eSource, Cloud-based Clinical Trials and the Future of “EDC“

 

The Electronic Date Capture (EDC) revolution began in the 1990’s and even earlier for those of us who wanted to do it with floppy drives integrated with a laptop at the clinical site. EDC, however, never fully realized it’s potential because all we did was replace data transcription from paper records to paper CRFs by the clinical sites, by data transcription from paper records to eCRFs within EDC systems, again by the clinical sites. We still had to do labor intensive on site monitoring including source document verification (SDV), which in itself added very little value. Now the new “buzz word“ is eSource. However, we need some definitions. Yes, moving data from devices such as BP and glucose monitors is eSource and is valuable for sure. But there is more to eSource than just moving data from medical devices to the study database. We also need to, in a seamless manner, enter data directly at the office visit, capture data from the electronic medical record and have more patient reported outcomes. We also must view these data in real time, perform appropriate analytics and make real-time decisions about the clinical trial such as “do nothing,“ amend the protocol, do more training and yes, stop a study. Thus EDC is no longer just a data collection tool, but must morph into “middleware,“ to manage and display data coming from disparate sources.

 

At Target Health, our current and future plans are to do all of this and more. We already have one product approved that used direct data entry (DDE) at the time of the clinic visit, an NDA with 7 studies is under review with flawless FDA pre-approval inspections and we have finished the first phase of the EHR integration and ready to initiate a study. We are also planning to put standard clinical trials in the cloud for all to use. And of course, we have been integrating data for outside sources for years.

 

www.fda.gov/newsevents/newsroom/pressannouncements/ucm476216.htm;

http://www.accessdata.fda.gov/cdrh_docs/pdf15/den150010.pdf

 

Heavenly Sunrise in the Valley of Fire at Roan Mountain – James Farley Photography

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Heavenly Sunrise in the Valley of Fire at Roan Mountain – ©James Farley Photography

 

A couple weeks ago, James Farley, photographer extraordinaire, took a couple days off and traveled to Roan Mountain, on the North Carolina / Tennessee border. All three of these shots are taken with his Canon 5D Mark III and 17mm Tilt-Shift lens. The Sunrise photo is each 5 bracketed shots merged into high dynamic range photos.

 

For more information about Target Health contact Warren Pearlson (212-681-2100 ext. 165). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel or Ms. Joyce Hays. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website.

 

Joyce Hays, Founder and Editor in Chief of On Target

Jules Mitchel, Editor

 

QUIZ

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Stroke

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CT scan slice of the brain showing a right-hemispheric ischemic stroke (left side of image). Source Wikipedia

 
A stroke, or cerebrovascular accident (CVA), is the rapid loss of brain function(s) due to disturbance in the blood supply to the 1) ___. This can be due to ischemia (lack of blood flow) caused by blockage (thrombosis, arterial embolism), or a hemorrhage. As a result, the affected area of the brain cannot function, which might result in an inability to move one or more limbs on one side of the body, inability to understand or formulate speech, or an inability to see one side of the visual field. A stroke is a medical emergency and can cause permanent neurological damage, complications, and death. Risk factors for stroke include old age, hypertension (high blood pressure), previous stroke or transient ischemic attack (TIA), diabetes, high cholesterol, cigarette smoking and atrial fibrillation. High blood pressure is the most important modifiable risk factor of stroke. It is the second leading cause of 2) ___worldwide. An ischemic stroke is occasionally treated in a hospital with thrombolysis (also known as a “clot buster”), and some hemorrhagic strokes benefit from neurosurgery. Treatment to recover any lost function is termed stroke rehabilitation, ideally in a stroke unit and involving health professions such as speech and language therapy, and occupational 3) ____. Prevention of recurrence may involve the administration of antiplatelet drugs such as aspirin and dipyridamole, control and reduction of hypertension, and the use of statins. Selected patients may benefit from carotid endarterectomy and the use of anticoagulants.

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A slice of brain from the autopsy of a person who suffered an acute middle cerebral artery (MCA) stroke. Source: Wikipedia Commons

 

Strokes can be classified into two major categories: ischemic and hemorrhagic. Ischemic strokes are those that are caused by interruption of the blood supply, while hemorrhagic strokes are the ones which result from rupture of a blood vessel or an abnormal vascular structure. About 87% of strokes are caused by ischemia, and the remainder by 4) ___. Some hemorrhages develop inside areas of ischemia (“hemorrhagic transformation”). It is unknown how many hemorrhages actually start as ischemic stroke. In an ischemic stroke, blood supply to part of the brain is decreased, leading to dysfunction of the brain tissue in that area. There are four reasons why this might happen:

 

1. Thrombosis (obstruction of a blood vessel by a blood clot forming locally)

2. Embolism (obstruction due to an embolus from elsewhere in the body.

3. Systemic hypoperfusion (general decrease in blood supply, e.g., in shock)

4. Venous thrombosis.

 

Stroke without an obvious explanation is termed “cryptogenic” (of unknown origin); this constitutes 30-40% of all 5) ___ strokes. There are various classification systems for acute ischemic stroke. The Oxford Community Stroke Project classification (OCSP, also known as the Bamford or Oxford classification) relies primarily on the initial symptoms; based on the extent of the symptoms, the stroke episode is classified as total anterior circulation infarct (TACI), partial anterior circulation infarct (PACI), lacunar infarct (LACI) or posterior circulation infarct (POCI). These four entities predict the extent of the stroke, the area of the brain affected, the underlying cause, and the prognosis. The TOAST (Trial of Org 10172 in Acute Stroke Treatment) classification is based on clinical symptoms as well as results of further investigations; on this basis, a stroke is classified as being due to (1) thrombosis or embolism due to atherosclerosis of a large artery, (2) embolism of cardiac origin, (3) occlusion of a small blood vessel, (4) other determined cause, (5) undetermined cause (two possible causes, no cause identified, or incomplete investigation).

