Hospitalized COVID-19 patients with diabetes are over 20% of ICU population

The COVID-19 pandemic presents new challenges for clinicians caring for infected patients with diabetes, according to new guidance published in the Endocrine Society’s Journal of Clinical Endocrinology & Metabolism.

Hospitalized patients with COVID-19 and diabetes need to receive glucose-lowering therapy in addition to other complex medical management as a way of minimizing risk for complications and death. However, appropriate glycemic management — including bedside glucose monitoring and insulin administration — requires intensive patient interactions and puts clinicians at risk.
“This manuscript provides guidance for healthcare providers caring for patients hospitalized for COVID-19 who also have a prior history of diabetes or who have high blood sugar levels at the time of hospitalization,” said lead author Mary T. Korytkowski, M.D., of the University of Pittsburgh School of Medicine in Pittsburgh, Pa. “These healthcare providers are at risk for contracting COVID-19, and while glycemic management in the hospital improves patient outcomes, it also intensifies the amount of time with direct patient contact.”
Clinicians may limit their risk of exposure by minimizing the use of IV insulin infusions and using remote glucose monitoring devices and non-insulin therapies when possible. Diabetes self-management by selected patients who are knowledgeable and capable of this in the hospital also can be considered as a way of limiting direct patient interactions. Clinicians should be aware that some medications used in treating COVID-19 patients, including glucocorticoids and hydroxychloroquine, can affect blood glucose levels.
Other authors include Kellie Antinori-Lent of the University of Pittsburgh Medical Center Shadyside Hospital in Pittsburgh, Pa.; Andjela Drincic of the University of Nebraska Medical Center in Omaha, Neb.; Irl B. Hirsch of the University of Washington in Seattle, Wash.; Marie E. McDonnell of Brigham and Women’s Hospital and Harvard Medical School in Boston, Mass.; Robert Rushakoff of the University of California in San Francisco, Calif.; and Ranganath Muniyappa of the National Institutes of Health in Bethesda, Md.

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Materials provided by The Endocrine Society. Note: Content may be edited for style and length.

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Journal Reference:

1. Ranganath Muniyappa, Robert Rushakoff, Marie E McDonnell, Irl B Hirsch, Andjela Drincic, Kellie Antinori-Lent, Mary Korytkowski. A Pragmatic Approach to Inpatient Diabetes Management during the COVID-19 Pandemic. The Journal of Clinical Endocrinology & Metabolism, 2020; DOI: 10.1210/clinem/dgaa342

https://www.sciencedaily.com/releases/2020/06/200605121518.htm

Ketamine effect on serotonin1B receptor binding in SSRI-resistant depression

Abstract

The glutamate N-methyl-d-aspartate receptor antagonist ketamine has a rapid antidepressant effect. Despite large research efforts, ketamine’s mechanism of action in major depressive disorder (MDD) has still not been determined. In rodents, the antidepressant properties of ketamine were found to be dependent on both the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and the serotonin (5-HT)_1B receptor. Low 5-HT_1B receptor binding in limbic brain regions is a replicated finding in MDD. In non-human primates, AMPA-dependent increase in 5-HT_1B receptor binding in the ventral striatum (VST) has been demonstrated after ketamine infusion. Thirty selective serotonin reuptake inhibitor-resistant MDD patients were recruited via advertisement and randomized to double-blind monotherapy with 0.5 mg/kg ketamine or placebo infusion. The patients were examined with the 5-HT_1B receptor selective radioligand [¹¹C]AZ10419369 and positron emission tomography (PET) before and 24–72 h after treatment. 5-HT_1B receptor binding did not significantly alter in patients treated with ketamine compared with placebo. An increase in 5-HT_1B receptor binding with 16.7 % (p = 0.036) was found in the hippocampus after one ketamine treatment. 5-HT_1B receptor binding in VST at baseline correlated with MDD symptom ratings (r = −0.426, p = 0.019) and with reduction of depressive symptoms with ketamine (r = −0.644, p = 0.002). In conclusion, reduction of depressive symptoms in MDD patients after ketamine treatment is correlated inversely with baseline 5-HT_1B receptor binding in VST. Further studies examining the role of 5-HT_1B receptors in the antidepressant mechanism of action of ketamine should be conducted, homing in on the 5-HT_1B receptor as an MDD treatment response marker.
https://www.nature.com/articles/s41398-020-0844-4

Effect of Personality Traits on Risk of Incident Pre‐dementia Syndromes

Abstract

OBJECTIVES

Personality traits have been shown to be associated with the risk of dementia; less is known about their association with pre‐dementia syndromes. The aim of the present study was to examine the role of personality traits as predictors of incident pre‐dementia, motoric cognitive risk (MCR), and mild cognitive impairment (MCI) syndromes.

