A simple (and time honoured) way to learn the information you need to know.
Source: Learning Clinical Medicine
Acute hypotension is an extremely common condition seen in a wide variety of patients and is defined as a condition in which the blood pressure is decreased to a point that is inadequate for normal tissue perfusion and oxygenation.
Hypotension may be a sign of shock or may progress to a ‘shock’ state. Its causes are multifactorial with etiologies such as fluid volume deficits (hypovolemic), decreased cardiac output (cardiogenic), inadequate intravascular volume (vasodilatory), or iatrogenic effects of certain classes of medications. The severity of the condition is related to the amount of circulating blood. If blood does not reach vital organs, perfusion is compromised, resulting in tissue hypoxia and damage to the vital organs of the brain, heart and kidneys.
The mortality rate for shock is extremely high, reaching 60% to 80% in cardiogenic shock. For this reason, it is imperative that interventions target resolving severe hypotension or shock as quickly and effectively as possible. One intervention commonly used to manage severe hypotension is Trendelenburg positioning, defined as a position in which the head is low and body and legs are on an inclined or raised plane.
Theoretically, it shifts abdominal organs upward and out of the pelvis and increases blood flow to the brain in case of hypotension or shock. However, use of this intervention is controversial, and many experts in the medical and nursing field question its efficacy. In addition, some clinicians and nurses concede that the intervention has harmful effects that may actually worsen patient outcomes. [Trendelenburg Positioning to Treat Acute Hypotension: Helpful or Harmful. Clinical Nurse Specialist: July/August 2007 – Volume 21 – Issue 4 – pp 181-187]
It is important to seek answers to the questions surrounding the efficacy of Trendelenburg positioning because it is frequently used by nurses and health care givers, who are patient advocates and are often the first to recognise a deteriorating patient condition. Trendelenburg positioning is used by nurses and health care givers because it is believed to improve patients’ outcomes.
The support for this intervention is anecdotal and can be traced to the 1800s. The position is named for the surgeon who originally coined it’s use in 1890, Dr. Friedrich Trendelenburg who studied medicine in Scotland and Berlin before becoming a professor of surgery and surgeon-in-chief in Leipzig, Germany. His fascination with urology linked his name to the positioning technique, now commonly known as the Trendelenburg position or head-down-tilt (HDT) position.
Dr. Trendelenburg used this head down, elevated body position to surgically manage strangulated hernias, bladder stones, and various gynaecological problems. Friedrich Adolf Trendelenburg placed patients supine with the head of the bed tilted 45 degrees downward to aid visualisation of abdominal organs for surgical procedures.
However, it was not until World War I that Walter Cannon, an American physiologist, introduced the position as a treatment of shock. He promoted the technique as a way to increase venous return to the heart, increase cardiac output, and improve blood flow to vital organs.
Today, some clinicians use this position, now called the Trendelenburg position, to treat hypotensive episodes. They believe this position shifts intravascular volume from the lower extremities and abdomen to the upper thorax, heart, and brain, improving perfusion to these areas.
But as far back as the 1960s, researchers found undesirable effects of the Trendelenburg position, including decreased blood pressure, engorged head and neck veins, impaired oxygenation and ventilation, increased aspiration risk, and greater risk of retinal detachment and cerebral oedema.
Evidence shows that while this position shifts fluid, it adversely engorges the right ventricle, causing it to become dilated, which further reduces cardiac output and blood pressure. It also impairs lung function by compromising pulmonary gas exchange. Abdominal contents shift upward, increasing pressure on and limiting movement of the diaphragm and reducing lung expansion. Lung compliance, vital capacity, and tidal volumes decrease while the work of breathing increases. The result is impaired gas exchange—hypercarbia and hypoxemia. Evidence also suggests that when obese patients are placed in Trendelenburg position, lung resistance increases significantly and pulmonary gas exchange worsens.
The Trendelenburg position has little, if any, positive effect on cardiac output and blood pressure. It impairs pulmonary gas exchange and increases the aspiration risk. The evidence doesn’t support its use to treat hypotension. However, evidence-based practice does support elevating the lower extremities—without using a head-down tilt position—to mobilize fluid from the lower extremities to the core during hypotensive episodes. Sometimes called a modified Trendelenburg position, this position has been found to support blood pressure without the negative consequences of the traditional Trendelenburg position.
An extensive search on Ovid Medline, CINAHL, and Evidence-Based Medicine Review Multifile was conducted to identify pertinent articles. The inclusionary criteria were, the use of HDT of greater than, or equal 10̊, and patients under general anesthesia. Six articles were identified and critically appraised. The data compiled in this systematic review suggest there is an increase in cardiac preload with no consequent increase in cardiac output or performance. The data suggest there are multiple negative consequences of HDT on pulmonary function including a decrease of functional residual capacity, an increase of atelectasis, and a decrease in oxygenation. This systematic review concluded, there is a lack of clear evidence to support the use of HDT as a treatment for acute hypotension. In the controlled environment of the surgical setting, head-down tilt should be utilized judiciously and for as short a duration as possible. HDT position should be avoided in patients who are obese, have pre-existing obstructive pulmonary disorders, have New York Heart Association class III heart failure, or other significant cardiopulmonary dysfunction.[Carter, Aaron T., “The Cardiopulmonary Consequences of the Trendelenburg Position in Patients Under General Anesthesia” (2010). School of Physician Assistant Studies. Paper 214. http://commons.pacificu.edu/pa/214]
Ensuring that healthcare practices are based on the best evidence can improve patient safety. To safely and effectively manage acutely ill patients, clinicians must evaluate traditional practices and systems.
Reference: Questioning Common Nursing Practices
What Does the Evidence Show? Am Nurs Today. 2013;8(3). http://www.medscape.com/viewarticle/780771_4
Ultrasound is defined by the American National Standards Institute as “sound at frequencies greater than 20 kHz.”
Ultrasounds are sound waves with frequencies higher than the upper audible limit of human hearing. Ultrasound is not different from ‘normal’ (audible) sound in its physical properties, only in that humans cannot hear it. This limit varies from person to person and is approximately 20 kilohertz (20,000 hertz) in healthy, young adults. Ultrasound devices operate with frequencies from 20 kHz up to several gigahertz. [https://en.wikipedia.org/wiki/Ultrasound]
Therapeutic applications of ultrasound, including microbubble-enhanced sonoporation, are stimulating widespread research activity aimed at both the characterization and control of ultrasonically mediated bioeffects.
Modern medical ultrasonics may be viewed as having evolved through three generations of applications.
The first generation emphasizes diagnostic imaging, employing ultrasound fields not intended to have tissue effects.
