eClinical Forum Autumn Meeting

 

The eClinical Forum is a non-commercial think-tank and a global consortium of organizations involved in clinical research. It provides a platform for member organizations to network and discuss ideas with industry peers in a non-competitive environment. Target Health is a member of the eClinical Forum and Dr. Mitchel, President of Target Health, is a member of the Steering Committee. Les Jordan just returned from Berlin where he attended the European meeting.

 

The eClinical Forum Autumn Meeting will be held on October 16-18 2017 at the Babson Executive Conference Center, Babson Park, MA.

 

The objectives of the meeting are to:

 

1. Leverage the knowledge of eClinical Forum members and develop an unrivalled insight into best practices driving the performance of global clinical research.

2. Remain up-to-date on current thinking  and explore emerging technology, process, people and regulatory trends.

3. Work with peers to design the future of eClinical Research and to develop leading-edge visions and implementable strategies Benefit from an extensive network of peers with global experience and insight for beyond the workshop interaction.

 

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. 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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Circadian Biological Clock

Sun and Moon, Nuremberg Chronicle, 1493

Source: Albrecht Durer – This is the scan of historical document, Nuremberg chronicle, from the original book, Nuremberg chronicle, Hartmann Schedel, 1493. This work is in the public domain in its country of origin and other countries and areas where the copyright term is the author’s life plus 100 years or less

 

A circadian clock, or circadian oscillator, is a hypothetical biochemical oscillator that oscillates with a stable phase relationship to 1) ___ time. Such a clock’s in vivo period, averaged over an earth year, is necessarily almost exactly 24 hours (the earth’s current solar day). In most living things, internally synchronized circadian clocks make it possible for the organism to coordinate its biology and behavior with daily environmental changes corresponding with the day-2) ___ cycle and derived diurnal behavior patterns (e.g. crepuscular feeding).

 

The term circadian derives from the Latin circa (about) diem (a 3) ___), since when taken away from external cues (such as the day-night cycle), they do not run to exactly 24 hours. Clocks in humans in a lab in constant low light, for example, will average about 24.2 hours per day, rather than 24 hours exactly. The normal body clock oscillates with an endogenous period of exactly 24 hours, it entrains, when it receives sufficient daily corrective signals from the environment, primarily daylight and darkness. Circadian clocks are the central mechanisms that drive 4) ___ rhythms. They consist of three major components:

 

1. a central biochemical oscillator with a period of about 5) ___ hours that keeps time;

2. a series of input pathways to this central oscillator to allow entrainment of the clock;

3. a series of output pathways tied to distinct phases of the oscillator that regulate overt rhythms in biochemistry, physiology, and behavior throughout an organism.

 

The clock is reset as an organism senses environmental time cues of which the primary one is 6) ___. Circadian oscillators are ubiquitous in tissues of the body where they are synchronized by both endogenous and external signals to regulate transcriptional activity throughout the day in a tissue-specific manner. The circadian 7) ___ is intertwined with most cellular metabolic processes and it is affected by the aging of an organism. The basic molecular mechanisms of the biological clock have been defined in vertebrate species, Drosophila melanogaster, plants, fungi, bacteria, and presumably also in Archaea.

 

While a precise 24-hour circadian clock is found in many organisms, it is not universal. Organisms living in the high Arctic or high Antarctic do not experience solar time in all seasons, though most are believed to maintain a circadian rhythm close to 24 hours, such as bears during hibernation. Much of the earth’s biomass resides in the dark biosphere, and while these organisms may exhibit rhythmic physiology, for these organisms the dominant rhythm is unlikely to be circadian. For east-west migratory organisms – and especially should an organism circumnavigate the globe – the absolute 24-hour phase might deviate over months, seasons, or years.

 

In vertebrates, the master circadian clock is contained within the suprachiasmatic nucleus (SCN), a bilateral nerve cluster of about 20,000 neurons. The SCN itself is located in the hypothalamus, a small region of the 8) ___ situated directly above the optic chiasm, where it receives input from specialized photosensitive ganglion cells in the retina via the retinohypothalamic tract. The SCN maintains control across the body by synchronizing “slave oscillators“, which exhibit their own near-24-hour rhythms and control circadian phenomena in local tissue. Through intercellular signaling mechanisms such as vasoactive intestinal peptide, the SCN signals other hypothalamic nuclei and the pineal gland to modulate body temperature and production of hormones such as cortisol and melatonin; these 9) ___ enter the circulatory system, and induce clock-driven effects throughout the organism. It is not, however, clear precisely what signal (or signals) enacts principal entrainment to the many biochemical clocks contained in tissues throughout the body.

