Neurontin and Lyrica are a Death Sentence for New Brain Synapses: The Saga Continue.

Neurontin and Lyrica are a Death Sentence for New Brain Synapses: The Saga Continue | Health Times

Male contraceptive compound stops sperm without affecting hormones

Medical Xpress: Male contraceptive compound stops sperm without affecting hormones

FDA Head Vows to Keep E-Cigs Away from Kids .

E-cigarettes may pose less risks than combustible tobacco, and may provide a “viable alternative,” for adults, but adult access to such products will be reined in if the number of kids using e-cigarettes continues to climb, according to FDA Commissioner Scott Gottlieb, MD.

“We’re going to have to step in … We can’t just addict a whole generation of young people on nicotine with e-cigarettes and consider that a public health advance,” Gottlieb said Tuesday to a subcommittee of the House Committee on Appropriations. “We’ll be taking some very vigorous enforcement steps … starting in the coming weeks.”

During the hearing on the FDA budget, subcommittee members stressed that the agency must act quickly to stop kids and teenagers from using e-cigarettes.

Rep. Nita Lowey (D-N.Y.), the top Democrat for the full Committee on Appropriations, raised a small rectangular device in her hand and said “Commissioner Gottlieb, what does this look like to you?”

Gottlieb said he said he knew what the device was, but played along. “It looks like a USB key,” he said.

“This is a JUUL, which is now among the most popular e-cigarette on the market … One JUUL pod, like this, contains as much nicotine as an entire pack of cigarettes,” Lowey stated.

She applauded the FDA for its work in reducing nicotine levels in cigarettes, but criticized the agency for its “silence” on e-cigarettes, saying it could “open the gates to the next public health emergency.”

Lowey also argued that “kid-friendly” flavors of e-cigarettes, such as mango and cucumber, had been introduced in apparent violation of FDA’s deeming rule, which blocks new e-cigarettes from entering the market after Aug. 8, 2016, without a premarket review from the FDA.

Asked whether JUUL had submitted an application for the new flavors, Gottlieb did not directly answer, saying that he did not want to “telegraph coming enforcement action.”

The FDA does have authority over e-cigarettes to inspect the products, impose good manufacturing practice standards, and enforce age restrictions, he noted.

He reiterated that the agency would be “stepping into this fight in a vigorous way in the coming weeks.”

On Wednesday, six leading public health and medical organizations, including the American Academy of Pediatrics, sent a letter to the FDA urging the agency to take action against JUUL, which has a boxy-sleek design that resembles a flash drive.

But not all committee members took issue with how the FDA has handled e-cigarettes so far. Rep. Sanford Bishop (D-Ga.) thanked Gottlieb for delaying certain regulations for e-cigarettes until 2022, noting that many of his constituents are switching to e-cigarettes to help them stop smoking.

However, Bishop did convey his concerns about children’s access to e-cigarettes.

Cannabis for Pain Control

Members also discussed marijuana as an alternative treatment for pain control, and whether or not its $5.8 billion budget request was sufficient.

Rep. David Young (R-Iowa) suggested that moving marijuana to a different schedule might make it easier to study. Marijuana (cannabis) is currently classified as a schedule I drug by the Drug Enforcement Agency, meaning that its “defined as drugs with no currently accepted medical use and a high potential for abuse.” However, many states have legalized cannabis for medicinal and/or recreational use.

Gottlieb said that it is already possible to study schedule I drugs, and that a supply of botanical marijuana, and its derivatives, is currently available for research through the National Institute on Drug Abuse (NIDA) supply program.

Asked for his “general thoughts,” on marijuana use, Gottlieb said that the “best way to deliver an active pharmaceutical ingredient is in a measured dose, in a form where you can purify the ingredient and you know what you’re getting. Rolling something up in a piece of paper and lighting it on fire and smoking it is not the most efficient way to deliver an active pharmaceutical ingredient.”

“I can’t think of another drug that we deliver that way, at least therapeutically… because you want to make sure the patient is getting a reliable dose and a reliable effect with each administration,” he added. “Also, the lung itself isn’t a very efficient drug deliver platform. We generally would prefer not to deliver drugs through the lung unless we were treating the lung in some fashion.”

A Bold Request

Gottlieb highlighted agency initiatives that would be made possible if the $5.8 billion FY 2019 budget request is met. The request includes $473 million in budget authorities and $190 million for user fees, he noted.

Subcommittee Chair Robert Aderholt (R-Ala.) called the request the “boldest and largest funding request in recent memory” for the agency.

Gottlieb touted plans to build a new “knowledge management system” for storing the “collected experience” of medical product review teams, identifying “scientific precedence,” and “bring[ing] more consistency to decision-making.”

The FDA will also open a policy office inside the Office of New Drugs to “promote policy, transparency, and consistency,” he said. Information culled from the new system could then be used to create hundreds of disease-focused guidance documents, he added, which would make drug development more efficient.

