Whether to screen for chronic kidney disease (CKD) is being rather heatedly debated these days. This is not a trivial question -- one in 10 American adults, more than 20 million, have some level of CKD, making CKD the eighth leading cause of death in the US. On one side is the American College of Physicians (ACP) which recommends:
- ACP recommends against screening for CKD in asymptomatic adults without risk factors for CKD. (Grade: weak recommendation, low-quality evidence).
- ACP recommends against testing for proteinuria in adults with or without diabetes who are currently taking an angiotensin-converting enzyme inhibitor or an angiotensin II-receptor blocker. (Grade: weak recommendation, low-quality evidence).
- ACP recommends that clinicians select pharmacologic therapy (high-quality evidence) in patients with hypertension and stage 1 to 3 chronic kidney disease. (Grade: strong recommendation).
- ACP recommends that clinicians choose statin therapy to manage elevated low-density lipoprotein in patients with stage 1 to 3 chronic kidney disease. (Grade: strong recommendation, moderate-quality evidence).
On the other side the American Society of Nephrology (ASN) strongly disagrees. Their argument is that CKD is usually asymptomatic but once discovered, can be treated and, while not cured, can provide a better quality of life for some time. Blood and/or urine tests such as eGFR with cystatin or creatinine can often detect CKD in an early state.
The USPSTF has made the following comments: "There is no generally accepted risk assessment tool for CKD or risk for complications of CKD. Diabetes and hypertension are well-established risk factors with strong links to CKD. Other risk factors for CKD include older age, cardiovascular disease, obesity, and family history. While there is insufficient evidence to recommend routine screening, the tests often suggested for screening that are feasible in primary care. The USPSTF could not determine the balance between the benefits and harms of screening for CKD in asymptomatic adults."
There are an estimated 30 000 patients (1 in 3900 births) in the US with cystic fibrosis (CF). This is a life-limiting, multisystem disease characterized by thick viscous secretions leading to recurrent lung infections, bronchiectasis, and progressive deterioration in lung function. CF is caused by loss or dysfunction of the CF transmembrane conductance regulator (CFTR) protein -- it is an inborn disease caused by at least 1900 different mutations in one gene. CF has been difficult to treat since it was first found.
In the past several years, two giant victories have been made on two fronts. On one was the development of the first truly breakthrough drugs -- VX-770 (now called Kalydeco) and VX-809. These are now in Phase III trials. While targeting only about 5% of CF patients, they provide a basis for developing other ‘personal' drugs.
The victory on the second front is the continued progress in developing gene therapy with the hope that it will essentially curve the disease. For example last year "a full-length plasmid encoding the cystic fibrosis transmembrane conductance regulator protein was achieved in the mouse lungs and airway cells, including a primary culture of mucus-covered human airway epithelium grown at air-liquid interface, without causing acute inflammation or toxicity". Highly compacted mucus penetrating DNA nanoparticles hold promise for lung gene therapy. And another study concluded "that CFTR-mRNA transfection could comprise a novel alternative for gene therapy to restore impaired CFTR function."
Many years ago, I gave a lecture on enzyme assays in the laboratory. When I was done talking about LDH, CPK, GGT, SGOT and SGPT; it occurred to me that anyone walking into that room who wasn't a laboratorian would wonder what language we were speaking. Sometimes I feel that way when I wander too far from chemistry.
But this is such an important topic I am going try to make it understandable to all the readers. The key is the first sentence. At a recent meeting of American Society of Hematology, a study (PD-1- and CTLA-4-Based Inhibitory Chimeric Antigen Receptors (iCARs) Divert Off-Target Immunotherapy Responses. Fedorov VD, Themeli M, Sadelain M. Sci Transl Med. 2013 Dec 11;5(215):215ra172) was presented illustrating that 45 of 75 leukemia patients saw complete regressions with CARs. CARS are chimeric antigen receptors that are types of T-cells. Research at the NIH, Sloan Kettering and the University of Pennsylvania have been working toward this for a number of years. They still admittedly have more to do as at present, the cells they use are highly specific for only a few cancers.
