longitudinal and linked cross-sectional biomedical with (whenever possible also local and global) physical environmental tnonitoring (or transdlsciplinary science - while safeguarding anonymity, privacy and security with lifelong follow-up. Vision ol Larry A. Beaty (www.sphygmochron.org) of the Phoenix Project (www.ohofinixic-ieee.otg/).1 (2) If abnormal, participants are advised to allow data and analyses transfer to care providers for surveillance, diagnosis, optimization of treatment, if and as need be, and for ding coin

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Modified from Figure 1 (Phoenix Architecture) in Adams C Privacy requirements for low-cost cnronomedical systems, Int Conf on the Frontiers of Biomedical Soerce: Chronobioiogy, Chengdu. China, September 24-26,2006, p. 64-69.

Increase in Vascular Disease Risk Assessed by Actual Outcomes within 6 years of Monitoring in 297 Patients in the Presence of Multiple Vascular Variability Disorders (WDs) Classified by Differing Primary Diagnosis (PD)*

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* Results stem from 297 patients, among which only 34.7% had uncomplicated MESOR-hypertension [upper left. N=0) and 40 7% were MESOR-normotensive, including 2.4%and 1 7% with only CHAT or DHRV, respectively (right top and bottom, N=0). For complementary results on 1,177 untreated patients, see Hypertension 2007; 49: 237-239.

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Figure 4

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