A portion of the budget, about $58 million, would be used to fund the transition to more modern manufacturing methods, such as continuous manufacturing.

Such a system would allow flu vaccines to be developed more quickly in a cell-based environment, rather than in eggs — the current process — and in a period of weeks, not months.

“You could scale up much more quickly and you could convert to different kinds of vaccine, if you saw changes in the contours of the resistant patterns over the course of a season,” he said

In other budget issues, Lowey noted that FY2019 budget represents a $372 million increase over the FY 2018 budget, but cautioned that the food safety budget, which saw a $10 million increase, was “insufficient” and barely enough to keep up with inflation.

She also pointed to the absence of a “vision” for how the agency would address the opioid epidemic.

“Every level of government must do all it can to combat the opioid epidemic,” she said.

First-Ever Suicide Prevention Recommendations Released

The first-ever recommendations to improve standard care for individuals at risk for suicide have been released by the National Action Alliance for Suicide Prevention.

Dr Mike Hogan

The feasible, practical, evidence-based recommendations include screening for patients at heightened risk for suicide, developing an intervention and “safety plan,” and timely follow-up, Mike Hogan, PhD, a principal of Hogan Health Solutions, a member of the National Action Alliance for Suicide Prevention Executive Committee and former New York state commissioner for mental health, told Medscape Medical News.

They recommendations are aimed at professionals who work in mental and behavioral health, primary care, and emergency department (ED) settings.

“For a very small fraction of patients — and in general medical settings, that percentage may be something like 2% — death by suicide is the greatest immediate health risk,” said Hogan.

“So we should not be blind to it, and we should be using feasible, brief interventions with those patients across all settings.” Identifying suicidality and using these brief interventions “would save thousands of lives,” he added.

Suicide prevention should be managed in the same way as prevention of medical conditions such as cardiovascular disease. Standard heart disease care includes not only interventional cardiology but also prevention advice, such as diet modification, and possibly taking a medication.

Statistics from the Centers for Disease Control and Prevention show that suicide is the tenth leading cause of death in the United States. More than 44,000 such deaths occurred in 2015. Among those aged 15 to 34 years, suicide is the second leading cause of death.

The rate of suicide deaths rose significantly between 2000 and 2015 — from 10.44 per 100,000 to 13.26 per 100,000.

Suicide is an important issue for the medical profession. At least two thirds of suicide deaths occur within about 30 days of a medical contact, be that an emergency department (ED), a primary care practice, or a mental health professional, said Hogan.

No Ownership

That statistic is even higher — up to 70% — among the older male psychiatric population, he said.

“I don’t think there’s any way to explain that, short of these individuals were having distress, pain of some kind, and they went to a trusted professional, and it didn’t get addressed. So we have many missed opportunities to do something.”

Until recently, suicide care was not seen as a core responsibility of most healthcare organizations. Managing patients at risk for suicide was left to mental health crisis care and inpatient psychiatry units.

The United States did not have a national strategy for suicide prevention until 2000, and it was not until that strategy was updated in 2012 that the goal of promoting suicide prevention as a core component of healthcare services was added.

A contributing factor is that “the medical profession, including the vast majority of mental health professionals, get little or no training in suicide,” said Hogan. He described the lack of education “shocking.” Also, he said, “In the US, there are no measures of suicide outcomes for health plans; it’s not established as a priority within Medicaid or Medicare.”

The idea that suicide prevention should be part of healthcare is “a very new idea,” noted Hogan, adding that this field is evolving “pretty quickly.”

To improve identification of patients at elevated suicide risk, Hogan and his team believe that screening should be introduced in all healthcare settings.

“We don’t recommend universal screening; we recommend screening in patients who have a mental health or substance use diagnosis or are getting treatment for a mental health or substance use issue,” he said.

Brief Interventions Endorsed

There are numerous tools to screen for heightened suicide risk. One of these is the Patient Health Questionnaire (PHQ).

Hogan referred to research involving thousands of patients who had completed the PHQ. That research showed that the vast majority of suicides occurred among those who had indicated they were having thoughts about suicide.

Another evidence-based screening tool is the Columbia Suicide Severity Rating Scale.

“These are both feasible screeners and are quite sensitive,” Hogan said. As well as screening tools, he said clinicians should use “their own judgment.”

One of the new recommendations is to introduce brief interventions. Evidence has emerged within the past 10 years or so that such interventions can be very effective, said Hogan.

“It’s almost like an intervention for problem drinking, but a little bit more robust, that helps the patient identify when these thoughts or feelings about suicide come on and gives them tools to change that trajectory.”

In addition, if the patient has thoughts about a specific means of suicide, the intervention would help that patient reduce the specific risk through, for example, safe storage of a weapon or use of medications, said Hogan.

“It’s important to just create some distance between the person and those impulses,” he said.

Such intervention involves creating a safety plan and should take only a half hour or 40 minutes. It can be carried out by a physician assistant or nurse, said Hogan.

“I don’t think this is unreasonable to ask for a very small percentage of patients who are going to have suicide risk,” he said.