We know also that T-cells can be very destructive when they attack targets found on both tumors and healthy cells. One large pharmaceutical company has invested heavily in the project and this year there will be clinical trials at the three research institutions on other cancers.
At this time there about 16,000 Americans awaiting liver transplants. This year only about 7000 will receive them due to a shortage of viable livers.
A team in Japan, where only 1 in 10 patients needing a liver will get one, described the beginning to generating livers from stem cells. The group were able to ‘reprogram' human skin cells into embryonic cells (which are often used in stem cell research as they are able to be coaxed into almost any type of cells). After combining these cells with two other types of cells, the new cells organized themselves into three-dimensional cells with blood vessels. When transplanted into a mouse, the cells exhibited many (but not all) of the functions of a liver.
At this time, a number of problems must be solved before an "off the shelf" liver is ready for humans. One of these is the size of these "liver buds." They are about 5 mm. long and too large to infuse into the blood stream. The missing functions of the human liver will need to be included. It is, however, an exciting step.
The FDA has authorized Investigational New Drug application for clinical testing of the human neural stem cells as a treatment for spinal cord injury. As a first action under this IND, the Company is working to open U.S. sites for its Phase 1/2 clinical trial for chronic spinal cord injury, which is currently underway in Switzerland and Canada. With the IND, the study will be open in the US. At this time there are seven patients being treated with the reprogrammed stem cells.
The current interest in vitamin D has increased significantly the number of persons supplementing their diet with vitamin D preparations (More than 50% of Americans use dietary). While rare, vitamin D intoxication can be life-threatening. Three cases of acute vitamin D intoxication possibly due to faulty production of a multivitamin preparation were recently reported. The symptoms of vitamin D intoxication include elevated levels of high levels of serum and urine calcium and low levels of parathyroid hormone (PTH).
One of the three cases involved 19-month-old girl who presented with abdominal pain, vomiting, and poor appetite. She was taking a multivitamin preparation once daily (the label indicated 200 IU) for a month, Laboratory parameters were Ca: 19.4 mg/dL (N=8.4-10.2), PTH: 3.3 pg/mL (N=15-65), 25(OH) vitamin D: 760 ng/mL (N=25-80), Her serum levels for inorganic phosphorus and creatinine were within the normal range. After 4 days of treatment her serum Ca level was still elevated (12.8 mg/dL), and the patient was discharged on day 7 with a serum Ca level of 10.5 mg/dL. The preparation she had been taking was not available to test, but it was possible to test another bottle of the same manufacturer. Assays of it indicted that the label was correct, leading to the possibility that there was different amount in her preparation. [The manufacturer of the vitamin D preparation was not contacted to verify the amount in her preparation.]1
Toxic levels of vitamin D due to errors in labeling and manufacturing have also been reported. Araki reported on two patients who had been consuming more than 1000 (sic) times the recommended daily dose. It took approximately 1 year to normalize the vitamin) D levels.2 However, once the levels decreased below 400 ng/mL, both patients became normocalcemic and asymptomatic without long-term consequences.
- J Clin Res Pediatr Endocrinol.2013;5(2):136-9
- J Clin Endocrinol Metab. 2011;96:3603-3608.
Here are 12 hemoglobin values from each of two instruments including the means, minimum and maximum as well as the difference between the pairs and the % difference between the pairs:
|| Instr. A
|t-test = 0.000516|
According to the t-test (paired) these two instruments are "highly significantly" different. Although the average difference between them is about 0.1 gm/dL (0.4%). Barely the CV of the methods. Too often you will see data being significant in a statistical sense, when clinically it is not of clinical significance. Since the editors and authors are not likely to change, we must be careful readeers.
Oh, and by the way, using the t-test (unpaired) there is no difference between the two methods. It seems that in some cases, the statistic chosen has a significant effect on the interpretation of the data.
In 2009, Diaz (1) remarked that "both Lyme Disease and Rocky Mountain Spotted Fever are endemic in Louisiana and the Gulf South." In 2012 Stromdahl and Hickling (2) noted that "publications on tick-pathogen systems in the south-eastern United States are primarily at risk from emerging diseases caused by tick-borne pathogens other than B. burgdorferi."