The second generation has deliberately exploited more aggressive ultrasound regimes for direct interventional approaches, including lithotripsy (of ductal calculi), phacoemulsification (of cataracts), and high intensity focused ultrasound (HIFU) for tumour ablation, thrombolysis, and haemostatis.
A third and emerging area involves an indirect therapeutic application of ultrasound to sensitize tissue actively, or otherwise enhance the efficacy for parallel administration of biotherapeutics. Here, particular progress has been achieved with ultrasound assisted transdermal delivery. However, this has been facilitated, in part, because the target tissue (i.e., stratum corneum) is non-viable. Perhaps the most challenging avenue for therapeutic ultrasound is to facilitate molecular delivery whilst retaining tissue viability, the criteria necessary for drug- and gene-based therapies. Excitingly, initial in vitro demonstrations of enhanced transfection, and also increased sensitivity to chemotherapeutic agents, have now also been realized with compelling in-vivo validations.
Evidently, this latter category of ultrasound-mediated therapy holds promise for a diversity of potential uses. However, reducing the multiplicity of these abstract possibilities to the more refined base of concrete realizations that are best suited to ultrasonic enhancement requires strategic action. Targeting research with the greatest impact requires an understanding of the strengths and weaknesses of ultrasonic bioeffects, which remain poorly understood at a mechanistic level. This situation hinders insight and indeed foresight into the future of this field.
Source: Paul Campbell and Mark R. Prausnitz: Ultrasound Med Biol. 2007 Apr; 33(4): 657. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1934612/
Lack of efficient drug and gene delivery is one of the major problems of cancer chemo- and bio-therapy. Different non-viral approaches have been proposed for drug and gene delivery, such as electroporation, chemical methods, liposomal delivery, gene gun mediated transfer. These techniques show a potential for drug and gene delivery, however, site-specific and efficient delivery still remains a difficult problem.
Recently, novel ultrasound-mediated techniques have been proposed for drug and gene delivery. In this approach, ultrasound radiation is used to induce cavitation, which can be applied to different organs. Therefore, this technique may have an advantage over other methods for delivery of drugs and genes to specific sites including tumours.
Ultrasound-induced cavitation has been shown to deliver macromolecules and genes in cells in vitro and in vivo and to improve cancer chemotherapy in nude mice. Since ultrasound-induced drug and gene delivery has a great potential for in vivo application in cancer chemoand bio-therapy, optimization of ultrasound-induced delivery of macromolecular drugs and DNA in cancer cells in vitro may provide a protocol which could routinely be used in anti-cancer drug design and in in vivo applications.
Source: Irina V, Larina B, Mark Evers, and Rinat O. Esenaliev: Optimal Drug and Gene Delivery in Cancer Cells by Ultrasound-Induced Cavitation. Anticancer Res. 25: 149-156 (2005). http://ar.iiarjournals.org/content/25/1A/149.long
Now scientists are developing innovative ways to adapt noninvasive ultrasound technology to deliver drugs and genes to specific organs and tissues in the body. Some traditional methods of drug delivery are often not suitable for large molecules such as proteins and DNA, underscoring the need for improved drug delivery strategies. Ultrasound holds considerable clinical promise in this realm.
Ultrasound is a very effective modality for drug delivery and gene therapy because energy that is non-invasively transmitted through the skin can be focused deeply into the human body in a specific location and employed to release drugs at that site. Ultrasound cavitation, enhanced by injected microbubbles, perturbs cell membrane structures to cause sonoporation and increases the permeability to bioactive materials. Cavitation events also increase the rate of drug transport in general by augmenting the slow diffusion process with convective transport processes. Drugs and genes can be incorporated into microbubbles, which in turn can target a specific disease site using ligands such as the antibody. Drugs can be released ultrasonically from microbubbles that are sufficiently robust to circulate in the blood and retain their cargo of drugs until they enter an insonated volume of tissue. Local drug delivery ensures sufficient drug concentration at the diseased region while limiting toxicity for healthy tissues.
Ultrasound-mediated gene delivery has been applied to heart, blood vessel, lung, kidney, muscle, brain, and tumour with enhanced gene transfection efficiency, which depends on the ultrasonic parameters such as acoustic pressure, pulse length, duty cycle, repetition rate, and exposure duration, as well as microbubble properties such as size, gas species, shell material, interfacial tension, and surface rigidity. Microbubble-augmented sonothrombolysis can be enhanced further by using targeting microbubbles.
Source: Liang, H.,D., Tang, J., Halliwell, M. Sonoporation, drug delivery, and gene therapy. Proc Inst Mech Eng H. 2010;224(2):343-61.
Transmission electron micrograph showing a prostate cancer cell immediately after exposure to ultrasound. The image has been colour enhanced to show the spot where the cell membrane has been removed. Image courtesy of Robyn Schlicher, Robert Apkarian, and Mark Baran.
Scientists have known for sometime now that exposure of cells to ultrasound at higher intensity levels and different frequencies than those used for diagnostic purposes can drive molecules into the living cells, thereby increasing the effects of drugs and the expression of genes. The mechanism by which ultrasound increases permeability of the protective outer membrane of cells, however, was uncertain until Dr. Mark Prausnitz, Professor of Chemical and Biomedical Engineering at Georgia Institute of Technology, and his team directed their research toward this phenomenon. With the aid of various microscopy techniques, the researchers showed that ultrasound can cause bubbles to oscillate and violently collapse – a process known as cavitation – in a cell suspension, producing a shock wave which, in turn, causes fluid to move and open up holes in the cell membranes. The holes allow macromolecules like proteins to enter the cell before the holes close in a matter of minutes by an internal cellular patching process.
Prausnitz and his team have seen that the extent to which the cellular membrane is disrupted can vary depending on the ultrasound parameters used. Through study of the physical, acoustic and biological conditions in which molecules are driven into cells, they found that the impact of ultrasound can also kill cells.
“The cell has it’s plasma membrane to regulate what is inside the cell, so when you disrupt the membrane all sorts of molecules can go inside the cell and that regulation is disrupted. The cell can be highly stressed by that, and therefore actively tries to repair the membrane. If the membrane breach is not that big, the membrane is able to reseal itself. But if it’s too big, we see evidence of various biochemical pathways of programmed cell death that kick into gear due to that stress.” says Prausnitz.
A major challenge that researchers face is determining the optimal ultrasound qualities that will open holes in cell membranes without killing the cells, so that drug delivery can be maximised while cell viability is maintained. The Prausnitz team is focussing it’s research on determining the mechanisms by which cellular bio-effects of ultrasound occur.
“If we can learn more about how cells respond to plasma membrane disruptions, we will have a valuable tool in designing a controllable therapeutic ultrasound system,” says Hutcheson, a graduate student in Prausnitz lab.