Part of the intervention is to try to refer the patient to an appropriate expert, for example, one who can provide psychotherapy.

Long Wait Times for Care

Hogan recognized that many referrals for mental health care will not be successful, owing to “problematic” waiting lists or because the patient is reluctant to engage in such care.

He also acknowledged that EDs face a “real challenge” in identifying suicidal patients.

“We don’t have the alternative crisis care we ought to have that can take care of the patients with behavioral health problems in this setting,” he said. “We know that EDs are overloaded as it is, yet, as advocates, we feel like just waiting until that problem gets solved may not be good enough.”

He would like to see ED staff screen for suicide risk “if there’s an injury that might have been self-inflicted or the patient has a known diagnosis or treatment.”

Another recommendation is next-day follow-up, by telephone or text message, to ask patients how they’re doing.

“The evidence for these brief, caring contacts is very strong,” said Hogan.

This might be especially applicable for patients after release from a psychiatric institution.

“The population at greatest risk of suicide across any demographic, any setting, is patients who got out of the hospital the day before,” said Hogan.

“So one example of change in practice would be a follow-up call within at least 48 hours. This is not commonly done but is common sense when you think of the risk and look at the literature,” he said.

Thumbs Up From the APA

The new recommendations are aimed at psychiatrists as well as other mental health experts.

“In good practices and hospitals, this is getting done, and it’s increasingly getting done, but it’s still not the norm, and so, yes, the recommendations apply to psychiatrists as well,” said Hogan.

He and his colleagues aim to seek endorsement of the recommendations from patient advocacy organizations and to approach professional groups, such as the American Psychiatric Association (APA)

The APA appears keen to embrace the recommendations.

“The recommendations have the potential to help transform how healthcare systems assess, treat, and prevent suicidal behaviors,” Dwight L. Evans, MD, chair of the APA Council on Research, told Medscape Medical News.

“They are based on thoughtful, evidenced-based approaches that can significantly impact the increasing mortality rate of suicide,” Evans said.

He noted that the recommendations are part of a national effort among the Action Alliance and the American Foundation for Suicide Prevention to reduce the annual suicide rate by 20% by 2025.

Allopurinol: Extra Caution Urged in High-Risk Groups

Allopurinol-associated cutaneous adverse reactions severe enough to require hospitalization occurred three to six times as often in Asians, blacks, and Native Hawaiians/Pacific Islanders than in whites or Hispanics, and up to 12 times as often in members of the high-risk groups who were also female and older than 60 years, researchers report in an article published online April 13 in the Annals of the Rheumatic Diseases.

The elevated risk paralleled the frequency of the HLA-B*5801 allele in each ethnic/racial group, and higher risk was also associated with initial allopurinol dosing of more than 100 mg/day. Neither gout nor prior diuretic use was associated with increased risk.

These findings support current recommendations that allopurinol be initiated at a dose of 100 mg/day or lower. The authors also recommend screening of Asian, black, and native Hawaiian/Pacific Islander patients for the presence of HLA-B*5801 before initiating allopurinol, particularly those who also have additional risk factors (female, age >60 years, or chronic kidney disease [CKD]). The risk for allopurinol-associated severe cutaneous reactions (AASCARs) was more than six times higher among Native Hawaiians/Pacific Islanders compared with whites, the first time this racial/ethnic group has been identified as at high risk.

Sarah F. Keller, MD, from the Division of Rheumatology, Allergy, and Immunology, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts, and colleagues write, “These findings support the use of extra caution among Native Hawaiians/Pacific Islanders, Asians and blacks when considering allopurinol (including screening for HLA-B*5801), particularly among elderly women with CKD. Importantly, a low initial allopurinol dose (eg, <100 mg/day) was the only modifiable risk factor, which is readily implementable and is also recommended by the latest rheumatology guidelines.”

Researchers Analyzed More Than 400,000 Allopurinol Users

Keller and colleagues used US Medicaid data to identify patients who began using allopurinol between 1999 and 2012. Among these 400,401 allopurinol initiators, they found 203 hospitalized AASCAR cases, with an average 9.6 days of hospitalization. There were also 43 (21%) deaths. They note the analysis included only hospitalized AASCAR cases and likely underestimates the AASCAR risk associated with allopurinol.

The study population was 62% white, 53% male, 52% younger than age 60 years, 5% with CKD, and 61% prescribed allopurinol at an initial dose higher than 100 mg/day.

The primary study objective was to identify high-risk patients, with the goal of finding ways to prevent severe cutaneous adverse events associated with allopurinol. These severe reactions can involve major organs, result in corneal damage and renal insufficiency, and be fatal in up to 32% of cases, the authors write. The researchers defined cutaneous adverse effects using International Classification of Diseases, Ninth Revision, Clinical Modification, codes for dermatitis resulting from drugs and medicines, erythema multiforme, Stevens-Johnson syndrome, Toxic Epidermal Necrolysis, unspecified erythematous conditions, and other unspecified erythematous conditions.