Wendy Orent, in an article titled Southern Gothic: The Confounding Debate Over Lyme Disease in the South, wrote that "many Lyme researchers, including some from the NIH and the CDC, won't believe a word of it. There is little or no true Lyme Disease anywhere in the South."
Thus the question, "If there is Lyme or one like it, what is spreading it, as it is most likely not blacklegged nymphs (Ixodes scaprlaris). It appears that the most likely culprit is the Amblyomma americanum or the lone star tick. Since few researchers think that the lone star tick transmits Lyme Borrelia, the disease in the South is called STARI, for Southern Tick-Associated Rash Illness. At this point, the cause of STARI is unknown.
This is not simply an argument among researchers, but the many patients who insist that they have Lyme disease or something very much like it. But they continue that they are treated late if at all and thus are sliding into an untreated chronic syndrome as are many Lyme disease patients in the North.
- J La State Med Soc. 2009 Nov-Dec;161(6):325-6, 328, 330-1 passim.
Diseases affecting the kidneys represent a major and unsolved health issue worldwide. The kidneys rarely recover function once they are damaged by disease, highlighting the urgent need for better knowledge of kidney development and physiology.
Recently, scientists have grown human stem cells into early-stage kidney structures responsible for reabsorbing water after toxins have been filtered out. In the laboratory, mouse embryonic kidney cells were used to coax the human stem cells to grow into the embryonic mushroom-shaped buds. This work is a major step in developing regenerative techniques for growing replacement human kidneys.
Now, a team of researchers led by scientists at the Salk Institute for Biological Studies has developed a novel platform to study kidney diseases, opening new avenues for the future application of regenerative medicine strategies to help restore kidney function.
For the first time, researchers have generated three-dimensional kidney structures from human stem cells, opening new avenues for studying the development and diseases of the kidneys and to the discovery of new drugs that target human kidney cells. Scientists had created precursors of kidney cells using stem cells as recently as this past summer, but the Salk team was the first to coax human stem cells into forming three-dimensional cellular structures similar to those found in our kidneys. Source November 17, 2013 in Nature Cell Biology and the Salk Institute.
Alcohol and driving definitely don't mix, but those most in need of a ride home usually the poorest judges of how much they've had to drink. As part of an anti-drink/drive campaign by a nightclub in Singapore, DDB Group Singapore developed the: a system fitted to urinals that measures patrons' alcohol levels.
The devices are paired with an RFID reader and when patrons park their car, they exchange their car keys for parking cards containing RFID tags. These tags can then be used to identify the patrons and record their alcohol levels.
If a patron is above the legal limit, the system notes the RFID tag and a bright message is flashed above the urinal suggesting that the patron take advantage of the club's drive home program or call a cab. Another RFID reader at the valet station flashes similar warnings when the patron presents their parking cards so the valets can make the same suggestion for a ride or cab.
The results of the campaign saw 573 drivers warned in two weeks. Of these, 342 used the drive home service or called a cab.
The system is far from perfect. One factor is tolerance which allows heavier drinkers to metabolize and excrete alcohol more quickly than light or non- drinkers. If tolerant and non-tolerant drinkers have urine at the same time after the same number of drinks and using the same collection process, the heavy drinker is likely to have a very different result from the light or non-drinker. Obviously, it doesn't help the female patrons who might be driving and it presumes that the driver will have the parking card on him, so there could be a logistical gap.
Sources: DDB Group Singapore, Cannes Lions via PSFK AND News from Medical Automation.org, David Szondy July 20, 2013
Point of Care glucose meters have been with us for some time, and have found a definite place is hospitals and even in patient's homes. The search for a noninvasive, bloodless glucose meter for the growing diabetes patient population is on. A number of companies are in the race for such a device. According to a recent article in Medcity News, these devices will have one or more of the following features:
- An ear clip. Whether the data measures glucose using spectroscopy-light-sensing technology-or ultrasound, if not for sheer number alone, the device will likely clip on the patient's ear.
- Substantial data storage. Patients want to be able to see, categorize and manipulate progress, for monitoring glucose levels. One instrument in the works stores up to a thousand readings and allows patients to look at a particular date or range of dates.