There is another method by which ultrasound can be used for drug or material delivery at the desired areas. Ultrasound is a method that was widely used for the synthesis of various nanomaterials, for example coating carbon nanotubes and nobel metals. In the biomedical field, ultrasound has been used in various application: destruction and fragmentation of contrast agents, gas release, destruction of polymers, albumin or lipid shells of microbubbles and in drug delivery (Unger, 1997). Recent studies showed that ultrasound can be used for destruction of Polyelectrolyte multilayer or PEM capsules (Shchukin, Gorin, & Möhwald,2006, Skirtach, De Geest, Mamedov, Antipov, Kotov, & Sukhorukov, 2007). Here, nanoparticles were used to increase the density of the shells of microcapsules, the ultrasound serves as a trigger to release encapsulated materials. It is worthwhile to notice that upon propagation an ultrasound wave experiences viscous and thermal absorption, and scattering in the medium. However, it is the cavitation microbubble which occur as a result of the collapse of the generated microbubble and the shear forces which cause the destruction of the polyelectrolyte capsules. Powers in the range of 100-500 W at frequencies of 20 KHz were applied for destruction of the capsules. It was found that nanoparticles adsorbed on microcapsules affect the action of ultrasound on their shells.
[Page 563, Biotechnology: Pharmaceutical Aspects. Nanotechnology in Drug delivery ©2009]
Polyelectrolyte multilayer (PEM) capsules engineered with active elements for targeting, labeling, sensing and delivery hold great promise for the controlled delivery of drugs and the development of new sensing platforms. PEM capsules composed of biodegradable polyelectrolytes are fabricated for intracellular delivery of encapsulated cargo (for example peptides, enzymes, DNA, and drugs) through gradual biodegradation of the shell components. PEM capsules with shells responsive to environmental or physical stimuli are exploited to control drug release. In the presence of appropriate triggers (e.g., pH variation or light irradiation) the pores of the multilayer shell are unlocked, leading to the controlled release of encapsulated cargos. By loading sensing elements in the capsules interior, PEM capsules sensitive to biological analytes, such as ions and metabolites, are assembled and used to detect analyte concentration changes in the surrounding environment.
[del Mercato, L., L., Ferraro M., M., Baldassarre F., Mancarella, S., Greco,V., Rinaldi, R., Leporatti S. Biological applications of LbL multilayer capsules: from drug delivery to sensing: Adv Colloid Interface Sci. 2014 May;207:139-54. doi: 10.1016/j.cis.2014.02.014. Epub 2014 Feb 21.]
Prausnitz perceives ultrasound-mediated drug delivery as having a potentially broad range of applications within therapeutic medicine, as this process is independent of both cell and drug type. He also envisions other applications in which the goal might not necessarily be to get molecules into cells, but rather to penetrate deeper into a multicellular tissue to sensitize it. “Ultrasound might be able to open up the permeability of the tissue as a whole and in that way drive drugs more generally into that tissue,” Prausnitz explains. The team is studying the effect of ultrasound on the uptake and viability of cells in explanted carotid arteries from pigs as a three-dimensional tissue model.
Widespread research activity is also under way to understand the bio-effects of ultrasound in the context of gene therapy. “It appears that ultrasound is doing other things to the cell [ in addition to enhancing DNA delivery ] that might further enhance that transfection efficiency of a cell,” says Prausnitz.
Previous applications of ultrasound as a diagnostic tool and as a direct interventional approach for the pulverization of kidney stones and tumour ablation, among other uses, have contributed to the current standing of medical ultrasonics as a well-developed, non invasive technology. The therapeutic application of ultrasound to enhance efficacy of drugs and gene based therapy, however, is still in early stages of development.
“If the ultrasonic parameters can be well controlled, drugs could be targeted to a specific region in the body. For example, a tumour site could be targeted so that drugs are preferentially delivered to the tumour cells. This could minimize the side-effects commonly associated with traditional chemotherapeutic treatments.” explains Hutcheson. Thus, non invasively focussed ultrasound has the potential to improve the delivery of drugs and genes to targeted tissues, and increasing efficacy.
Prausnitz believes that a number of challenges need to be overcome before ultrasound-mediated therapy can be used in humans. Researchers need to determine the optimum cavitational activity, as well as other physical and chemical parameters, within the body for each given application. To control the impact of ultrasound on cells, researchers first need to better understand the pathways that mediate cell death so that maximum cell viability can be preserved. Further studies are needed to determine whether other cellular and physiological pathways are affected by ultrasound. There is still a long way to go to fully validate initial demonstrations that the ultrasound bioeffects that are effective and desirable in vitro – enhanced transfection and increased sensitivity to chemotherapeutics and other agents – are reproducible in vivo.
Evidence from other research fields suggests that cell membranes are continually ripped open and repaired inside the body without long-term effects. Mechanical impacts such as the beating of the heart, the motility of the gut, and the movement of muscles rip open cells in our bodies, and a similar mechanism of membrane repair as that shown by the Prausnitz team was demonstrated earlier with these mechanical stresses. While these data would suggest that cells may similarly withstand the effects of ultrasound, thorough studies are needed to corroborate this hypothesis and address other safety concerns.
Despite these obstacles, Prausnitz and the ultrasound research community remain optimistic that the day will come when ultrasound-mediated therapy will be widely applied in humans.
In the past two decades, research has underlined the potential of ultrasound and microbubbles to enhance drug delivery. However, there is less consensus on the biophysical and biological mechanisms leading to this enhanced delivery. Sonoporation, i.e. the formation of temporary pores in the cell membrane, as well as enhanced endocytosis is reported. Because of the variety of ultrasound settings used and corresponding microbubble behavior, a clear overview is missing. Therefore, in this review, the mechanisms contributing to sonoporation are categorized according to three ultrasound settings:
i) low intensity ultrasound leading to stable cavitation of microbubbles,
ii) high intensity ultrasound leading to inertial cavitation with microbubble collapse, and
iii) ultrasound application in the absence of microbubbles.
Using low intensity ultrasound, the endocytotic uptake of several drugs could be stimulated, while short but intense ultrasound pulses can be applied to induce pore formation and the direct cytoplasmic uptake of drugs. Ultrasound intensities may be adapted to create pore sizes correlating with drug size. Small molecules are able to diffuse passively through small pores created by low intensity ultrasound treatment. However, delivery of larger drugs such as nanoparticles and gene complexes, will require higher ultrasound intensities in order to allow direct cytoplasmic entry.