 

A key feature of clocks is their ability to synchronize to external stimuli. The presence of cell autonomous oscillators in almost every cell in the 10) ____ raises the question of how these oscillators are temporally coordinated. The quest for universal timing cues for peripheral clocks in mammals has yielded principal entrainment signals such as feeding, temperature, and oxygen. Both feeding rhythms and temperature cycles were shown to synchronize peripheral clocks and even uncouple them from the master clock in the brain (e.g., daytime restricted feeding). Recently, oxygen rhythms were found to synchronize clocks in cultured cells.

Sources: nih.gov; Wikipedia

 

ANSWERS: 1) solar; 2) night; 3) day; 4) circadian; 5) 24; 6) light; 7) clock; 8) brain; 9) hormones; 10) body

The Nobel Prize in Physiology or Medicine 2017

 

The distinguished award goes to: Jeffrey C. Hall, Michael Rosbash, Michael W. Young, for their discoveries of molecular mechanisms controlling the circadian rhythm.

Michael Rosbash: Photo credit: Howard Hughes Medical Institute

 

Jeffrey Hall                                                                 Michael Young

Photo credit: Wikipedia                                        Photo credit: Wikipedia

 

Life on Earth is adapted to the rotation of our planet. For many years we have known that living organisms, including humans, have an internal, biological clock that helps them anticipate and adapt to the regular rhythm of the day. But how does this clock actually work? Jeffrey C. Hall, Michael Rosbash and Michael W. Young were able to peek inside our biological clock and elucidate its inner workings. Their discoveries explain how plants, animals and humans adapt their biological rhythm so that it is synchronized with the Earth’s revolutions.

 

Nobel winner, Jeffrey C. Hall was born 1945 in New York, USA. He received his doctoral degree in 1971 at the University of Washington in Seattle and was a postdoctoral fellow at the California Institute of Technology in Pasadena from 1971 to 1973. He joined the faculty at Brandeis University in Waltham in 1974. In 2002, he became associated with University of Maine.

 

Nobel winner, Michael Rosbash was born in 1944 in Kansas City, USA. He received his doctoral degree in 1970 at the Massachusetts Institute of Technology in Cambridge. During the following three years, he was a postdoctoral fellow at the University of Edinburgh in Scotland. Since 1974, he has been on faculty at Brandeis University in Waltham, USA.

 

Nobel winner, Michael W. Young was born in 1949 in Miami, USA. He received his doctoral degree at the University of Texas in Austin in 1975. Between 1975 and 1977, he was a postdoctoral fellow at Stanford University in Palo Alto. From 1978, he has been on faculty at the Rockefeller University in New York.

 

The earliest recorded account of a circadian process dates from the 4th century BCE, when Androsthenes, a ship captain serving under Alexander the Great, described diurnal leaf movements of the tamarind tree. The observation of a circadian or diurnal process in humans is mentioned in Chinese medical texts dated to around the 13th century, including the Noon and Midnight Manual and the Mnemonic Rhyme to Aid in the Selection of Acu-points According to the Diurnal Cycle, the Day of the Month and the Season of the Year. The first recorded observation of an endogenous circadian oscillation was by the French scientist Jean-Jacques d’Ortous de Mairan in 1729. He noted that 24-hour patterns in the movement of the leaves of the plant Mimosa pudica continued even when the plants were kept in constant darkness, in the first experiment to attempt to distinguish an endogenous clock from responses to daily stimuli. In 1896, Patrick and Gilbert observed that during a prolonged period of sleep deprivation, sleepiness increases and decreases with a period of approximately 24 hours. In 1918, J.S. Szymanski showed that animals are capable of maintaining 24-hour activity patterns in the absence of external cues such as light and changes in temperature.

 

In the early 20th century, circadian rhythms were noticed in the rhythmic feeding times of bees. Extensive experiments were done by Auguste Forel, Ingeborg Beling, and Oskar Wahl to see whether this rhythm was due to an endogenous clock. Ron Konopka and Seymour Benzer isolated the first clock mutant in Drosophila in the early 1970s and mapped the “period“ gene, the first discovered genetic determinant of behavioral rhythmicity. Joseph Takahashi discovered the first mammalian circadian clock mutation (clock delta19) using mice in 1994. However, recent studies show that deletion of clock does not lead to a behavioral phenotype (the animals still have normal circadian rhythms), which questions its importance in rhythm generation.