- A design reminiscent of an i-Pod. Something small, cute, portable and handheld.
- A fast read. If it takes more than a minute, the competition has already got it beat (several times over). One of the meters presents the value in less than 3 seconds.
Read more: http://medcitynews.com/2013/10/will-first-noninvasive-bloodless-glucometers-look-like-theyll-probably-clip-ear/#ixzz2ivLVIL5V
Recently in an online issue of the British Medical Journal, an interventional cardiology specialist registrar at Croydon University Hospital, London, says government obsession with reducing total cholesterol has led to millions of people being overmedicated with statins, when the real issue is not cholesterol but a more complex of 3 lipid abnormalities called "atherogenic dyslipidemia."
The article stated that "recent prospective cohort studies have not supported any significant association between saturated fat intake and cardiovascular risk," and "Instead, saturated fat has been found to be protective,"
On the other hand, a 1994 meta-analysis from the University of Sydney of the effect on coronary events and total mortality in dietary intervention trials found a 6% reduction in mortality and 13% reduction in cardiac events. Most trials prescribed a reduced saturated fat and cholesterol intake with partial replacement by polyunsaturated oils. The review noted that a large controlled trial "may no longer be ethical."
In 2013 a systematic review of cardiovascular disease, information about the role of oxidized LDL and the role of saturated and poly-unsaturated fats role in the formation of atherosclerosis found several studies where polyunsaturated fats are the main contributor to atherosclerosis and coronary heart disease.
Similarly, a 2011 systematic review from The Cochrane Library analyzed 48 studies conducted between 1965 and 2009 and included 65,508 participants. All studies reduced or modified participants' dietary fat or cholesterol by at least 30 percent for at least six months. The conclusion: reducing saturated fat by reducing and/or modifying dietary fat reduced the risk of having a cardiovascular event, such as heart attack, stroke and unplanned heart surgery, by 14 percent. Of the 65,508 participants, 7 percent had a cardiovascular event.
As I write this I am looking at a book titled The Great Cholesterol Myth: Why Lowering Your Cholesterol Won't Prevent Heart Disease.
An HIV/AIDS vaccine candidate developed by researchers at Oregon Health & Science University appears to have the ability to completely clear an AIDS-causing virus from the body. The vaccine is being tested through the use of a non-human primate form of HIV, called simian immunodeficiency virus, or SIV, which causes AIDS in monkeys.. "To date, HIV infection has only been cured in a very small number of highly-publicized but unusual clinical cases in which HIV-infected individuals were treated with anti-viral medicines very early after the onset of infection or received a stem cell transplant to combat cancer," said Louis Picker, M.D., associate director of the OHSU Vaccine and Gene Therapy Institute. "This latest research suggests that certain immune responses elicited by a new vaccine may also have the ability to completely remove HIV from the body." "Through this method we were able to teach the monkey's body to better 'prepare its defenses' to combat the disease," explained Picker. "Our vaccine mobilized a T-cell response that was able to overtake the SIV invaders in 50 percent of the cases treated. Moreover, in those cases with a positive response, our testing suggests SIV was banished from the host. We are hopeful that pairing our modified CMV vector with HIV will lead to a similar result in humans." The Picker lab is now investigating the possible reasons why only a subset of the animals treated had a positive response in hopes that the effectiveness of the vaccine candidate can be further boosted.
A recent note in the New England J. Med discussed a poll on whether physician assisted suicide should be permitted.
To begin, experts provided opposing viewpoints on physician-assisted suicide. J. Donald Boudreau and Margaret Somerville of McGill University argued that physicians should not be permitted to assist in suicide as doing so conflicts with the duty of physicians to heal.
Nikola Biller-Andorno of the University of Zurich presented the position that physicians have a duty not only to heal but also to ease suffering and that in the case of some patients, this may involve assisting them in ending their lives.
U.S. readers from 49 states cast 1712 votes. In those votes from the US, 67% of the readers thought that physician-assisted suicide should not be permitted. Eighteen U.S. states had a majority of votes supporting physician-assisted suicide. Interestingly, Oregon and Washington, where physician-assisted suicide is permitted were not in that group.