The incident AASCAR cases requiring hospitalization began to appear within 10 days of allopurinol initiation, peaked at about 30 days, and subsided by 90 days. Hospitalization risk was 1 in 3883 whites and Hispanics, 1 in 1227 blacks, 1 in 1429 Asians, and 1 in 571 Native Hawaiians/Pacific Islanders.

AASCAR Risk for Ethnic/racial Groups Linked to HLA-B*5801

Multivariable-adjusted relative risks (RR) for AASCARs compared with those among whites and Hispanics were 3.00 among blacks, 3.03 among Asians, and 6.68 among Native Hawaiians/Pacific Islanders. AASCAR risk roughly paralleled the estimated allele frequency of HLA-B*5801 in these groups in the United States: 1% in whites and Hispanics, 4% in blacks, and 7.4% in Asians. A prior meta-analysis reported the risk of developing AASCARs was up to 97 times higher in patients with the allele than in those without it.

The authors further warn that allele frequency is higher in other Pacific Island countries such as Malaysia, where it is 11% to 22%, so the risk for patients from those areas would be expected to be at least as high as that observed in the current study. The authors explain that the 20% prevalence of HLA-B*5801 in Taiwan is why the Taiwanese Food and Drug Administration adopted an alternate first-line urate-lowering drug for patients with CKD.

Furthermore, allele frequencies are 7% to 10% among blacks in Kenya and 8% in black South Africans, suggesting a higher AASCAR risk in those populations as well.

The authors write, “The recommendation to screen for HLA-B*5801 or to consider the use of an alternative [urate-lowering drug] would be applicable to Native Hawaiians/Pacific Islanders prior to initiating allopurinol therapy, particularly when additional AASCAR risk factors are present (eg, in the case of being an elderly woman with CKD).”

Furthermore, the various independent risk factors combine to produce even greater risk. Female sex (RR, 1.96) and age 60 years or older (RR, 2.79) were significant independent risk factors for AASCAR. But women older than 60 years from high-risk race/ethnicity groups had a 12-fold higher risk for hospitalized AASCARs than younger men from a low-risk subgroup. Men older than 60 years from one of the high-risk race/ethnicity groups had a more than six-fold higher risk for hospitalized AASCAR than younger men from the same subgroup.

CKD was associated with a multivariable-adjusted RR of 2.33, and initial allopurinol dose more than 100 mg/day was associated with a multivariable-adjusted RR of 1.85. Combining these two independent risk factors in a patient from a high-risk race/ethnicity group produced a relative risk nine times higher than for a patient without CKD with an initial allopurinol dose 100 mg or lower who was from a low-risk race/ethnicity group.

More Cautious Approach to Allopurinol Recommended

The researchers conclude, “[T]hese findings from a large, racially diverse cohort indicate that Native Hawaiians/Pacific Islanders, Asians and blacks all have a substantially higher risk for hospitalized AASCARs compared with whites and Hispanics, calling for heightened vigilance when initiating allopurinol in these racial/ethnic groups. Furthermore, female sex, older age, CKD and an initial allopurinol dose >100 mg/day are all independent risk factors for hospitalised AASCARs and should also be considered when initiating allopurinol to help prevent this severe and potentially fatal adverse reaction.”

Math, Music and Imagination

Math can be experienced as play much as music is—just what’s needed to enlarge the tribe of creative problem solvers in mathematics and other human disciplines

Math, Music and Imagination
Marcus Miller on sax. 

Like most New Yorkers, I tend to work late. My typical evening involves leaving the stage shortly after midnight and then preparing some problems in number theory or combinatorics until about 3 or 4 AM. I am a jazz musician and mathematician. My skill set allows me to interpret musical experience through the language of mathematical structure and creative problem solving.

My practice involves using ideas of mathematical transformations on melodies, rhythms, and harmony. My compositions are developed using relationships between sound frequencies. But, to me, the notion that math and music are the same thing is both terribly poetic and also too reductionist to be useful. Still I believe the two disciplines are connected by an uncanny similarity in the roles creativity and imagination play in both.

I started learning music at nine years old and worked as a musician through my teenage years, but opted to attend a university instead of a conservatory on the advice of my music mentors who encouraged me to learn more about the world. At school, I became enamored of math because of the allure of the elegant theoretical worlds mathematicians built. Upon graduation, however, I decided to spend my twenties back on stage rather than in a graduate school library. Still, I continued reading math texts, as well as tutoring high school and college students, whenever I wasn’t touring around the world.

The uses of math in music are legion. You can find math the construction of modern harmony and counterpoint, development of rhythms, and the proportioning of arrangements. What I would like to see further explored, are the commonalities between the subjective experiences of doing math and music. Although the lifestyles of mathematicians and musicians might seem worlds apart, at least for me, the “thought work” behind them are more closely related than you might think: the magic of engaging with math and music fundamentally changes the way you imagine and create.

Marcus Miller.