 

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An intraparenchymal bleed (bottom arrow) with surrounding edema (top arrow)

Source: Wikipedia Commons

 

 

Intracranial hemorrhage is the accumulation of blood anywhere within the 6) ___ vault. A distinction is made between intra-axial hemorrhage (blood inside the brain) and extra-axial hemorrhage (blood inside the skull but outside the brain). Intra-axial hemorrhage is due to intraparenchymal hemorrhage or intraventricular hemorrhage (blood in the ventricular system). The main types of extra-axial hemorrhage are epidural hematoma (bleeding between the dura mater and the skull), subdural hematoma (in the subdural space) and subarachnoid hemorrhage (between the arachnoid mater and pia mater). Most of the hemorrhagic stroke syndromes have specific symptoms (e.g., headache, previous head injury).Stroke symptoms typically start suddenly, over seconds to minutes, and in most cases do not progress further. The symptoms depend on the area of the brain affected. The more extensive the area of brain affected, the more functions that are likely to be lost. Some forms of stroke can cause additional symptoms. For example, in intracranial hemorrhage, the affected area may compress other structures. Most forms of stroke are not associated with headache, apart from subarachnoid hemorrhage and cerebral venous thrombosis and occasionally intracerebral hemorrhage.

 

Various systems have been proposed to increase recognition of stroke. Different findings are able to predict the presence or absence of stroke to different degrees. Sudden-onset face weakness, arm drift (i.e., if a person, when asked to raise both arms, involuntarily lets one arm drift downward) and abnormal speech are the findings most likely to lead to the correct identification of a case of stroke increasing the likelihood by 5.5 when at least one of these is present). Similarly, when all three of these are absent, the likelihood of stroke is significantly decreased (- likelihood ratio of 0.39). While these findings are not perfect for diagnosing 7) ____, the fact that they can be evaluated relatively rapidly and easily make them very valuable in the acute setting. Proposed systems include FAST (stroke) (face, arm, speech, and time), as advocated by the Department of Health (United Kingdom) and The Stroke Association, the American Stroke Association (www.strokeassociation.org), National Stroke Association (US www.stroke.org), the Los Angeles Prehospital Stroke Screen (LAPSS) and the Cincinnati Prehospital Stroke Scale (CPSS). Use of these scales is recommended by professional guidelines.

 

For people referred to the emergency room, early recognition of stroke is deemed important as this can expedite diagnostic tests and treatments. A scoring system called ROSIER (recognition of stroke in the emergency room) is recommended for this purpose; it is based on features from the medical history and physical examination. If the area of the brain affected contains one of the three prominent central nervous system pathways – the spinothalamic tract, corticospinal tract, and dorsal column (medial lemniscus), symptoms may include:

 

1. hemiplegia and muscle weakness of the 8) ___

2. numbness

3. reduction in sensory or vibratory sensation

4. initial flaccidity (hypotonicity), replaced by spasticity (hypertonicity), hyperreflexia, and obligatory synergies.

 

In most cases, the symptoms affect only one side of the body (unilateral). Depending on the part of the brain affected, the defect in the brain is usually on the opposite side of the 9) ___. However, since these pathways also travel in the spinal cord, and any lesion there can also produce these symptoms, the presence of any one of these symptoms does not necessarily indicate a stroke. In addition to the above CNS pathways, the brainstem gives rise to most of the twelve 10) ___ cranial nerves. A stroke affecting the brain stem and brain therefore can produce symptoms relating to deficits in these cranial nerves:

  • altered smell, taste, hearing, or vision (total or partial)
  • drooping of eyelid (ptosis) and weakness of ocular muscles
  • decreased reflexes: gag, swallow, pupil reactivity to light
  • decreased sensation and muscle weakness of the face
  • balance problems and nystagmus
  • altered breathing and heart rate
  • weakness in sternocleidomastoid muscle with inability to turn head to one side
  • weakness in tongue (inability to protrude and/or move from side to side)

If the cerebral cortex is involved, the CNS pathways can again be affected, but also can produce the following symptoms:

  • aphasia (difficulty with verbal expression, auditory comprehension, reading and/or writing Broca’s or Wernicke’s area typically involved)
  • dysarthria (motor speech disorder resulting from neurological injury)
  • apraxia (altered voluntary movements)
  • visual field defect
  • memory deficits (involvement of temporal lobe)
  • hemineglect (involvement of parietal lobe)
  • disorganized thinking, confusion, hypersexual gestures (with involvement of frontal lobe)
  • lack of insight of his or her, usually stroke-related, disability

If the cerebellum is involved, the patient may have the following:

  • altered walking gait
  • altered movement coordination
  • vertigo and or disequilibrium

Loss of consciousness, headache, and vomiting usually occurs more often in hemorrhagic stroke than in thrombosis because of the increased intracranial pressure from the leaking blood compressing the brain. If symptoms are maximal at onset, the cause is more likely to be a subarachnoid hemorrhage or an embolic stroke.