Source: Lentacker I, De Cock I, Deckers R, De Smedt SC, Moonen CT. Understanding ultrasound induced sonoporation: definitions and underlying mechanisms. Adv Drug Deliv Rev. 2014 Jun;72:49-64. doi: 10.1016/j.addr.2013.11.008. Epub 2013 Nov 21.
Image Source: http://library.med.utah.edu/WebPath/INFEHTML/INFEC033.html
Direct sputum smear microscopy is the most widely used means for diagnosing pulmonary TB and is available in most primary health-care laboratories at health-centre level. Most laboratories use conventional light microscopy to examine Ziehl-Neelsen-stained direct smears; this has been shown to be highly specific in areas with a high prevalence of TB but with varying sensitivity (20–80%).
Fluorescence microscopy is more sensitive (10%) than conventional Ziehl-Neelsen microscopy, and examination of fluorochrome-stained smears takes less time.
Uptake of fluorescence microscopy has, however, been limited by its high cost, due to expensive mercury vapour light sources, the need for regular maintenance and the requirement for a dark room.
LED microscopy was developed mainly to give resource-limited countries access to the benefits of fluorescence microscopy.
LED microscopy showed 84% sensitivity (95% confidence interval [CI], 76–89%) and 98% specificity (95% CI, 85–97%) against culture as the reference standard. When a microscopic reference standard was used, the overall sensitivity was 93% (95% CI, 85–97%), and the overall specificity was 99% (95% CI, 98–99%). A significant increase in sensitivity was reported when direct smears were used rather than concentrated smears (89% and 73%, respectively).
LED microscopy was statistically significantly more sensitive by 6% (95% CI, 0.1–13%), with no appreciable loss in specificity, when compared with direct Ziehl-Neelsen microscopy.
LED microscopy was 5% (95% CI, 0–11%) more sensitive and 1% (95% CI, -0.7% – 3%) more specific than conventional fluorescence microscopy.
In qualitative assessments of user characteristics and outcomes in relation to implementation, such as time to reading, cost-effectiveness, training and smear fading, the main findings were:
Source: WHO Policy Statement http://apps.who.int/iris/bitstream/10665/44602/1/9789241501613_eng.pdf
So I have just one wish for you – the good luck to be somewhere where you are free to maintain the kind of integrity I have described, and where you do not feel forced by a need to maintain your position in the organisation, or financial support, or so on, to lose your integrity. May you have that freedom.
(1974 commencement address to Cal Tech)
Every man depends on the work of his predecessors. When you hear a sudden unexpected discovery- a bolt from the blue as it were- you can always be sure that it has grown up by the influence of one man on another, and it is the mutual influence which makes the enormous possibility of scientific advance.
The picture is not thought out and determined beforehand, rather while it is being made it follows the mobility of thought. Finished, it changes further, according to the condition of him who looks at it.
Experimental ideas are very often born by chance as a result of fortuitous observations. Nothing is more common, and it is really the simplest way to begin a piece of scientific work. We walk, so to speak, in the realm of science, and we pursue what happens to present itself accidentally to our eyes.
The destinies of man are guided by the most extraordinary accidents.
Concerning all acts of initiative (and creation), there is one elementary truth…. the moment one definitely commits oneself, then Providence moves too. All sorts of things occur to help one that would never otherwise have occurred. A whole stream of events issues from the decision, raising in one’s favour all manner of unforeseen incidents and meetings and material assistance which no man could have dreamt would have come his way. I have learned a deep respect for one of Goethe’s couplets:
“Whatever you can do, or dream you can, begin it. Boldness has genius, power and magic in it.”
W. H. Murray
I find that a great part of the information I have was acquired by looking up something and finding something else on the way.
Franklin P. Adams
Serendipity has played a crucial role in science. The majority of the most important and revolutionary discoveries in biology and medicine have a serendipitous element in them (Beveridge, 1957, 1980).[Beveridge, W.I.B. (1957). The Art of Scientific Investigation. New York: Vintage Books.][Beveridge, W.I.B. (1980). Seeds of Discovery: The Logic, Illogic, Serendipity, and Sheer Chance of Scientific Discovery. New York: W.W. Norton.]
A few examples are the discovery of penicillin, heparin, Dramamine, X-rays, the Gram staining technique, the pancreas role in diabetes, and the anaesthetic effects of ether and nitrous oxide. In other areas of science, the discovery of pulsars, the electric current, the connection between electricity and magnetism, and the detection of cosmic microwave radiation background, all involved serendipitous events.
The word serendipity was coined by Horace Walpole, an eccentric English writer, in a letter to Sir Horace Mann in 1754.”This discovery is almost of that kind which I call serendipity, a very expressive word…. I once read a silly fairy tale ‘The Three Princes of Serendip’: as their highnesses travelled they were always making discoveries, by accidents and sagacity, of things which they were not in quest of…”
Almost all recent popular dictionaries have changed Walpole’s definition of serendipity although they still credit him with the origin of the word. Examples of recent definitions include
In the original story, sagacity permeates the lives of The Three Princes of Serendip. Although they’ve been incorrectly portrayed as bimbos who keep accidently bumping into good fortune, their actual abilities are more akin to those of Sherlock Holmes.
The three princes received the best formal education possible. The king correctly realised when his sons had reached the peak of their book knowledge and decided their further education best come from the experience of travelling in other lands.
In Persia, the three princes encountered a camel driver searching for his animal. Through astute observation, the princes were able to determine that the camel was blind in one eye, missing a tooth and lame. They also concluded that the animal was carrying a load of butter on one side, honey on the other, and a pregnant woman. Convinced that only thieves could know such details, the camel driver had the princes arrested. When the missing camel was subsequently found, the princes were asked how they were able to determine so many details. The answer, of course, relies more on the sagacity than on chance. The brothers, in turn, confessed the following….
This excerpt was selected to illustrate the princes’ keen perception and intelligence, although it fails to display their good judgement. Throughout the rest of the story, their highly developed mental powers enable them to take advantage of the chance opportunities they encounter.
The Princes of Serendip have their parallels in the scientific world. Perhaps the most famous example of serendipity is the discovery of penicillin, a story which essentially captures the powerful interaction of chance with the prepared mind.
Source: Serendipity And Scientific Discovery by Martin F. Rosenman; Creativity and Leadership in the 21st Century Firm, Volume 13, pages 187-193. Copyright © 2001 by Elsevier Science Ltd. ISBN: 0-7623-0803-6
Staphylococci played an important role in the discovery of penicillin G (benzylpenicillin). As Alexander Fleming writes in his Nobel lecture, December 11, 1945:
“The origin of penicillin was the contamination of a culture plate of staphylococci by a mould. It was noticed that for some distance around the mould colony the staphylococcal colonies had become translucent and evidently lysis was going on. This was an extraordinary appearance and seemed to demand an investigation, so the mould was isolated in pure culture and some of its properties were determined. The mould was found to belong to the genus Penicillium and it was eventually identified as Penicillium notatum,…”
“It arose simply from a fortunate occurrence which happened when I was working on a purely academic bacteriological problem which had nothing to do with antagonism, or moulds, or antiseptics, or antibiotics.”