Much of this “thought work” can be summarized as first creating, in the senses (and perhaps on a whiteboard or an instrument), a representation of an idea, and then imagining it transformed in creative and useful ways. Developing the representation is thus a form of self discovery, while transforming it is a kind of play. Can you spot the inference to be made here? It deeply informs my life and I would love to see it become more present in our culture:

Math can be experienced as play in much the same way music is.

Let me explain. To improvise or compose one must learn the technique of the instrument and the harmonic and rhythmic language of music. All the while, the fun comes in imagining and experimenting with the technical and linguistic components one has incorporated, in order to invoke a sensation, express an emotion, or tell a story. As the mastery of both the instrument and the underlying language expand, the mind becomes more sensitive to different ideas while the body becomes more competent at putting those ideas in practice. The process thus expands naturally from creative absorption to transformation, and eventually to execution.

Math can work similarly. A student must become adept with numbers and other symbols, various rules of algebra and calculus to manipulate symbols, and several functions. This is the language of mathematics; its grammar, and its technique. Mathematical problems can be viewed as structured opportunities to play with what is already known in order to discover what is not.

Through this process, a mathematician begins to develop a sense of the nature of mathematical ideas and their logical interrelationships, thus becoming sensitive to new ideas while becoming better equipped to manipulate them internally. To think of math as just formulas memorized through rote learning and mechanical thoughtless symbol shunting tragically misses the point.

As with music, everyone incorporates the underlying language, grammar and technique in their senses differently, and thus comes to their own individual understanding that leads them to express ideas in their own unique way. Contrary to the trope of the socially dysfunctional lone genius, mathematicians collaborate for most of their work, which makes them in some sense much like musicians. Expressing our internal worlds through pictures, words, and symbols and sharing them with one another, riffing off of each other’s ideas is how much of modern mathematics is done.

What if the world understood math in this way? What if we educated with the idea of playing with numbers in order to master arithmetic the same way improvising musicians are taught to play with musical notes to learn their scales? What if we honored the unique way that people understand and taught from that space rather than by rote? What if we refined people’s logical aesthetics to the point that mathematics felt more personal, more artsy, and the profound experiences of mathematical “beauty,” “elegance” or “risk” weren’t reserved for an intellectual elite?

Math as self-discovery, math as play. These two ideas may seem foreign at first, but I am convinced this change in paradigm is exactly what’s needed in order to enlarge the tribe of creative problem solvers in mathematics and many other human disciplines—equipping them to “jam” on the world’s toughest challenges.

Should Quantum Anomalies Make Us Rethink Reality?

Inexplicable lab results may be telling us we’re on the cusp of a new scientific paradigm

Should Quantum Anomalies Make Us Rethink Reality?

Every generation tends to believe that its views on the nature of reality are either true or quite close to the truth. We are no exception to this: although we know that the ideas of earlier generations were each time supplanted by those of a later one, we still believe that this time we got it right. Our ancestors were naïve and superstitious, but we are objective—or so we tell ourselves. We know that matter/energy, outside and independent of mind, is the fundamental stuff of nature, everything else being derived from it—or do we?

In fact, studies have shown that there is an intimate relationship between the world we perceive and the conceptual categories encoded in the language we speak. We don’t perceive a purely objective world out there, but one subliminally pre-partitioned and pre-interpreted according to culture-bound categories. For instance, “color words in a given language shape human perception of color.” A brain imaging study suggests that language processing areas are directly involved even in the simplest discriminations of basic colors. Moreover, this kind of “categorical perception is a phenomenon that has been reported not only for color, but for other perceptual continua, such as phonemes, musical tones and facial expressions.” In an important sense, we see what our unexamined cultural categories teach us to see, which may help explain why every generation is so confident in their own worldview. Allow me to elaborate.

The conceptual-ladenness of perception isn’t a new insight. Back in 1957, philosopher Owen Barfield wrote:

“I do not perceive any thing with my sense-organs alone.… Thus, I may say, loosely, that I ‘hear a thrush singing.’ But in strict truth all that I ever merely ‘hear’—all that I ever hear simply by virtue of having ears—is sound. When I ‘hear a thrush singing,’ I am hearing … with all sorts of other things like mental habits, memory, imagination, feeling and … will.” (Saving the Appearances)

As argued by philosopher Thomas Kuhn in his book The Structure of Scientific Revolutions, science itself falls prey to this inherent subjectivity of perception. Defining a “paradigm” as an “implicit body of intertwined theoretical and methodological belief,” he wrote:

“something like a paradigm is prerequisite to perception itself. What a man sees depends both upon what he looks at and also upon what his previous visual-conceptual experience has taught him to see. In the absence of such training there can only be, in William James’s phrase, ‘a bloomin’ buzzin’ confusion.’”

Hence, because we perceive and experiment on things and events partly defined by an implicit paradigm, these things and events tend to confirm, by construction, the paradigm. No wonder then that we are so confident today that nature consists of arrangements of matter/energy outside and independent of mind.