 

ANSWERS: 1) brain; 2) death; 3) therapy; 4)  hemorrhage; 5) ischemic; 6) skull; 7) stroke; 8) face; 9) body; 10) cranial

 

Curare

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Franz Eugen Kohler: Kohler’s Medizinal-Pflanzen, Strychnos toxifera by Koehler 1887

 

Curare is a common name for various plant extract alkaloid arrow poisons originating from Central and South America. These poisons function by competitively and reversibly inhibiting the nicotinic acetylcholine receptor (nAChR), which is a subtype of acetylcholine receptor found at the neuromuscular junction. This causes weakness of the skeletal muscles and, when administered in a sufficient dose, eventual death by asphyxiation due to paralysis of the diaphragm. According to pharmacologist Rudolf Boehm’s 1895 classification scheme, the there are 3 main types of curare, and of these 3 types, some formulas belonging to the tube curare are the most toxic, relative to their LD50 values:

 

1. Tube or bamboo curare (so named because of its packing into hollow bamboo tubes; main toxin is D-tubocurarine).

2. Pot curare (originally packed in terra cotta pots; main alkaloid components are protocurarine, protocurine, and protocuridine). Protocurarine is the active ingredient; protocurine is only weakly toxic, and protocuridine is not toxic.

3. Calabash or gourd curare (originally packed into hollow gourds; main toxin is curarine).

 

Curare was used as a paralyzing poison by South American indigenous people. The prey was shot by arrows or blowgun darts dipped in curare, leading to asphyxiation owing to the inability of the victim’s respiratory muscles to contract. The word ?curare’ is derived from wurari, from the Carib language of the Macusi Indians of Guyana. Curare is also known among indigenous peoples as Ampi, Woorari, Woorara, Woorali, Wourali, Wouralia, Ourare, Ourari, Urare, Urari, and Uirary.

 

In 1596, Sir Walter Raleigh mentioned the arrow poison in his book Discovery of the Large, Rich, and Beautiful Empire of Guiana (which relates to his travels in Trinidad and Guayana), though the poison he described possibly was not curare. In 1780, Abbe Felix Fontana discovered that it acted on the voluntary muscles rather than the nerves and the heart. In 1832, Alexander von Humboldt gave the first western account of how the toxin was prepared from plants by Orinoco River natives. During 1811-1812, Sir Benjamin Collins Brody (1783-1862) experimented with curare. He was the first to show that curare does not kill the animal and the recovery is complete if the animal’s respiration is maintained artificially. In 1825, Charles Waterton described a classical experiment in which he kept a curarized female donkey alive by artificial respiration with a bellows through a tracheostomy. Waterton is also credited with bringing curare to Europe. Robert Hermann Schomburgk, who was a trained botanist, identified the vine as one of the Strychnos genus and gave it the now accepted name Strychnos toxifera. George Harley (1829-1896) showed in 1850 that curare (wourali) was effective for the treatment of tetanus and strychnine poisoning. In 1857, Claude Bernard (1813-1878) published the results of his experiments in which he demonstrated that the mechanism of action of curare was a result of interference in the conduction of nerve impulses from the motor nerve to the skeletal muscle, and that this interference occurred at the neuromuscular junction.

 

From 1887, the Burroughs Wellcome catalogue listed under its ?Tabloids’ brand name, tablets of curare at 1/12 grain (price 8 shillings) for use in preparing a solution for hypodermic injection. In 1914, Henry Hallett Dale (1875-1968) described the physiological actions of acetylcholine. After 25 years, he showed that acetylcholine is responsible for neuromuscular transmission, which can be blocked by curare. The best known and historically most important (because of its medical applications) toxin is d-tubocurarine. It was isolated from the crude drug – from a museum sample of curare – in 1935 by Harold King (1887-1956) of London, working in Sir Henry Dale’s laboratory. He also established its chemical structure. It was introduced into anesthesia in the early 1940s as a muscle relaxant for surgery. Curare is active – toxic or muscle-relaxing, depending on the intended use – only by an injection or a direct wound contamination by poisoned dart or arrow. It is harmless if taken orally because curare compounds are too large and highly charged to pass through the lining of the digestive tract to be absorbed into the blood. For this reason, people can eat curare-poisoned prey safely. In medicine, curare has been superseded by a number of curare-like agents, such as pancuronium, which have a similar pharmacodynamic profile, but fewer side effects.

 

The various components of curare are organic compounds classified as either isoquinoline or indole alkaloids. Tubocurarine is the major active component in the South American dart poison. As an alkaloid, tubocurarine is a naturally occurring compound that consists of nitrogenous bases-though the chemical structure of alkaloids is highly variable. Like most alkaloids, tubocurarine consists of a cyclic system with a nitrogen atom in an amine group. Because of this structure, tubocurarine can bind readily to the receptors for acetylcholine (ACh) at the neuromuscular junction, which blocks nerve impulses from being sent to the skeletal muscles, effectively paralyzing the muscles of the body. Since the tubocurarine will bind irreversibly to the ACh receptors, treatment for curare poisoning involves adding an acetylcholinesterase (AChE) inhibitor, which will stop the destruction of acetylcholine so that it can compete with curare. The time of onset varies from within one minute (for tubocurarine in intravenous administration, penetrating a larger vein), to between 15 and 25 minutes (for intramuscular administration, where the substance is applied in muscle tissue). Isolated attempts to use curare during anesthesia date back to 1912 by Arthur Lawen of Leipzig, but curare came to anesthesia via psychiatry (electroplexy). In 1939 Abram Elting Bennett used it to modify metrazol induced convulsive therapy. Muscle relaxants are used in modern anesthesia for many reasons, such as providing optimal operating conditions and facilitating intubation of the trachea. Before muscle relaxants, anesthesiologists needed to use larger doses of the anesthetic agent, such as ether, chloroform or cyclopropane to achieve these aims. Such deep anesthesia risked killing patients that were elderly or had heart conditions.