“…penicillin started as a chance observation. My only merit is that I did not neglect the observation and that I pursued the subject as a bacteriologist. My publication in 1929 was the starting-point of the work of others who developed penicillin especially in the chemical field.”
This “fortunate occurrence” (and more or less fortunate occurrences that followed) led a team of Howard W. Florey (Ernst Chain, Norman Heatley and other scientists) to the mass production of penicillin.
It is impossible to know how many lives have been saved by penicillin but it is estimated that penicillin saved 80,000,000 to 200,000,000 lives. Penicillin has saved and is still saving, millions of people around the world.
To understand what these numbers mean it’s good to realise that the total casualties of the World War II were about 75 million people.
When Alexander Fleming noticed a mould had grown in one of his culture dishes and the staphylococcal colonies around the mould were dead, he decided to explore this promising lead. At least 28 scientists believed Flemming reported a mould killing one or more colonies of bacteria during an experiment, but all chose to view it as an unfortunate error rather than an opportunity for discovery [Selye H. (1975). Presentation at the American Association of Marriage and Family Counselors Annual Meeting, Toronto.]
For example, Scott noticed the inhibition of a staphylococcal colony by a mould; he viewed it as a nuisance. He later emphasised that Fleming’s discovery was mainly attributable to tenacity in seizing an opportunity others had let pass rather than due to just pure chance. [ Scott W.M. (1946). Veterinary record, 59, 680.]
What caused A. Flemming to pursue the promising lead that was ignored by so many scientists before him? There is no single answer.
As Austin (1978) [ Austin J.H. (1978). Chase, Chance and Creativity: The Lucky Art of Novelty. New York: Columbia University Press.] observes, “the most novel, if not the greatest discoveries occur when several levels of chance coincide.”
Nine years before his discovery of penicillin, A. Flemming observed that the bacteria in one of his dishes died after being contaminated with his nasal drippings [Maurois A. (1959). The Life of Sir Alexander Flemming. New York: Dutton.] This serendipitous occurrence led to his discovering the bacterial enzyme, lysozyme, which is found in nasal mucus. Although lysozyme proved inappropriate for medical use, the experiments reinforced his professional interest in bacterial inhibitors, furthered his career, and made him more receptive to the potential implications of the penicillin mould he would eventually encounter.
Other contributing factors include his being an artist with acute powers of observation, his frugal Scottish background which encouraged his tendency not to discard any laboratory dish until learning all he possibly could from it.[Austin J.H. (1978). Chase, Chance and Creativity: The Lucky Art of Novelty. New York: Columbia University Press.], and his damp and readily contaminated laboratory in St. Mary’s Hospital in London. (Interestingly, he chose St Mary’s because of it’s swimming pool where he could play water polo, rather than because of it’s scientific facilities.) Although most reports say the penicillin mould came into the laboratory through the window, possibly with the London fox, Hare [ Hare R. (1970). The Birth of Penicillin and the Disarming of Microbes. London: George Allen and Unwin.] suggests that the mould came from Dr. La Touche’s laboratory one floor below. Hare supports his hypothesis by noting that when American pharmaceutical companies studied hundreds of strains of penicillin in the late 1940s, they found only two which produced a better yield than Flemming’s original strain. It is now also known that had the London summer temperatures been at their normal level during those crucial days in 1928, the higher temperatures would have prevented penicillin from having any effect on the staphylococcal colonies [ Ellis-Peglar R.B (1986). Serendipity and the Discovery of Penicillin. New Zealand Medical Journal, 99, 545-549.]
Fleming’s excitement at the time of the discovery was not shared by his colleagues. The antiseptics they had used in field hospitals during World War I killed white blood cells, which protect the body against germs, more efficiently than they killed the germs themselves. A. Flemming was able to show that penicillin did not impair white blood cells, but he was unable to develop it as an effective antiseptic. For some reason, perhaps the lack of resources and encouragement at St. Mary’s or the many other promising areas of research A. Flemming was pursuing, the development of Penicillin stopped for ten years. [ Sheehan J.C. (1982). The Enchanted Ring: The Untold Story of Penicillin. Cambridge, MA: MIT Press.]
During the 1930s, the discovery and successful use of sulfa drugs finally convinced the medical community that safe and effective antiseptics were possible [ Shapiro G. (1986). A skeleton in the Darkroom: Stories of Serendipity in Science. New York: Harper and Row.]
Florey and Chain restarted the research on penicillin and miraculously cured mice infected with deadly pneumonia [ Florey H. (1946). Steps Leading to the Therapeutic Application of Microbial Antagonisms. British Medical Bulletin, 4, 248-258.]
A. Flemming might have been able to do that experiment, but he had never attempted it.
Comroe [ Comroe J.H. (1977). Roast Pig and Scientific Discovery, Part I. American Review of Respiratory Disease, 115, 853-860.] notes that chance favoured Chain and Florey when they used mice rather than guinea pigs; Penicillin is non-toxic to mice but quite toxic to guinea pigs. Although they thought their extract was relatively pure penicillin, in actuality it was only 1% penicillin and 99% impurities. Had the impurities been toxic, penicillin would have appeared dangerous, delaying further development. [Taton R. (1957). Reason and Chance in Scientific Discovery. London: Hutchinson Scientific and Technical.]
Even with this fortunate ending, 17 years elapsed between the initial discovery of penicillin and the awarding of the 1945 Nobel Prize in medicine to A. Flemming, Florey and Chain. Serendipity does not provide an instant solution.
Systemic scientific work always follows the initial fortuitous observation, with the eventual application evolving from rigorous experimentation and extensive knowledge of the field.
As Pasteur observed in the mid-1800s, “chance favours only the prepared mind.” Several years earlier Joseph Henry, the first director of Smithsonian, said: “The seeds of great discoveries are constantly floating around us, but they only take root in minds well prepared to receive them.”
Winston Churchill made a similar point: “Men occasionally stumble across the truth but most of them pick themselves up and hurry off as if nothing happened.”
Serendipity can indeed play a role in uncovering the truth, but because traditional scientific training and thinking favour logic and predictability over chance, that role is often overlooked in the scientific literature.