 

The term circadian was coined by Franz Halberg in the 1950s.

 

Using fruit flies as a model organism, this year’s Nobel laureates isolated a gene that controls the normal daily biological rhythm. They showed that this gene encodes a protein that accumulates in the cell during the night, and is then degraded during the day. Subsequently, they identified additional protein components of this machinery, exposing the mechanism governing the self-sustaining clockwork inside the cell. We now recognize that biological clocks function by the same principles in cells of other multicellular organisms, including humans. With precision, our inner clock adapts our physiology to the dramatically different phases of the day. The clock regulates critical functions such as behavior, hormone levels, sleep, body temperature and metabolism. Our well-being is affected when there is a temporary mismatch between our external environment and this internal biological clock, for example when we travel across several time zones and experience “jet lag.“ There are also indications that chronic misalignment between our lifestyle and the rhythm dictated by our inner timekeeper is associated with increased risk for various diseases.

 

Most living organisms anticipate and adapt to daily changes in the environment. During the 18th century, the astronomer Jean Jacques d’Ortous de Mairan studied mimosa plants, and found that the leaves opened towards the sun during daytime and closed at dusk. He wondered what would happen if the plant was placed in constant darkness. He found that independent of daily sunlight the leaves continued to follow their normal daily oscillation. Plants seemed to have their own biological clock. Other researchers found that not only plants, but also animals and humans, have a biological clock that helps to prepare our physiology for the fluctuations of the day. This regular adaptation is referred to as the circadian rhythm, originating from the Latin words circa meaning “around“ and dies meaning “day“. But just how our internal circadian biological clock worked remained a mystery.

 

During the 1970’s, Seymour Benzer and his student Ronald Konopka asked whether it would be possible to identify genes that control the circadian rhythm in fruit flies. They demonstrated that mutations in an unknown gene disrupted the circadian clock of flies. They named this gene period. But how could this gene influence the circadian rhythm?

 

This year’s Nobel Laureates, who were also studying fruit flies, aimed to discover how the clock actually works. In 1984, Jeffrey Hall and Michael Rosbash, working in close collaboration at Brandeis University in Boston, and Michael Young at the Rockefeller University in New York, succeeded in isolating the period gene. Hall and Rosbash then went on to discover that PER, the protein encoded by period, accumulated during the night and was degraded during the day. Thus, PER protein levels oscillate over a 24-hour cycle, in synchrony with the circadian rhythm. The next key goal was to understand how such circadian oscillations could be generated and sustained. Hall and Rosbash hypothesized that the PER protein blocked the activity of the period gene. They reasoned that by an inhibitory feedback loop, PER protein could prevent its own synthesis and thereby regulate its own level in a continuous, cyclic rhythm. The model was tantalizing, but a few pieces of the puzzle were missing. To block the activity of the period gene, PER protein, which is produced in the cytoplasm, would have to reach the cell nucleus, where the genetic material is located. Hall and Rosbash had shown that PER protein builds up in the nucleus during night, but how did it get there? In 1994 Michael Young discovered a second clock gene, timeless, encoding the TIM protein that was required for a normal circadian rhythm. In elegant work, he showed that when TIM bound to PER, the two proteins were able to enter the cell nucleus where they blocked period gene activity to close the inhibitory feedback loop. Such a regulatory feedback mechanism explained how this oscillation of cellular protein levels emerged, but questions lingered. What controlled the frequency of the oscillations? Michael Young identified yet another gene, double-time, encoding the DBT protein that delayed the accumulation of the PER protein. This provided insight into how an oscillation is adjusted to more closely match a 24-hour cycle. The paradigm-shifting discoveries have established key mechanistic principles for the biological clock. During the following years other molecular components of the clockwork mechanism were elucidated, explaining its stability and function. For example, this year’s laureates identified additional proteins required for the activation of the period gene, as well as for the mechanism by which light can synchronize the clock. The biological clock is involved in many aspects of our complex physiology. We now know that all multicellular organisms, including humans, utilize a similar mechanism to control circadian rhythms. A large proportion of our genes are regulated by the biological clock and, consequently, a carefully calibrated circadian rhythm adapts our physiology to the different phases of the day. Since the seminal discoveries by the three laureates, circadian biology has developed into a vast and highly dynamic research field, with implications for our health and wellbeing.