 

The source of curare in the Amazon was first researched by Richard Evans Schultes in 1941. Since the 1930s, it was being used in hospitals as a muscle relaxant. He discovered that different types of curare called for as many as 15 ingredients, and in time helped to identify more than 70 species that produced the drug. In the 1940s, it was used on a few occasions during surgery as it was mistakenly thought to be an analgesic or anesthetic. The patients reported feeling the full intensity of the pain though they were not able to do anything about it since they were essentially paralyzed. On January 23, 1942, Harold Griffith and Enid Johnson gave a synthetic preparation of curare (Intercostrin/Intocostrin) to a patient undergoing an appendectomy (to supplement conventional anesthesia). Safer curare derivatives, such as rocuronium and pancuronium, have superseded d-tubocurarine for anesthesia during surgery. When used with halothane d-tubocurarine can cause a profound fall in blood pressure in some patients as both the drugs are ganglion blockers. However, it is safer to use d-tubocurarine with ether. In 1954, an article was published by Beecher and Todd suggesting that the use of muscle relaxants (drugs similar to curare) increased death due to anesthesia nearly sixfold. This was refuted in 1956. Modern anesthetists have at their disposal a variety of muscle relaxants for use in anesthesia. The ability to produce muscle relaxation irrespective of sedation has permitted anesthetists to adjust the two effects independently and on the fly to ensure that their patients are safely unconscious and sufficiently relaxed to permit surgery. The use of neuromuscular blocking drugs carries with it a very small risk of anesthesia awareness.

 

Plant sources utilized by indigenous tribes of Central and South America for the production of arrow poisons include dozens of plants from which isoquinoline and indole alkaloids with curarizing effects can be isolated. Traditionally prepared curare is a dark, heavy, viscid paste with a very bitter taste. In the Amazon there is such a bounty of plants so rich in alkaloids that an effective curare can be made by boiling down several kilos of any combination of 20 different species of jungle leaves. Once it becomes a thick syrupy tar it will most likely be able to bring down anything from a monkey to a man. It is known that the final preparation is often more potent than the concentrated principal active ingredient. Various irritating herbs, stinging insects, poisonous worms, and various parts of amphibians and reptiles are added to the preparation. Some of these accelerate the onset of action or increase the toxicity; others prevent the wound from healing or blood from coagulating.

 

Curare poisoning can be indicated by typical signs of neuromuscular-blocking drugs such as paralysis including respiration but not directly affecting the heart. Curare poisoning can be managed by artificial respiration such as mouth-to-mouth resuscitation. In a study of 29 army volunteers that were paralyzed with curare, artificial respiration managed to keep an oxygen saturation of always above 85%, a level at which there is no evidence of altered state of consciousness. Yet, curare poisoning mimics the total locked-in syndrome in that there is paralysis of every voluntarily controlled muscle in the body (including the eyes), making it practically impossible for the victim to confirm consciousness while paralyzed. Spontaneous breathing is resumed after the end of the duration of action of curare, which is generally between 30 minutes to 8 hours, depending on the variant of the toxin and dosage. Cardiac muscle is not directly affected by curare, but if more than four to six minutes has passed since respiratory cessation the cardiac muscle may stop functioning by oxygen-deprivation, making cardiopulmonary resuscitation including chest compressions necessary. Muscle paralysis can be reversed by administration of a cholinesterase inhibitor such as pyridostigmine.

 

Some Women with PCOS May Have an Adrenal Disorder

 

PCOS is a group of symptoms related to high levels of hormones known as androgens. In many women with the condition, the ovaries contain numerous small, cyst-like sacs. Women with PCOS may have irregular, missing, or prolonged menstrual periods, excessive facial and body hair, insulin resistance, and problems with fertility. Treatment may include drugs that block androgens, and oral contraceptives, which contain the hormones estrogen and progesterone. According to an article published online in the Journal of Clinical Endocrinology and Metabolism (27 June 2016), a subgroup of women with PCOS, may produce excess adrenal hormones.

 

In their article, the authors noted that earlier studies had found that in some women with PCOS, androgens were produced by the adrenal glands, rather than by the ovaries. On the basis of these observations, the authors decided to test the adrenal functioning of women with PCOS. Study participants included a total of 38 women with PCOS along with 20 healthy women, who served as a control group. Adrenal functioning was measured with a diagnostic procedure known as Liddle’s test, used to diagnose disorders of the adrenal glands. The test consists of a two-part sequence in which women take the drug dexamethasone, which mimics the adrenal hormone cortisol, first in a low dose and then in a high dose. At the end of the test, people with disorders of the adrenal glands often will produce high levels of adrenal hormones. Results showed that 15 of the 38 PCOS patients produced more adrenal hormones than normal and that these women also had adrenal glands that were smaller than normal. The authors theorized that the women’s adrenal glands may resemble those seen in a condition called micronodular adrenocortical hyperplasia-in which tiny lumps or nodules appear on the adrenal glands and begin producing adrenal hormones. Because the nodules produce hormones, the adrenals produce fewer hormones and shrink.

 

The authors noted that additional studies with a larger number of patients will be needed to examine the adrenal glands of women with PCOS to confirm the study results and to determine whether the women have micronodular adrenocortical hyperplasia or some other condition affecting the adrenal glands.