Comroe [Comroe J.H. (1977). Roast Pig and Scientific Discovery, Part II, American Review of Respiratory Diseases, 115, 1035-1044.] after reviewing 33 major discoveries in biochemical science in which serendipity played a crucial role and questioning other researchers, concluded that when it comes to ‘chance’ factors, few scientists “tell it like it was” in their writings. Even if they did, journal editors would probably delete, as unscientific, the ‘chance’ aspects in the paper. When interviewers used tape recorders and asked certain structured questions about the work environment [Amabile T.M., Gryskiewicz S.S. (1987). Creativity in the R & D Laboratory (Technical Report No. 30) Greensboro NC: Centre for Creative Leadership.] scientists tended to overlook or not mention the significance of chance occurrences. Not surprisingly, older scientists who have achieved high honours are more willing to acknowledge their indebtedness to chance. [Comroe J.H. (1977). Roast Pig and Scientific Discovery, Part II, American Review of Respiratory Diseases, 115, 1035-1044.]
In a two-year research project at the prestigious Salk Institute, Latour [Latour B, Woolgar S. (1979). Laboratory Life: The Social Reconstruction of Scientific Facts. Beverly Hills C.A: Sage Publications.] studied the scientists around him while working as a laboratory assistant. He found that unpredictable events which critically influenced the research were usually omitted in the final publication. Instead, rational processes and a pseudo-sense of underlying logic were superimposed on the experiments. Often this distortion was not deliberate. Gordon and Poze [Gordon W.J.J, Poze T.(1981). Conscious/Subconscious Interaction in a Creative Act: Journal of Creative Behaviour, 15, 1-10.][Gordon W.J.J, Poze T. (1987). The New Art of the Possible: The Basic Course in Synectics. Cambridge MA: Porpoise Books.] emphasise that people are usually unaware of the exact thinking processes preceding a discovery and therefore are unable to provide a completely accurate account of what transpired.
Real-life science is quite different from the neat logical process conveyed in journal articles. Parkes [ Parkes A.S. (1958). The Art of Scientific Discovery. Perspectives in Biology and Medicine,1, 366-378.] states that most discoveries in biology could not have been arrived at through reason alone. “To perceive the unexpected result or to discern the promising clue from among the multitude of irrelevant odd things that happen almost every day in an active laboratory is perhaps the very essence of the art of research.”
Successful researchers watch closely and are willing to view the data from several different perspectives. They have questioning minds which challenge existing assumptions when they are incongruent with empirical observations. These scientists, realising that serendipitous events can generate important research ideas, recognise and appreciate the unexpected, and encourage laboratory assistants to observe and discuss unusual happenings.
Serendipity can be enhanced in appropriate group settings. What’s needed is a “critical mass” of scientists from diverse disciplines working together in an environment conducive to frequent and open communication. In such an environment, researchers are more likely to consult with colleagues when developing and evaluating research ideas, with the results illustrating the old adage that “the whole is greater than the sum of the parts.” An unusual observation that doesn’t fit in with a scientist’s work or interests can be shared with a colleague who may be able to find an application for the new information.
Even scientists who recognise and appreciate the significance of the unexpected may find their time and resources totally committed to existing projects. For example, most grant proposals require clearly defined research, leaving little room for discovering anything truly new. Although hypothesis can be explored and checked out, possible outcomes are already explicit in the grant application.
Humphrey [Humphrey J.H. (1984). Serendipity in Immunology. Annual Review of Immunology, 2, 1-21.] states that an ideal application would read “these are the lines along which I expect to begin my experiments, but I really hope an unforeseen observation will prompt an unexpected idea,” but he realises only an unusually enlightened committee would award such a grant. Yet this is how breakthrough discoveries are usually made.
As Koestler [Koestler A. (1964). The Act of Creation. New York: Macmillan.] said,
“The history of discovery is full of arrivals at unexpected destinations, and arrivals at the right destination by the wrong boat.”
Scientists have the analytical training and the keen intelligence necessary for their exploratory voyages. By realising that discovery involves a dynamic interplay between conventional scientific methods and chance in all of its forms, and by cultivating an aptitude for serendipity, scientists can greatly enhance their investigative powers.
Source: Serendipity and Scientific Discovery by Martin F. Rosenman
Respected Sir (Dr. M. C. Misra),
I read your vision statement SIR at the following web address http://www.aiims.edu/images/vision-statement.pdf. Most humbly, although would look a bit absurd: I, Jeevanshu Dhawan being an independent citizen of a democratic country would like to provide you with few inputs regarding the future of healthcare and premier medical institutions in India; which I think is very important for every citizen, who truly believes India has every right to become a knowledge and research powerhouse for the entire world, as it did many centuries ago. This quote aptly describes my endeavour.
“Every heart that has beat strong and cheerfully has left a hopeful impulse behind it in the world, and bettered the tradition of mankind.” -Robert Louis Stevenson
Sir, you start your vision statement with the following lines “AIIMS has become a household name in India and abroad with people from all strata of society looking up to it to provide unbiased, affordable and quality healthcare. This stature and trust from fellow citizens have not come overnight. It has taken decades of extreme hard work, by our founding fathers, to reach to this level. I believe that there is immense untapped potential in AIIMS which with the proper nurturing can make AIIMS a truly global brand.”
Indeed what you said is true, but a lot of credit for the success of ‘AIIMS’ as a brand, also goes to the public in general, who let go of a few thousand schools that could provide their children world-class education and other basic amenities like toilets, which they forgo, and provided you with a budget which surpasses the best in the world
[around ₹11.24 billion (US$180 million) per annum; https://en.wikipedia.org/wiki/All_India_Institute_of_Medical_Sciences_Delhi].They also provided you with a vast gene pool, from amongst whom, you could find the best talent currently available in the world. They also provided you with rarest of rare diseases, providing the basis on which to perform your research, and a vast population of diseased patients, on whom you could practice your talents, eventually realising your true potential. AIIMS that you envision should keep the betterment of the 125 crore population of India and that of neighbouring countries, and not just a select few. One should work with the aim of service to these citizens of the country, not as masters with a thought of having a firm grip on their future, rather, as servants with care and compassion.
Where there is righteousness in the heart
There is beauty in the character.
When there is beauty in the character,
there is harmony in the home.
When there is harmony in the home.
There is an order in the nation.
When there is order in the nation,
There is peace in the world.
————Dr. APJ Abdul kalam
These are the excerpts from the Inaugural Address at the ILLUMINATI 2014 Armed Forces Medical College, Pune, September 15, 2014.
Culture of Excellence
Excellence in thinking and action is the foundation for any mission.
What is excellence?
Friends, you all belong to a youth community, which should stand for a culture of excellence. Moreover, excellence is not by accident.
It is a process, where an individual, organization, or nation continuously strives to better oneself.