Yet, as Kuhn pointed out, when enough “anomalies”—empirically undeniable observations that cannot be accommodated by the reigning belief system—accumulate over time and reach critical mass, paradigms change. We may be close to one such a defining moment today, as an increasing body of evidence from quantum mechanics (QM) renders the current paradigm untenable.

Indeed, according to the current paradigm, the properties of an object should exist and have definite values even when the object is not being observed: the moon should exist and have whatever weight, shape, size and color it has even when nobody is looking at it. Moreover, a mere act of observation should not change the values of these properties. Operationally, all this is captured in the notion of “non-contextuality”: the outcome of an observation should not depend on the way other, separate but simultaneous observations are performed. After all, what I perceive when I look at the night sky should not depend on the way other people look at the night sky along with me, for the properties of the night sky uncovered by my observation should not depend on theirs.

The problem is that, according to QM, the outcome of an observation can depend on the way another, separate but simultaneous, observation is performed. This happens with so-called “quantum entanglement” and it contradicts the current paradigm in an important sense, as discussed above. Although Einstein argued in 1935 that the contradiction arose merely because QM is incomplete, John Bell proved mathematically, in 1964, that the predictions of QM regarding entanglement cannot be accounted for by Einstein’s alleged incompleteness.

So to salvage the current paradigm there is an important sense in which one has to reject the predictions of QM regarding entanglement. Yet, since Alain Aspect’s seminal experiments in 1981–82, these predictions have been repeatedly confirmed, with potential experimental loopholes closed one by one. 1998 was a particularly fruitful year, with two remarkable experiments performed in Switzerland and Austria. In 2011 and 2015, new experiments again challenged non-contextuality. Commenting on this, physicist Anton Zeilinger has been quoted as saying that “there is no sense in assuming that what we do not measure [that is, observe] about a system has [an independent] reality.” Finally, Dutch researchers successfully performed a test closing all remaining potential loopholes, which was considered by Nature the “toughest test yet.”

The only alternative left for those holding on to the current paradigm is to postulate some form of non-locality: nature must have—or so they speculate—observation-independent hidden properties, entirely missed by QM, which are “smeared out” across spacetime. It is this allegedly omnipresent, invisible but objective background that supposedly orchestrates entanglement from “behind the scenes.”

It turns out, however, that some predictions of QM are incompatible with non-contextuality even for a large and important class of non-local theories. Experimental results reported in 2007 and 2010 have confirmed these predictions. To reconcile these results with the current paradigm would require a profoundly counterintuitive redefinition of what we call “objectivity.” And since contemporary culture has come to associate objectivity with reality itself, the science press felt compelled to report on this by pronouncing, “Quantum physics says goodbye to reality.”

The tension between the anomalies and the current paradigm can only be tolerated by ignoring the anomalies. This has been possible so far because the anomalies are only observed in laboratories. Yet we know that they are there, for their existence has been confirmed beyond reasonable doubt. Therefore, when we believe that we see objects and events outside and independent of mind, we are wrong in at least some essential sense. A new paradigm is needed to accommodate and make sense of the anomalies; one wherein mind itself is understood to be the essence—cognitively but also physically—of what we perceive when we look at the world around ourselves.

Steroids and Saline in the ICU: One Critical Care Physician’s Perspective

New studies inform ongoing controversies about steroids for patients with septic shock and about crystalloid solutions for fluid resuscitation in the intensive care unit.

On March 1, 2018, three studies that generated much discussion in the critical care community were published in the New England Journal of Medicine. Two of these studies focused on use of corticosteroids in treating patients with septic shock; in the third study, researchers examined whether crystalloid choice in intensive care unit (ICU) patients influenced outcomes. Are these trials practice-changing?

Should steroids be given to septic shock patients?

The controversy regarding corticosteroids for treating patients with septic shock has been ongoing for nearly 2 decades. These two new trials add to the debate but probably won’t end it, because they generated partially conflicting results. In one trial, APROCCHSS, 90-day mortality was significantly lower in patients who were treated with both the glucocorticoid hydrocortisone (50 mg every 6 hours for 1 week) and the mineralocorticoid fludrocortisone than in placebo recipients (43% vs. 49%; NEJM JW Gen Med Mar 1 2018 and N Engl J Med 2018; 378:797). In contrast, the other trial (ADRENAL) was a comparison of hydrocortisone alone versus placebo, and mortality was virtually the same in both groups – about 28% (NEJM JW Gen Med Apr 15 2018 and N Engl J Med 2018; 378:809). Key differences between the trials were use of a mineralocorticoid and higher overall mortality (suggesting a sicker patient population) in APROCCHSS. Notably, in both studies, the mean duration of septic shock was shorter in the steroid groups; in ADRENAL, this translated into less time in the ICU. Corticosteroid side effects were minimal in both trials.