 

1976 Ebola Outbreak Holds Lessons Relevant Today

 

With the recent Ebola epidemic in West Africa reviving interest in the first outbreak of the deadly hemorrhagic fever 40 years ago, a report, published in online in the Journal of Infectious Diseases (June 2016), highlights lessons learned from the smaller, more quickly contained 1976 outbreak. According to the authors, key to diagnosis in 1976 was the relatively quick clinical recognition of a severe, possibly new disease by national authorities, and international notification and specimen provision occurred within five weeks from onset of the first cases. In contrast, this did not occur in the 2013-2016 epidemic, when the delay was over three months.

 

The report identifies an adult male who was hospitalized in late August 1976 at Yambuku Mission Hospital in the Democratic Republic of Congo (DRC) — known as Zaire at the time — as the first Ebola patient. It describes how “several dozen patients developed a similar febrile hemorrhagic syndrome and died in about one week, as did many of their contacts. A month after “patient zero“ was hospitalized, blood taken from a Belgian midwife-nun who had contracted the virus was sent to Belgium for analysis. Within days of the nun’s death, the area where the outbreak was occurring was placed under quarantine and Yambuku Hospital was shut down on the advice of Zairean, Belgian and French health officials. In total, there were 318 cases of Ebola in 1976 and 280 deaths in an outbreak that lasted less than 11 weeks. In the recent West Africa outbreak, there were 11,310 deaths out of nearly 29,000 cases, and the epidemic lasted more than two years — almost 10 times as long as in 1976. The death rate in 1976 was 88%, which was much higher than around 50% in the recent outbreak in Liberia, Guinea and Sierra Leone.

 

The report also tries to settle the debate over who “discovered“ the Ebola virus in 1976. Local Zairean, Belgian and French doctors and health officials were the first to see and assess patients in Yambuku, while the Institute of Tropical Medicine in Antwerp, Belgium, received the first Ebola specimens and recovered what they called “a Marburg-like virus.“ However, according to the report, it was the Centers for Disease Control and Prevention in the United States that identified and recognized a new, unknown virus that fulfilled the criteria for discovery of a new virus. Specific credit was given to Drs. Patricia Webb, James Lange and Karl Johnson, of the CDC’s Special Pathogens Branch.

 

As for what carried the virus into DRC in the first place, investigators in Zaire determined by questioning community leaders, people recovering from Ebola and the families of 1976 victims about their contact with animals, that bats were not the vector. However, in the 40 years since the first Ebola outbreak, fruit bats have been found to be probable reservoirs for filoviruses — the type that causes Ebola — and the Ebola genome and antibodies have been found in bat and rodent species in East and West Africa.

 

According to the authors, more extensive preparations, including improved screening capabilities, are needed to detect and manage future outbreaks promptly, and that primary prevention through strengthened prediction models, detection, response, control mechanisms, and international cooperation and coordination are essential for all countries in Africa and elsewhere where Ebola and new and re-emergent pathogens are sure to surface again.

 

Test Cleared To Detect Genetic Markers For Antibiotic-Resistant Bacteria

 

According to the Centers for Disease Control and Prevention, Carbapenem-resistant Enterobacteriaceae (CRE) infections most commonly occur in people with exposure to health care settings, like hospitals and long-term care facilities. Because of this, these types of infections often occur among patients who are receiving treatment for other serious conditions. Patients whose care requires devices like ventilators, urinary catheters, or intravenous catheters, and patients who are taking long courses of certain antibiotics are among those at risk for CRE infections. CRE are usually resistant to many other antibiotics in addition to carbapenems, and several CRE outbreaks of these highly resistant bacteria have been reported in the U.S. When bacteria become resistant to carbapenems, few treatment options may remain. Some CRE bacteria have become resistant to almost all available antibiotics and present a significant public health threat.

 

The FDA has cleared for marketing the Xpert Carba-R Assay, an infection control aid that tests patient specimens to detect specific genetic markers associated with bacteria that are resistant to Carbapenem antibiotics. Carbapenem antibiotics are widely used in hospitals to treat severe infections. These CRE resistant organisms have been reported in almost all states within the U.S.

 

Current methods to identify colonization with CRE or other resistant organisms rely on growing bacteria from fecal material in cultures, which are then subjected to antimicrobial susceptibility testing to determine in vitro susceptibility to antimicrobial agents. Bacterial culture methods and susceptibility testing may take up to four days, and additional testing is often also required to confirm that carbapenemase, an enzyme that inactivates carbapenem antibiotics, is present. The Xpert Carba-R Assay tests specimens directly taken from patients, which are usually obtained by rectal swabs, for the presence of five different genetic markers that are associated with carbapenemase, the enzyme produced by CRE.

 

The Xpert Carba-R Assay is intended as an aid in infection control and can be used in conjunction with other clinical and laboratory findings. Although the Xpert Carba-R Assay tests for the most prevalent carbapenemase genes associated with resistance to carbapenem antibiotics, it does not detect the bacteria, carbapenemase activity or other possible non-enzymatic causes of carbapenem resistance. The Xpert Carba-R Assay tests only for genetic material. The Xpert Carba-R Assay also does not detect all types of carbapenemase genes, and it is important to recover bacteria for accurately tracking the spread of carbapenem resistance. Labs should continue to perform standard bacterial culture in conjunction with the Xpert Carba-R Assay. In addition, concomitant cultures are necessary to recover organisms for epidemiological typing, antimicrobial susceptibility testing, and for confirmatory bacterial identification.