 

The circadian clock anticipates and adapts our physiology to the different phases of the day. Our biological clock helps to regulate sleep patterns, feeding behavior, hormone release, blood pressure, and body temperature.

 

Read more about Michael Rosbash

Read more about Jeffrey Hall

Read more about Michael Young

Excellent article: New Yorker

 

Sources: Nobel Foundation: “2017 Nobel Prize in Physiology or Medicine: Molecular mechanisms controlling the circadian rhythm;“ ScienceDaily, 2 October 2017; Wikipedia

 

Experimental Treatment For Niemann-Pick Disease Type C1

 

Niemann-Pick disease type C1 (NPC1) is a rare genetic disorder that primarily affects children and adolescents, causing a progressive decline in neurological and cognitive functions. The U.S. Food and Drug Administration has not approved any treatments for the condition.

 

According to an article published in The Lancet (10 August 2017), an experimental drug appears to slow the progression of NPC1. The drug, 2-hydroxypropyl-beta-cyclodextrin (VTS-270), is being tested under a cooperative research and development agreement, or CRADA, between NIH and Sucampo Pharmaceuticals. In April 2017, Sucampo acquired Vtesse Inc., which previously had been developing VTS-270.

 

The study was a phase 1/2a clinical trial designed to test the drug’s safety and effectiveness. A group of 14 participants, ranging from ages 4 to 23 years, received the experimental drug once a month at NIH for 12 to 18 months. Another group of three participants received the drug every two weeks for 18 months at Rush University Medical Center in Chicago. Initially, participants were divided into groups receiving different doses of the drug, but after observing that the drug was safe and well-tolerated by those receiving the highest doses, the dose was increased for all participants. Clinical progress was compared to a previous group of 21 NPC1 participants enrolled in an earlier study that documented disease progression.

 

In terms of safety, no serious adverse outcomes related to the drug were observed. However, the participants, most of whom had already experienced hearing loss because of the disease, had additional hearing loss after treatment. Earlier studies had shown that the treatment carries the risk for hearing loss. In the current study, hearing loss was compensated with hearing aids, which enabled participants to go about their daily lives. Because NPC1 symptoms result from cholesterol buildup in brain cells, the authors also measured cholesterol metabolism in the participants’ central nervous system. Results showed that after treatment, a molecule derived from cholesterol metabolism in neurons, 24(S)-hydroxycholesterol, had increased. In addition, most participants had lower levels of two proteins indicative of brain injury, FABP3 and calbindin D, implying that there was less damage in the brain. According to the study authors, these results suggest that VTS-270 can improve cholesterol metabolism in neurons, thereby targeting the root of the problem. The authors also evaluated the drug’s effectiveness using a neurological severity score, where higher scores indicate more severe effects from the disease. Compared to an earlier group of patients who had not received the drug, VTS-270-treated participants had lower scores in measures of cognition and speech, with mobility scores also trending lower. The authors believe these differences indicate that treatment with the drug can stabilize or slow disease progression.

 

NICHD researchers led the design, data collection and analysis of the phase 1/2a clinical trial. VTS-270 was provided by Janssen Research & Development, a Johnson & Johnson company. Researchers are now working on a randomized, controlled phase 2b/3 clinical trial (NCT02534844) has been approved by the FDA and the European Medicines Agency. The trial is sponsored by Sucampo, and its results will help determine which symptoms are most responsive to the drug and provide information for refining the dose and dosing frequency. The goal of this trial is to obtain regulatory approval of VTS-270.

 

Midlife Cardiovascular Risk Factors May Increase Dementia Risk

 

According to a study published in JAMA Neurology (7 August 2017), a large, long-term study suggests that middle aged Americans who have vascular health risk factors, including diabetes, high blood pressure and smoking, have a greater chance of suffering from dementia later in life.