Multiple trials now have shown that steroids shorten the duration of septic shock. If this effect shortens the length of ICU stay, as it did in ADRENAL, steroid use might result in cost savings and less arduous hospitalizations for some patients and families. In other words, even if the mortality benefit is marginal, these secondary effects might be worthwhile, given the low cost and apparent absence of harm from relatively brief courses of moderate-dose steroids.

After talking to several colleagues in Seattle and across the country, my sense is that these studies will reinforce previous practice preferences, whatever they might have been. Those who previously were steroid skeptics will not necessarily change their practice, whereas clinicians who had low thresholds for giving steroids will continue to do so and will note that APROCCHSS supports their practice. Like many of my peers, I will continue using glucocorticoids for patients with refractory septic shock who are on escalating doses of vasopressors or who require multiple vasopressors. In my discussions, reactions to adding fludrocortisone were mixed. My take is that fludrocortisone is inexpensive and low risk, so I probably will add it when I start glucocorticoids.

Is a balanced crystalloid better than normal saline for ICU patients?

The third trial (SMART) was conducted because of concern about potential adverse renal effects of the high chloride content of normal saline. Investigators compared normal saline with “balanced” crystalloid solutions (either lactated Ringer’s solution or Plasma-Lyte A) in more than 15,000 patients in ICUs at Vanderbilt University. The primary outcome was major adverse kidney events — a composite outcome that included death, renal-replacement therapy, or doubling of creatinine at discharge. Patients in the normal saline group had more primary outcome events than those in the balanced solution group (15% vs. 14%); this small difference was statistically significant for the composite outcome, but no significant difference was found for any individual component (NEJM JW Gen Med Apr 15 2018 and N Engl J Med 2018; 378:819).

In my discussions with other intensivists, most told me that their practices already were changing to preferential use of lactated Ringer’s instead of normal saline, except in unique patient populations (e.g., those with traumatic brain injury). So, although debate continues on how to interpret the results of SMART, and experts express caution about using a single-center trial to drive practice, the results reinforce the practice of reaching for lactated Ringer’s first, for most critically ill patients who require fluid resuscitation.

The silent struggles of survivorship in cancer

The experience of every cancer, from diagnosis through treatment to survivorship, is full of transitions, adaptation and unique stressors. These include the silent struggles with fear of recurrence, existential distress and anticipatory grief, the system processes required for screening for distress and transitioning care, the survivors’ challenges in returning to work and optimizing health with supported self-management (SSM).

Experts from Canada (Fitch, Howell, Jacobson, Maheu and Galica,), Portugal (Coelho and Barbosa), UK (de Brito), Germany (Vehling and Philipp), Australia (Girgis, Smith and Durcinoska), the Netherlands (Duijts) and the United States (Mitchell) eloquently review recent evidence and describe the various facets of survivorship, including personal, health system, practical and recovering health.

Several themes emerge in these nine articles. Caregiver experience often mirrors that of the patient; many challenges of survivorship apply equally across the trajectory, from diagnosis to recovery—they are not sequential, but parallel threads that should be kept in mind throughout. For example, demoralization may occur in one patient at diagnosis and in another at disease progression; return to work planning and employer accommodation need to start early for success. Many facets have been conceptually developed and phenomenologically described, but few have rigorous research evidence for interventions to improve the experience. Treating the cancer is expected but not sufficient; providing biopsychosocial-spiritual care for the whole person and facilitating and supporting adaptation are also necessary.

It is heartening to review the body of work on the personal challenges of accepting cancer, living with uncertainty and coping with potential loss of life—challenges that are intimately linked with existential distress, fear of cancer recurrence (FCR) and anticipatory grief. FCR is no longer a nebulous term, and research into methods of assessment, predictors of and interventions for FCR, as well as FCR in caregivers is summarized in some detail Maheu and Galica (pp. 40–45). Coelho et al. (pp. 52–57) remind us that we should look for clinically significant symptoms of anticipatory grief in 12.5–38.5% of caregivers, mediated by the end-of-life experience and progressive losses, past and future. They identify key clinical features such as separation anxiety, anticipation of death and future absence of the person, as well as denial. They also identify emerging evidence for interventions, such as validating grief, providing adequate information on illness progression, supporting caregiving skills, encouraging coping and self-care, anticipating future losses and role changes and reformulating the relationship with the dying patient. Vehling and Philipp (pp. 46–51) help us understand how the experience of a cancer diagnosis may challenge fundamental beliefs about safety, sense of control and priorities, which in turn may lead to distress in 30–50% of patients with cancer. Possible interventions to reduce demoralization (loss of meaning and a sense of helpless struggle) include those that support personal meaning and facilitate psychological adaptation. Existential interventions can help patients manage uncertainty, integrate cancer into their narrative and find daily meaning and gratitude, despite living with an uncertain future.