 

The FDA’s decision to provide clearance was based on data from two clinical studies. A prospective study used rectal swabs from 755 patients in hospitals or long-term care facilities to compare results from the Xpert Carba-R Assay with results from reference cultures and automated real-time polymerase chain reaction (PCR) sequencing. A second study designed to test the clinical performance of the Xpert Carba-R Assay used 432 rectal swabs that were artificially prepared with specific concentrations of bacteria containing the genes detected by the test. The results of these studies demonstrated similar performance between the Xpert Carba-R Assay and culture method. The Xpert Carba-R Assay is manufactured by Cepheid, located in Sunnyvale, Calif.

 

Melt in Your Mouth Moroccan Salmon

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Full bodied flavor and a new take on lentil sauce. ©Joyce Hays, Target Health Inc.

 

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Could not stop eating the salmon. ©Joyce Hays, Target Health Inc.

 

 

Ingredients

 

1 pound fillet of salmon

2 Tablespoons extra-virgin olive oil

1 large onion, finely diced, about 2 cups

14 garlic cloves, minced

2 or 3 fresh scallion stalks, thinly sliced up to half of the green part

1 Tablespoon dried ginger

2 pinches black pepper

2 teaspoons turmeric

1 teaspoon toasted and ground, cumin

3 pinches chili flakes

3 big pinches of crumbled saffron

1 (3-inch) piece cinnamon stick

4 cups diced ripe tomato, fresh or canned Cento

2 Tablespoons chopped celery leaves

4 heaping Tablespoons chopped cilantro

3 heaping Tablespoons, fresh, finely chopped dill weed

Pinch Salt

1 cup brown (uncooked) lentils, rinsed

1 cup red lentils (uncooked), rinsed

1 cup fresh, in pod (uncooked) fava beans (or substitute 1 cup dried chickpeas, soaked overnight)

(optional) 1/4 pound angel hair pasta (capellini) broken into 1-inch pieces

Lemon wedges, for serving

 

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Directions

 

Cook the pasta and/or saffron rice, separately. Serve it separately with the salmon and sauce, or serve the salmon and sauce, over the rice or pasta.

Chop onions, garlic, and scallion all at the same time.

 

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It saves time to chop everything at once, on same cutting board. ©Joyce Hays, Target Health Inc.

 

 

In a skillet, put olive oil over medium-high heat. Add onion and cook, stirring, until softened and lightly colored, 8 to 10 minutes. Stir in garlic, ginger, pepper, turmeric, cumin, cayenne, saffron and cinnamon. Cook for about 2 minutes more. Continue to stir.

 

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Saute onions, garlic & scallions. ©Joyce Hays, Target Health Inc.

 

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Just added green part of scallions, thinly sliced. ©Joyce Hays, Target Health Inc.

 

 

In a heavy soup pot or Dutch oven, add the tomato, celery leaves and cilantro and bring to a brisk simmer. After the onion/garlic mixture is cooked for 10 minutes, add this to the heavy pot.

 

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Cooking fresh tomatoes in a heavy pot. ©Joyce Hays, Target Health Inc.

 

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Just added onions, garlic, scallions to tomatoes. ©Joyce Hays, Target Health Inc.

 

 

Cook, stirring, about 5 minutes, until mixture thickens somewhat, then add 1 teaspoon salt, the brown lentils, red lentils and dried favas. Add 4 cups water and 4 cups chicken broth. Bring to a boil, then reduce to a gentle simmer, covered with the lid, slightly ajar.

 

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Just added the fava beans to pot. ©Joyce Hays, Target Health Inc.

 

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Just added brown lentils to pot. ©Joyce Hays, Target Health Inc.

 

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Finally, the red lentils added, stirred and starting to smell wonderful! ©Joyce Hays, Target Health Inc.

 

 

Let soup simmer for 30 minutes, then taste broth and adjust salt.

Cook for 1 hour more at a gentle simmer, until the legumes are soft and creamy. It may be necessary to add more liquid from time to time to keep soup from being too porridge-like. It should be on the thick side, but with a pourable consistency. (With every addition of water, taste and adjust for salt.)

Preheat oven to 375 degrees.

 

Get Salmon Ready to Bake

 

I’ve done this recipe with salmon strips and with the 1 pound fillet of salmon, not cut. My conclusion, is that the whole piece of salmon bakes the best. But the most important thing is to get the very best, most fresh salmon you can find, for optimal results. Cutting in strips, just makes the salmon easier to serve at the table.

 

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Lovely fresh salmon, from Whole Foods, where the fish monger cut the strips. ©Joyce Hays, Target Health Inc.

 

I have experimented with this recipe several times. Please take note: The salmon turns out even better, if NOT cut into strips. Keep the 1 pound salmon fillet, whole, with the lentil mixture poured over the top of the baking dish.

 

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©Joyce Hays, Target Health Inc.

 

Slightly oil a baking dish and put the salmon strips on the bottom. . I have experimented with this recipe several times. Please take note: The salmon turns out even better, if NOT cut into strips. Keep the 1 pound salmon fillet, whole, with the lentil mixture poured over the top of the baking dish.

 

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Pour the Moroccan bean mixture over the salmon and bake for 15 to 20 minutes. ©Joyce Hays, Target Health Inc.

 

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Going into the oven. ©Joyce Hays, Target Health Inc.

 

Just before serving, add pasta and let cook for 2 to 3 minutes. Ladle soup into small bowls and pass lemon wedges for squeezing.

 

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Chilled wine and warm sourdough rolls — Mmmmmm ©Joyce Hays, Target Health Inc.