 

The study was partially funded by NIH’s National Institute of Neurological Disorders and Stroke (NINDS), which also created the Mind Your Risks® public health campaign to make people more aware of the link between cardiovascular and brain health. The study analyzed the data of 15,744 people who participated in the Atherosclerosis Risk in Communities (ARIC) study. From 1987-1989, the participants, who were black or white and 45-64 years of age, underwent a battery of medical tests during their initial examinations at one of four centers in four different states. Over the next 25 years they were examined four more times. Cognitive tests of memory and thinking were administered during all but the first and third exams. Results showed that 1,516 participants were diagnosed with dementia during an average of 23 follow-up years. Initially, when the authors analyzed the influence of factors recorded during the first exams, they found that the chances of dementia increased most strongly with age followed by the presence of APOE4, a gene associated with Alzheimer’s disease. Caucasian Americans with one copy of the APOE4 gene had a greater chance of dementia than African Americans. Other factors included race and education: African Americans had higher chance of dementia than Caucasian Americans; those who did not graduate from high school were also at higher risk. In agreement with previous studies, an analysis of vascular risk factors showed that participants who had diabetes or high blood pressure, also called hypertension, had a higher chance of developing dementia. In fact, diabetes was almost as strong a predictor of dementia as the presence of the APOE4 gene. Unlike other studies, the authors discovered a link between dementia and prehypertension, a condition in which blood pressure levels are higher than normal but lower than hypertension. Also, race did not influence the association between dementia and the vascular risk factors they identified. Diabetes, hypertension and prehypertension increased the chances of dementia for white and black participants. Finally, smoking cigarettes exclusively increased the chances of dementia for Caucasian Americans but not African Americans.

 

Further analysis strengthened the idea that the vascular risk factors identified in this study were linked to dementia. For instance, in order to answer the question of whether having a stroke, which is also associated with the presence of vascular risk factors, may explain these findings, the team reanalyzed the data of participants who did not have a stroke and found similar results. Diabetes, hypertension, prehypertension and smoking increased the risk of dementia for both stroke-free participants and those who had a stroke.

 

Recently, in a separate study, the authors analyzed brain scans from a subgroup of ARIC participants who did not have dementia when they entered the study (JAMA: 11 April 2017). Results showed that the presence of one or more vascular risk factors during midlife was associated with higher levels of beta amyloid, a protein that often accumulates in the brains of Alzheimer’s patients. This relationship was not affected by the presence of the APOE4 gene and not seen for risk factors present in later life. The presence of vascular risk factors detected in participants older than 65 years of age during the final examination was not associated with greater levels of beta amyloid.

 

In the future, the authors plan to investigate ways in which subclinical, or undiagnosed, vascular problems may influence the brain and why race is associated with dementia.

 

Real World Evidence (RWE) and Real World Data (RWD)

 

On August 30, 2017, the U.S. Food and Drug Administration released a final guidance document on the Use of Real-World Evidence to Support Regulatory Decision-Making for Medical Devices. This guidance clarifies how the agency determines whether real-world data may be sufficient for use in regulatory decisions, without changing the evidentiary standards FDA uses to make those decisions. It clarifies how FDA plans to evaluate real-world data to determine whether it may be sufficiently relevant and reliable for various regulatory decisions, and it also clarifies when an Investigational Device Exemption (IDE) may be needed to collect and use real-world data for purposes of determining the safety and effectiveness of a device.

 

Real-world data, which relate to patient health status and/or the delivery of health care routinely collected from a variety of sources, can provide powerful insight into the benefits and risks of medical devices, including how they are used by health care providers and patients. This guidance is a cornerstone of FDA’s strategic priority to build a national evaluation system for health technology (NEST).

 

On October 10, 2017 from 1:00-2:30pm EST, the FDA will hold a webinar about this guidance. 

Registration is not necessary.

 

To hear the presentation and ask questions: Dial: 800-779-8625; passcode: 7388850 | International: 1-210-234-0098; passcode: 7388850

To view the slide presentation during the webinar:

More information about this webinar or our complete webinar series can be found on the Medical Device Webinars and Stakeholder Calls webpage.

 

Following the conclusion of the webinar, you will be able to complete a brief survey about your FDA medical device webinar experience. The survey can be found at www.fda.gov/CDRHWebinar immediately following the conclusion of the live webinar.

 

If you have general questions about this guidance, please contact the Division of Industry and Consumer Education (DICE) in the Center for Devices and Radiological Health (CDRH) at 1-800-638-2041 or 301-796-7100 or dice@fda.hhs.gov.