The performance standards are set by themselves, they work on their dreams with focus, and are prepared to take calculated risks, and do not be deterred by failures as they move towards their dreams. Then they step up their dreams, as they tend to reach the original targets. They strive to work to their potential, in the process, they increase their performance thereby multiplying further their potential, and this is an unending life cycle phenomenon. They are not in competition with anyone else, but themselves.
That is the culture of excellence.
I am sure; each one of you will aspire to become unique with culture of excellence. Now, let me visualize how a dynamic healthcare centre or a hospital should be.
My visualization of great Healthcare centers
Dear friends, I visualize a great healthcare center with the following characteristics where:
1]. Patient is the most important person in the hospital. When the patient enters, the hospital presents an angelic look and all the team members of the hospital always wear smiles. The patient feels that “I am going to get cured”.
2]. The hospital consumes less electricity and less water by adopting green building for all modernization tasks. The choice of the power source is solar and wind.
3]. The hospital premises are totally noise free.
4]. All the test reports and treatment schedule are attached to the database of the patient through Electronic Medical Record without the need of the patient or the relatives to search for the reports. The data-base is updated and authenticated every hour.
5]. Maintain the database of all the cases treated by the hospital in the past, which are easily retrievable.
6]. Patient is not subjected to diagnostic pain.
7]. The surroundings of the hospital are green with full of trees with seasonal flowers and pleasant wall paintings.
8]. Further expansion of the hospital is in vertical mode leading to fast movement of the patient and doctors for medical treatment.
9]. There is no case of hospital-induced infection to the patients due to bio-contamination.
10]. The patients feel that this is the best place to get treated.
11]. The hospital is fully IT enabled leading to virtual connectivity of the patient to the doctor, nurse and the chief of the hospital 24×7. Hospital is also networked with other hospitals nationally and internationally for seeking expert medical advice on unique cases.
12]. The daily medical conference, attended by the Chief of the hospital, doctors, nurses, paramedics, and relatives of patients of unique cases, reviews problems of the patient and find integrated solutions.
Biology of Beliefs
Now friends, I was asking myself, is there any inputs and research which is coming from both, physio-psycho and brain researches, because of the advent of neuro-sciences coupled with quantum theory. I was reading a book, “The Secret Path” by Paul Brunton.
According to the author, the conscience is explained scientifically for the reason that the thinking process and biological processes converge through quantum mechanics. He says, that Physics and Biology are interlinked and that “At atomic level matter doesn’t even exist, it only has a tendency to exist”.
Recently, a friend of mine, who is a scientist sent me a book “Biology of Beliefs” by Dr. Bruce Lipton. The author is one of the greatest scientists in the bio-science and after 20 years of research he attributes the origin of human diseases and their cure have a basis on our intrinsic thinking and the relationship with our bio cells. The book talks about a new approach which highlights the importance of placebo effect and how it is actually a powerful belief effect. The author says “Doctors should not regard the power of belief as something inferior to the power of chemicals and scalpel. They should let go of the belief that the body and its parts are essentially stupid”.
Brainstorming in John Hopkins Hospital
Friends, Institute of Health in the US, in a survey found that 95,000 deaths every year occur in the United States due to medical errors. Though this information can be debated, this information was found to be very disturbing. It was recognized that there is a need for change in approach in medicare to improve the safety and quality of care to patients. In this connection, it was felt that it is important to train the doctors, nurses, paramedics, technicians and everyone connected with medicare the need to follow the treatment line meticulously. Modern hospital is a very complex organization and there are challenges ahead to improve the safety of the patients. Quality medicare is possible only when people work together as a team. I am told, that a seminar was conducted at Johns Hopkins Hospital where there was a brainstorming session between the doctors, medicare personnel, patients and the relatives of the patients, which brought out all these factors very clearly. I will be very happy if our super specialty hospitals conduct such type of review periodically in the combined meeting of doctors, nurses and paramedical staff. I am sharing this to the medical community, because this type of integrated conference has been conducted after the occurrence of tragic incident in Johns Hopkins Hospital. A child’s life was lost because of poor judgment in the diagnosis. The mother of the child briefed the whole incident to the combined gathering of the hospital team. It was a moving experience of the mother. I would like to share with you, particularly while attending the cardiac patients in pre operative, operative, post operative and recovery period, large number of sophisticated instruments and monitoring systems are used. In this scenario, experience of treatment profile and the problems have to be shared together on fixed days of the week and the results documented. It will become a teaching wealth for cardiac care specialists.
Six virtues a care giver must possess
Friends, in conclusion, I would like to share my experiences with Choakyi Nyima Rinpoche, the Chief Monk in Kathmandu and a medical researcher. After nearly a kilometer of walk, I reached the white Kumbha where the chief Monk and his disciples were waiting to receive me. After reception the Chief Monk said, let us go to our study room and I followed him. He climbed the first floor, the second floor, the third floor, the four floor and the fifth floor, just like a young boy. Probably the life style has a positive impact on the mind and body. All along I was following and following. When I reached his chamber, I saw a laboratory and a spiritual environment over-looking the Himalayas. What surprised me was, his research students come from different parts of the world. Particularly he introduced me to his co-author David R Shlim, MD who is working on a research area, Medicine and Compassion. The Chief Monk Choakyi Nyima Rinpoche and myself exchanged few books. The Monk has written with Dr. David R. Shlim a book titled “Medicine and Compassion”. I liked this book and read it during my journey from Kathmandu to Delhi. This book gives six important virtues which a medical practitioner has to possess towards their patients.
First virtue is generosity;
the second virtue is pure ethics;
third is tolerance,
fourth is perseverance,
fifth is cultivating pure concentration
sixth virtue is to be intelligent.
These virtues will empower the care givers with a humane heart. I am sure, the medical community assembled here, practice all these six virtues as a habit while dealing with the needy patients. This itself is a great example of synergy between mind, body and medicine.
Friends, I want to leave you all with a thought today.
What is the one action, which will make you great?
Every one of you has a page in the history of the world?
What is that page?
How do you make that page which is going to be referred by the posterity?
There is a need to give a vision to your ambitions.
What is that mantra?
Yes, the mantra is the following:
“What I will be remembered for?”
If you find an answer for this question in a few lines, that out-of-the-box idea will drive you for the rest of the life. You will be definitely thinking something different ?
an out of box mission, what are they?
Can I visualize along with you?
Each one of you will derive your own vision.
1]. Will you be remembered for bringing smiles of health and joy to all the patients?
2]. Will you be remembered for helping create a unique, cost effective vaccine against malaria and thereby saving more than one million people, mostly children who lose their lives due to the disease?