 

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We missed our June anniversary for a whole slew of reasons, so celebrated this past weekend. We started dinner with icy, special anniversary glasses, of our favorite white wine of the moment, Louis Jadot, Pouilly-Fuisse, and sourdough rolls just out of the oven. Next an appetizer of fresh figs baked in a nest of Burrata mozzarella and basil leaves, and an aged balsamic reduction. Next a slightly new tomato/avocado salad; then the entr?e the melt in your mouth salmon/lentil recipe. Finally a new recipe for dessert. We saw the Disney musical, Aladdin at the recommendation of a cultured friend, but were disappointed. Disney’s Little Mermaid was better; Phantom was better. But we love the theater and didn’t mind, that much, that we got sucked into a kiddy show. This was a perfect weekend for us, relaxing, stimulating, tasty, with lovely weather.

 

 

From Our Table to Yours!

 

Bon Appetit!

 

BREXIT: Global Emergency

 

On a much more serious note: One of our European clients who is also a good friend, sent me two excellent articles by the incomparable, highly respected, Martin Wolf who writes for the Financial Times. Because, here in the U.S. we care deeply about European politics and economics and a quick solution to the Brexit issue, we include the two articles by Martin Wolf. The dissolution of the EU would be catastrophic for the world. Because of four huge global problems that affect all of us, (climate change, roboticism, terrorism, never-ending refugee stream) we feel that this is a crucial time for uniting and not dissolving. The four major problems named, cannot be solved without the cooperation of the global community.

 

The Financial Times

 

Brexit will reconfigure the UK economy

 

Britain has prospered inside the EU but it will not do as well outside

June 26, 2016

Martin Wolf

 

by: Martin Wolf

 

David Cameron took a huge gamble  and lost. The fearmongering and outright lies of Boris Johnson, Michael Gove, Nigel Farage, The Sun and the Daily Mailhave won. The UK, Europe, the west and the world are damaged. The UK is diminished and seems likely soon to be divided. Europe has lost its second-biggest and most outward-looking power. The hinge between the EU and the English-speaking powers has been snapped. This is probably the most disastrous single event in British history since the second world war. Yet the UK might not be the last country to suffer such an earthquake. Similar movements of the enraged exist elsewhere – most notably in the US and France. Britain has led the way over the cliff. Others might follow. The UK and, to a lesser degree, the EU are now at the beginning of an extended period of uncertainty. The Conservatives will have new leadership. Whether they will manage to produce a coherent government is another matter. They then will have to do what Brexiters failed to do during their mendacious campaign – map out a plan for unravelling the UK’s connections with the EU. They broke it; they now own it. But, alas, it seems unlikely that there is any plan on which Brexiters can agree. This will probably consume the energies of that government and its successors over many years. It will also involve making some huge decisions. One point seems evident: it is now politically inevitable that the UK will have to bring in controls over immigration from the EU. That rules out what might at first glance seem the best option: membership of the European Economic Area, which would permit membership of the single market. At best, the UK might participate in a free trade area in goods. But the services, on which it depends, would be excluded from the single market. Meanwhile, the rest of the EU, burdened with so many challenges, will have to work out its own negotiating positions. They will surely be tough ones. Why should they treat generously a country that has given them a kick in the teeth? Why should they encourage other European politicians to believe exit is a cheap option? If Mr Johnson were to become prime minister, how might one expect Germany’s chancellor to deal with a man who thinks the EU has the same goal as Hitler’s Reich? Yes, Germany has a trade surplus with the UK. But that will not be decisive, not least because its manufacturers will continue to sell the high-quality products the UK does not make, regardless. The pound has already plunged. If it stays low, which is likely, that might cushion the effect on output, at least in the medium term. But the unavoidable uncertainty (http://www.prospectmagazine.co.uk/politics/how-brexit-should-be-doneeuropean-union-referendum-result) will last for years, not months, and is likely to destabilise asset markets repeatedly. If the pound’s fall generates a short-term jump in inflation, so be it: the Bank of England can ignore that. But the loss of confidence in the UK might be so severe, particularly given the size of the UK’s current account deficit, that the UK authorities cannot manage it. If so, sizeable foreign support might be needed. Will it arrive? George Osborne’s fiscal warnings were not altogether foolish. The provinces will have to learn, possibly soon, what the likely loss of economic dynamism means for the tax revenues on which they depend. An emergency Budget is unnecessary. But it is You tell us probable that the structural, not just the cyclical, fiscal position has now deteriorated. If so, that will surely demand a fiscal tightening at some point. The UK economy is going to be reconfigured. Those businesses that have set up in the UK to serve the EU market must reconsider their position. The City’s role in trading in euro-denominated assets will be undermined. Manufacturers will also have to consider how to readjust their productive capacity. Many will relocate. Businesses who depend on their ability to employ European nationals freely will have to reshape operations. Many will want to move inside the EU single market. Such decisions will not have to be made at once. But they will drive down investment now. In economic life, the future is always, to an extent, here today. In the short term, however, it will be difficult to make any such decisions sensibly. Business simply does not know how politicians will end up approaching the difficult negotiations ahead. This uncertainty has always been the obvious result of a vote to leave. Only time will clear this fog. But the view that, beyond a lengthy period of transition, the UK will be poorer than it would otherwise have been is overwhelmingly probable. The UK did well inside the EU. It is unlikely to do as well outside it. Yet economics are just a part of what matters. The UK’s decision to join the EU was taken for sound reasons. Its decision to leave was not. It is a choice to turn its back on the great effort to heal Europe’s historical divisions. This is, for me, among the saddest of hours. martin.wolf@ft.com (mailto:martin.wolf@ft.com)