From posted comments it was noted that those readers who opposed physician-assisted suicide questioned "whether suicide was a civil right or a human right, expressed the belief that assisting suicide violated a physician's oath to do no harm, and worried about a slippery slope in which physician-assisted suicide could eventually lead to euthanasia."
On the other side, remarks favoring physician-assisted suicide "highlighted the importance of honoring patients' autonomy and noted that if physicians assist at birth, they should also have a role in assisting at death. A large number of commentators on both sides of the divide agreed on the importance of palliative care, including hospice, for helping terminally ill patients manage their symptoms, both physical and psychological." "The voting and commentary indicate that the way in which patients die and the role of palliative care will remain issues of much debate."
Salivary cortisol is a measure of active free cortisol and follows the diurnal rhythm of serum or plasma cortisol. The saliva sample may be collected by drooling or through the use of absorbent swabs which are placed into the mouth until saturated.
Clinically, the most common use for salivary cortisol is measuring late-night salivary cortisol as a screening test for Cushing's syndrome. Several studies have shown diagnostic sensitivities and specificities of over 90%, which compares very favorably with other screening tests for Cushing's syndrome such as the 24-h urinary-free cortisol and the 1-mg overnight dexamethasone suppression test.
There are emerging roles for the use of salivary cortisol in diagnosing adrenal insufficiency, particularly in conditions associated with low cortisol-binding globulin levels, and in the monitoring of glucocorticoid replacement.(1) The pathophysiology of depression has been associated to dysregulation of the hypothalamic-pituitary-adrenal axis and the use of salivary cortisol measures is increasingly being incorporated into research.
A meta-analysis study of twenty case-control studies, including 1354 patients with depression and 1052 control persons were identified. In a random-effects meta-analysis salivary cortisol was increased for depressed patients as compared to control persons on average 2.58 nmol/l in the morning and on average 0.27 nmol/l in the evening.
The reference intervals for morning salivary cortisol in depressed patients (0-29 nmol/l) and control persons (1-23 nmol/l) showed substantial overlap suggesting lack of discriminative capacity. Based on the available studies there is not firm evidence for a difference of salivary cortisol in depressed patients and control persons and salivary cortisol is unable to discriminate between persons with and without depression.(2)
- Clin Endocrinol (Oxf). 2012 Nov;77(5):645-51
- Psychoneuroendocrinology. 2010 Oct;35(9):1275-86.
For several decades, the difference of laboratory results between samples said to be from the same patient (delta checks) have been used as adjuncts to quality control samples as part of a quality monitoring and control system as well as to detect significant changes within a patient.
For example imagine an INR on patient 456789 of 1.2 on July 14 and a value of 2.3 on that ‘same' patient on July 15. This is difficult to understand and bears investigating to find out which sample(s) were mislabeled.
Imagine another pair of samples with a hemoglobin on July 21 of 11.2 and another of 9.1 on the 22 -- same patient, this is possibly internal bleeding and the physician should be alerted.
It may seem to you as it has to a number of investigators over the years is a good argument for instituting a delta check system. It seems more realistic today with computers and middleware to use delta checks to reduce preanalytical errors as well as to detect significant changes within a patient.
In some recent reports there are disagreements about the utility of delta checks. For example Ovens and Naugler used repeat test values for five analytes (sodium, potassium, chloride, bicarbonate, and creatinine) from approximately 8000 inpatients. They simulated specimen mix-up errors by randomly switching a set number of pairs of second test results.
Delta check specificities ranged from 50% to 99%; however the sensitivities were generally below 20% with the exception of creatinine had a sensitivity of 82.8%. "This finding casts doubt on the ongoing clinical utility of delta checks in the setting of low rates of specimen mix-ups."
On the other hand, Straseski and Strathmann argued that "patient results can be used to detect error or identify potential testing complications at all phases of the total testing process. Patient-specific data algorithms include delta checks, tests to verify specimen or tube type, absurdity checks, and result-based reporting. Delta checks are highlighted because they can uniquely point to issues all along the testing cycle, from preanalytical to postanalytical concerns. When used properly, patient results can work to minimize risk and increase the quality of individual patient results."
I confess that I side with the latter.