 

Apple Cheese Cake with Autumn Attitude Crust

Sometimes, I brag and this is one of those times. Because apples are in season now, I wanted to use them in a new dessert; but last year I already did several apple cakes. Then a light went off. As I had never heard of an apple cheese cake, this became a new challenge. The first attempt was delicious but wasn’t presentable enough for photos. I also wanted to experiment more with the crust, as well as the filling. We ate our way through the week, all the variations I could think of. You get to make it one time and savor the flavors delicieux. ©Joyce Hays, Target Health Inc.

 

Ingredients

Filling

4 or 5 fresh apples

4 containers of Tofutti (soy cream cheese)

1/2 teaspoon vanilla

7 Tablespoons sugar (fine grains)

5 Tablespoons extra virgin olive oil

1 and 1/2 teaspoons baking powder

Zest of 1/2 fresh lemon

2 teaspoons fresh lemon

6 large eggs

Crust

15 graham crackers (2 and 1/2 inches x 5 inches) or 8 ounces

3 Tablespoons dark brown sugar

1 stick butter, soft and cut into pieces

1 teaspoon cinnamon

1 pinch ground nutmeg

 

Try to buy the best available ingredients.  ©Joyce Hays, Target Health Inc.

 

Directions

Do the crust first

Crust

1. Place graham crackers in the bowl of a food processor. Process until they are almost fine crumbs. Add dark brown sugar, cinnamon, nutmeg and butter. Process until mixture clumps together like damp sand.

 

Processing all the crust ingredients. ©Joyce Hays, Target Health Inc.

 

2. With the paper the butter stick was wrapped in, oil a large pie dish.

3. With your fingers, press the graham cracker mixture evenly into the bottom of a 9 or 10 inch pie dish and refrigerate 30 minutes while preparing filling.

 

Get the processed crust out of the food processor with a spatula and press into the bottom and sides (if only enough for the bottom, that’s fine, don’t worry about it). Press as hard as you can and make the crust even all over. Then put in fridge for 30 minutes. ©Joyce Hays, Target Health Inc.

  

Filling

1. Heat oven to 325 degrees.

2. If your food processor is small and you can’t do all the filling at once in it, don’t worry, simply do each step, then remove the contents from processor into a large bowl and continue with the next step, until all ingredients have gone through the processor. Then mix all ingredients in the large bowl, very well.

3. Peel skin and core 3 apples and puree in food processor until smooth

 

Processing the 3 apples. ©Joyce Hays, Target Health Inc.

  

4. Add Tofutti and process until smooth.

5. Add superfine sugar, and with motor running, add eggs one at a time.

 

Processing the rest of the filling. I need a new food processor; this one is too small to hold all the filling ingredients. ©Joyce Hays, Target Health Inc.

 

6. Add lemon or lime juice, and process until blended.

After each processing step I scrape the pureed ingredients, into a large bowl. ©Joyce Hays, Target Health Inc.

 

7. Cut and core (leave skin on) the other 2 apples. Then on a cutting board, chop these apples into small dice-shaped pieces and set aside.

 

Chopping two apples with skin left on. ©Joyce Hays, Target Health Inc.

 

8. Wait until crust has been in fridge for 30 minutes.

 

Contents of bowl have all been pureed in food processor and are now ready to pour into the crust. ©Joyce Hays, Target Health Inc.

 

9. Scrape all the filling out of food processor (or out of the large bowl) and into the pie dish with crust.

10. Now, with your hands or a spoon, sprinkle the cut up apple pieces with skin on, over the top of the cheese cake.

 

Cheese cake going into oven. ©Joyce Hays, Target Health Inc.

 

11. Put pie dish into the oven.

12. Bake for about 1 hour and 45 minutes, until filling is set and wobbles slightly in the center (it will continue to cook as it cools). After baking for 1 hour and 30 minutes, check to be sure cheese cake isn’t too dark around the edge.

13. When cheese cake is done and wiggling a little in center, remove and allow it to do its thing, while cooling down completely.

 

Just out of oven. ©Joyce Hays, Target Health Inc.

 

14. When cool, refrigerate overnight. Then serve the next day.

 

Yummy apple cheese cake; creamy filling and crunchy crust! ©Joyce Hays, Target Health Inc.

 

We’re drinking an icy Sauvignon Blanc from the Marlborough district of New Zealand. A delicious wine with a rating in the 90s and worth every penny (do they still exist?). We chilled the glasses first. ©Joyce Hays, Target Health Inc.

 

From Our Table to Yours

Bon Appetit!