Then, follows two articles on transition of care and screening for distress; both highlight a need for improvements in evidence-based standards, changes in the process of cancer care in different settings, as well as more knowledge translation. Fitch (pp. 74–79) summarizes recent literature on transitioning the growing number of cancer survivors out of cancer centers to primary care providers, highlighting both their necessity and the challenges of implementing them. Survivorship care plans—and the ingredients required to make them successful—are identified as a possible solution, although in current practice, such models are inconsistent. The right timing and use of evidence-based tools and best practice have yet to be clearly described and survivor and family practitioner knowledge, confidence and trust in the follow-up system need to be built. Girgis et al. (pp. 86–91) address the need for systematizing distress screening in cancer survivors as part of routine cancer care. Although there is evidence that distress screening may reduce emergency room visits and potentially reduce costs, implementation remains variable. Brief validated tools such as the single-item Distress Thermometer are recommended, though more evidence is needed regarding what cutoff score should be used. In addition, the need to ensure further assessment, education, self-management, pathways of referral and intervention is also emphasized. Further research is needed to determine the best way to screen for distress in long-term cancer survivors who are followed in the community. Greater use of patient and caregiver feedback may reveal what type of help is needed – as one remaining issue is that even if significant distress is identified, many patients do not accept specialized referral.

Next, two articles review issues related to return of functioning; first, Duijts (pp. 80–85) reviews the challenges and facilitators of return to work, using the seasons of cancer survivorship as a timeframe. The first season of survivorship begins at diagnosis, when 40–50% of survivors are of working age, highlighting the importance of illness disclosure as well as employer and healthcare provider flexibility. At the end of treatment, the season of extended survival begins, when it may feel like work as usual may not be possible because of FCR, cognitive and physical limitations. Long-term remission is permanent survival, a season which needs prospective studies on return to work outcomes and facilitators and barriers and in which medical appointments should, where possible, accommodate work schedules. Duijts also emphasizes the importance of financial disability payments for survivors who are unable to work. Then, Howell (pp. 92–99) reviews SSM programmes in recovery and rehabilitation in cancer survivorship. Living well with cancer and the use of self-management in survivorship are empowering concepts after the dictates of treatment. The healthcare system has the capacity to integrate another specialty – that of SSM into supportive care for survivorship across the cancer trajectory in cancer centers and the community. Thus far, research reveals the need for tailored programmes for specific cancers and symptoms, for collaboration between the clinician and patient.

The article ends with review articles on two specific topics: hematopoietic stem cell transplantation (HSCT); and head and neck cancer (HNC) survivorship, including laryngectomy. Mitchell (pp. 58–64) synthesizes literature on palliative care during and following allogeneic HSCT, noting recent evidence supporting early palliative care delivery in parallel with cancer treatment for advanced cancer patients experiencing high physical and emotional symptom burden. The focus on physical and emotional suffering and shared decision-making in palliative care makes it ideal to integrate into care during HSCT. Next, Jacobson (pp. 65–73) describes HNC survivorship, including laryngectomy. She describes the complex physical, functional and psychosocial challenges related to upper aerodigestive tract dysfunction. Unmet needs of both HNC survivors and their family members still exist, and the involvement of multiple disciplines is necessary to meet HNC guidelines.

The multiple dimensions of screening for and managing emotional and physical distress, supporting coping and self management, return to work and quality models of follow up care, as well as concrete examples of two specific illness trajectories illuminate the importance of supportive and rehabilitative care in survivorship and the integration of psychosocial and palliative care into oncology from diagnosis to long-term remission.

Applying Precision Medicine to Ovarian Cancer: Proof-of-Principle for a “Molecular Second Look”

Objectives The objectives of this study were to assess if targeted investigation for tumor-specific mutations by ultradeep DNA sequencing of peritoneal washes of ovarian cancer patients after primary surgical debulking and chemotherapy, and clinically diagnosed as disease free, provides a more sensitive and specific method to assess actual treatment response and tailor future therapy and to compare this “molecular second look” with conventional cytology and histopathology-based findings.

Methods/Materials We identified 10 patients with advanced-stage, high-grade serous ovarian cancer who had undergone second-look laparoscopy and for whom DNA could be isolated from biobanked paired blood, primary and recurrent tumor, and second-look peritoneal washes. A targeted 56 gene cancer-relevant panel was used for next-generation sequencing (average coverage, >6500×). Mutations were validated using either digital droplet polymerase chain reaction (ddPCR) or Sanger sequencing.

Results A total of 25 tumor-specific mutations were identified (median, 2/patient; range, 1–8). TP53 mutations were identified in at least 1 sample from all patients. All 5 pathology-based second-look positive patients were confirmed positive by molecular second look. Genetic analysis revealed that 3 of the 5 pathology-based negative second looks were actually positive. In the 2 patients, the second-look mutations were present in either the original primary or recurrent tumors. In the third, 2 high-frequency, novel frameshift mutations in MSH6 and HNF1A were identified.

Conclusions The molecular second look detects tumor-specific evidence of residual disease and provides genetic insight into tumor evolution and future recurrences beyond standard pathology. In the precision medicine era, detecting and genetically characterizing residual disease after standard treatment will be invaluable for improving patient outcomes.

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