___________________________________________________________.

 

The Financial Times

 

 

What a Prime Minister Boris Johnson should do next

 

He might forget the whole Brexit thing or, alternatively, call another referendum

 

by: Martin Wolf

 

On May 22, one Boris Johnson gave his forecast for the UK’s post-referendum future: “Given the choice between taking back control or being sucked ever deeper into the federal superstate, the British voted for independence on June 23. To no one’s very great surprise, Project Fear turned out to be a gigantic hoax. The markets were calm. The pound did not collapse.“ Alas, untrue. After the biggest ever proportional two-day decline, the pound touched a 30-year low against the dollar. Standard & Poor’s and Fitch have downgraded UK public debt. Investors have savaged bank shares. So far, the experts, dismissed by Michael Gove, justice secretary, have been proved right. Mr Johnson is to economic forecasting what England is to football. Any well-informed person knew that a vote for Brexit would inflict medium-term pain on the economy. The Treasury might even have been underestimating the shock. It would be astonishing if there were to be no recession. This self-inflicted folly will hurt millions of innocent people. It is likely that buyers’ remorse will soon set in. Voters might conclude that the leaders of the Leave campaign were fools or liars. It is easy to sympathise with the view of Harvard’s Kenneth Rogoff that the hurdle for a change to the status quo had to be far higher than 50% of votes in a referendum on an issue as profound as this one. As it is, 36% of eligible voters have been allowed to decide “without any appropriate checks and balances“. This is just one aspect of the irresponsibility shown by David Cameron, Britain’s prime minister, throughout this immensely important process. It is not surprising, for example, that he found it hard to argue credibly for Remain after spending JUNE 28, 2016 7:27 PM Suggestions below based on Boris Johnson FirstFT – an unpalatable dawn Carney hit by Leave flak as Bank battles to steady economic ship Boris Johnson’s backing for BoE governor has not filtered down to Out supporters Theresa May gains momentum in Tory leadership race Candidates neck and neck ahead of nomination day Merkel, the great procrastinator, could be Britain’s saviour The German chancellor’s talent for delay will be crucial, writes Alan Beattie Merkel: no cherry picking deal for UK More on this topic more than five years denigrating almost everything about the EU. He has proved calamitously short-sighted. Might it be possible to abort the entire process? Legally, yes. As Brexiters rightly say, the UK is a parliamentary, not a plebiscitary, democracy. The step that must be taken, if the UK is to leave the EU, is for it to issue a declaration under Article 50 of the Lisbon treaty, to trigger the process. In law, a referendum is solely advisory. Only parliament can do this, because only it makes valid law. After selection of a new leader by the Conservative party, and perhaps even a general election, Prime Minister Johnson might, to paraphrase Emperor Hirohito’s remarks at the end of the second world war, declare that, given the “unexpected“ economic damage and the risk of a break-up of the UK, the situation “had developed not necessarily to the UK’s advantage“. He might forget the whole thing or, alternatively, call another referendum, merely to make sure the people remained as determined. The desire of the Leave side not to trigger Article 50 and the determination of EU leaders not to negotiate until it does could then give the time needed to change minds. Politically, however, this option would surely be too slippery, even for Mr Johnson. If so, a second option would be to suggest to the rest of the EU that the principle of unrestricted movement might be reconsidered. What, the UK might ask, about a safeguard arrangement? After all, UK membership and continued (if modestly restricted) access to the UK labour market would be better than Brexit and a tightly restricted entry. Moreover, only with safeguards on movement might Turkish or Ukrainian membership ever be feasible. The US could quietly indicate to the EU how much is at stake. Then there could be a referendum on new terms and so the UK might remain in the EU. Yet it is probable that the EU will rule out restrictions on movement. If so, Brexiters must recognise something they prefer to deny: they cannot have their cake and eat it.Mr Johnson insists there will be “democratic control of immigration policy“. He also states that there will be “free trade, and access to the single market“. But, if the EU sticks to its current policies, then the access to the single market the UK has today is unavailable, because that is incompatible with controls on EU immigration. Mr Johnson needs to make a choice. “Access to the single market“ are weasel words. Most will take it to mean the access the UK now enjoys. But it might mean the more limited access that the US, say, has. If that is all the UK seeks, it must say so. But leaving the EU and seeking to retain current access to the single market, while accepting free movement of labour, would be mad. If the UK were willing to accept all this, it should stay inside the EU, since it would continue to possess a voice in the single-market regulations that would affect it. Controls on immigration are the crux. If they are inescapable for the post-referendum UK and if the EU will not shift on the issue, then the UK must lose its access to the single market. It should, instead, open discussions on the best trade agreement to allow such controls. Right now, however, the best thing to do is nothing. The UK must work out what it wants. The EU must consider whether free movement is inviolable. The UK should avoid triggering Article 50: that would eliminate its leverage and would push it out of the EU within two years, probably with no further trade agreement. Any such stalemate cannot continue forever. But there could be benefits, for both sides, in avoiding too hasty and brutal an ending. The story goes that a man condemned to death told his king: “I could teach your horse to sing, within a year.“ The king replied: “Very well. But if the horse is not singing a year from now, you will be executed.“ Upon the criminal’s return, his cellmate remonstrated: “You know you can’t teach that horse to sing.“ He replied: “I have a year I didn’t have before. A lot of things can happen in a year. The king might die. The horse might die. I might die. “And, who knows? Maybe the horse will sing.“ I suggest we try that year or so.

 

martin.wolf@ft.com (mailto:martin.wolf@ft.com); The Financial Times