3]. Will you be remembered for creating a roadmap for reviving the 23,000 Primary Healthcare Centres, across the nation, which would enable them to deliver the much needed primary health facilities to the remote regions?
4]. Will you be remembered as a champion of preventive healthcare in the areas of cardiology, diabetic and infectious diseases?
5]. Will you be remembered as a great teacher in preventive care for the disease to the families of patients?
6]. Will you be remembered for contributing in a unique way in finding a cure for diseases such as cancer and HIV?
My best wishes to all the participants of ILLUMINATI 2014 for their deliberations and success of AFMC in the mission of providing quality and research oriented medical education. May God bless you.
Oath for medical professionals
Dr A.P.J Abdul Kalam
Let me close my letter with these famous lines by H.W. Longfellow:
“So let us be up and going, With a heart for any fate, Still achieving, still pursuing, Learn to labour and to wait.”
Image Courtesy: NUHS Paediatric Residency Program
With more facts,our minds are not only sorting and eliminating but also correlating. The human mind uses several means to correlate. One example is pattern recognition. The German idiom augenblick (“blink of the eye”) illustrates this.
Every examiner brings with him or her a lifetime’s experience. Moreover, observers may have had similar experiences but have incorporated them differently.
To illustrate this, there is the old story of two men walking down the street at the same time a woman is walking on the opposite side. One of the men notices her and says to the other,
“Look at that elderly woman. She seems to be in her early seventies, has gray hair, walks with a mild limp, holds her left arm and wrist slightly flexed, but speaks quite fluently with what seems to be a middle-European accent.”
The second man replies, “Oh, that’s my mother.”
Thus we all look at things in the aggregate or in its parts based on our own personal experience. With less experience, the learner is more likely to use a systematic approach, whereas the more experienced physician may be more likely to use the augenblick approach. However, it is important to realize that no matter how much experience a physician may have, if the augenblick approach does not render a comfortable feeling with the diagnosis, it is necessary to fall back on the systematic approach. Thus it is incumbent on all of us not to forget how to use a systematic approach.
The definition of fever is a core temperature of 38.0°C (100.4°F) or higher. There is a tendency among lay people to call any temperature above 37.0°C (98.6°F) a fever. This often leads to inappropriate treatment with antipyretics and can result in inappropriate diagnostic procedures.
Unlike adults, who become hypotensive early in the course of shock, children are able to preserve their blood pressure until the late stages of shock, partly through peripheral vasoconstriction but primarily by increasing their cardiac output through tachycardia.
Therefore, tachycardia with normal blood pressure is frequently the presentation of shock.
Hypovolemia and hypovolemic shock are usually identifiable in the early stages by tachycardia, but septic shock also can present initially as tachycardia and can, if diagnosed soon enough, be treated with volume.
Since heart rate and central arterial pressure will vary immediately after changes in position, measurements taken right on position change are almost certain to be abnormal. It is preferable to wait after each position change before the next measurement, as in the following procedure:
Orthostatic tachycardia and hypotension may occur in a patient who has been at bed rest for a prolonged time. Thus it is important to have the patient sit up as frequently as possible while in bed.
Other causes of orthostatic tachycardia and hypotension include hypovolemia, autonomic dysfunction, and chronic malnutrition.
Failure to thrive is weight loss or failure to gain weight without obvious cause.
Making correct medical diagnoses is a scientific endeavour. Humankind has employed scientific reasoning since ancient times, although it came more to fruition during the Renaissance.
Over long years, technology has changed, but this only involves the tools we use. Sadly, we often resort to high-technology “tests” before we perform a complete history and physical examination.
Studies have demonstrated that state-of-the art magnetic resonance imaging may yield diagnoses not consistent with those ultimately found at autopsy. Good clinical evaluation is still essential to developing working hypotheses, which then get “tested.”
Tests test hypotheses, not patients. Good working hypotheses serve two purposes: to guide us to which tests to employ and to guide us in their interpretation.
Human minds are capable of thinking on one end of the spectrum, scientifically, based solely on cold facts, or thinking, on the other end of the spectrum, religiously, based solely on faith. Historically, medical reasoning has developed along scientific lines.
However, we all know that medicine is not a perfect science, and although we strive to gather the most appropriate data and to interpret them correctly, physicians and patients are complex entities whose experiences have profound effects on gathering and interpreting data.
Hippocrates knew this when he stated,
“It is more important to know what sort of person has a disease than to know what sort of disease a person has.”
Thus clinicians, although doing their best to apply the scientific method, still find themselves
embedded in that “tug of war” between fact and opinion. We must recognize, humbly, that we can gather imperfect data and that we have to make judgments every day.
The human mind always seeks information,
eliminates what appears to be irrelevant,
correlates the data,
then puts together the remainder into a unifying hypothesis.
It often repeats this sequence, not necessarily consciously. Thus the time-tested diagnostic framework has evolved out of the scientific method (adapted from De Gowin):
Step 1: Take a history. Elicit symptoms.
Step 2: Develop hypotheses. Generate a mental list of pathophysiologic processes and diseases that might produce these symptoms. Then use processes of sorting, eliminating, and correlating to narrow it down.
Step 3: Perform a physical examination. Look for signs of the physiologic processes and diseases suggested by the history, determine what corroborates it, eliminate further what is irrelevant, and perhaps identify new problems to add to the list.
Step 4: Generate a differential diagnosis. List the most probable hypotheses in the order of their possibility.
Step 5: Test the hypotheses. Select laboratory tests, imaging studies, procedures, and consultations with appropriate likelihood ratios to evaluate your hypotheses. Do this mindful of risk, cost, benefit, and logistics.
Step 6: Modify your differential diagnosis. Use the results of the tests to evaluate your hypotheses, perhaps eliminating some and adding others and adjusting the probabilities.
Step 7: Repeat steps 1 to 6. Reiterate your process until you have reached a diagnosis or have decided that a definite diagnosis is neither likely nor necessary.
Step 8: Make the diagnosis or diagnoses. When the tests of your hypothesis are of sufficient certainty that they meet your stopping rule, you have reached a diagnosis.
Step 9: If uncertain, consider a provisional diagnosis or watchful waiting. Decide whether more investigation (return to step 1), consultation, treatment, or watchful observation is the best course based on the severity of the illness, the process, and co-morbidities. If the diagnosis remains obscure, retain a problem list of the unexplained symptoms and signs, as well as the laboratory and imaging findings; assess the urgency for further evaluation; and schedule regular follow-up visits.
Adapted from the Pediatric Diagnostic Examination by
Donald E. Greydanus, MD
Arthur N. Feinberg, MD
Dilip R. Patel, MD
Douglas N. Homnick, MD, MPH