DESIGN

We prospectively examined the association between five personality traits (neuroticism, extraversion, conscientiousness, agreeableness, and openness) and the risk of incident MCR or MCI. MCR builds on MCI operational definitions, substituting the cognitive impairment criterion with slow gait, and it is associated with increased risk for both Alzheimer’s disease and vascular dementia.

SETTING

Community based.

PARTICIPANTS

Nondemented participants (n = 524; 62% women) aged 65 years and older.

MEASUREMENTS

Cox proportional hazard analysis, adjusted for demographics and disease burden, was used to evaluate the risk of each pre‐dementia syndrome based on baseline personality traits, measured using the Big Five Inventory.

RESULTS

Over a median follow‐up of 3 years, 38 participants developed incident MCR, and 69 developed incident MCI (41 non‐amnestic and 28 amnestic subtypes). Openness was associated with a reduced risk of developing incident MCR (adjusted hazard ratio [aHR] = .94; 95% confidence interval [CI] = .89‐.99), whereas neuroticism was associated with an increased risk of incident non‐amnestic MCI (aHR = 1.06; 95% CI = 1.01‐1.11). These associations remained significant even after considering the confounding effects of lifestyle or mood. None of the personality traits were associated with MCI overall or amnestic MCI.

CONCLUSION

These findings provide evidence of a distinct relationship between personality traits and development of specific pre‐dementia syndromes.

The five‐factor model (neuroticism, extraversion, openness, agreeableness, and conscientiousness) is widely used to describe and define aspects of personality.1 Longitudinal associations between personality traits with cognitive outcomes in older adults have been described, and they link neuroticism and conscientiousness to incident cognitive syndromes.2–7 However, results regarding effects of other personality traits on cognitive states are more mixed. Several studies have reported associations between lower levels of openness and increased risk for mild cognitive impairment (MCI)5 and Alzheimer’s disease,8 whereas others report no association.6 An association between lower agreeableness and increased risk for dementia was reported in one study3 but not in others.7 Extraversion was not associated with risk for MCI or dementia in previous studies.7 The mixed results reported for certain personality traits may be due to the relationship between certain personality traits and specific cognitive domains.9 The association between personality traits and motoric cognitive risk (MCR) syndrome10 was recently examined.11 MCR builds on the operational definition of MCI, substituting the objective cognitive criterion assessed through neuropsychological testing with slow gait, increasing clinical accessibility.10, 12 MCR is common in older adults and predictive of dementia.10, 12 Only partial overlap between individuals diagnosed with MCR and MCI syndromes was reported,10, 12 indicating that risk factors and cognitive trajectories for these syndromes may vary. Stephan et al identified cross‐sectional associations of prevalent MCR with lower openness, extraversion, and conscientiousness as well as higher neuroticism in two large aging cohorts.11
This prospective study builds on previous research to examine whether the five major personality traits1 are associated with risk of incident pre‐dementia syndromes, MCR and MCI syndromes, as well as MCI subtypes (amnestic and non‐amnestic MCI). We hypothesized that higher levels of openness and conscientiousness would be associated with a lower risk of MCR and MCI, and higher levels of neuroticism would be associated with an increased risk of MCI and MCR. We did not expect to find a relationship between agreeableness with either pre‐dementia syndrome, and we expected to find a relationship between extraversion and MCR alone.

METHODS

Participants

We studied community‐residing adults age 65 years and older enrolled in the Central Control of Mobility in Aging (CCMA) study. The primary goal of CCMA is to determine cognitive control of mobility.13, 14 CCMA procedures have been reported.13, 14 In brief, potential participants were identified from a Westchester County registered voter list that included individuals aged 65 years and older who voted in local or national elections in the past 2 years. They were first contacted by mail and then by telephone inviting them to participate. Potential participants were assessed for eligibility using a structured telephone screening interview and to rule out dementia using cognitive screeners.13, 14 Exclusion criteria included inability to speak English, inability to ambulate independently, presence of dementia (previous physician diagnosis or using cut scores on the validated cognitive screeners15, 16), significant loss of vision and/or hearing, current or history of neurologic or psychiatric disorders, recent or anticipated medical procedures that may affect mobility, and receiving hemodialysis.
Eligible individuals were scheduled for in‐person visits at the research center. During study visits, participants received comprehensive cognitive, psychological, and mobility assessments. Neuropsychological tests were administered by research assistants under the supervision of a licensed neuropsychologist and included a test of general cognitive function, Repeatable Battery for the Assessment of Neuropsychological Status (RBANS),17 as well as tests to assess various cognitive domains including the Digit Symbol Substitution Test (subtest of Wechsler Adult Intelligence Scale‐Third Edition),18 the Trail Making Test,19 Free and Cued Selective Reminding Test,20 Controlled Oral Word Association Test‐Semantic and Phonemic Fluency,21 and Boston Naming Test.22 Diagnosis of dementia was assigned according to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) (DSM‐IV )23 at consensus diagnostic case conferences, as previously described.24 CCMA participants were followed longitudinally at yearly intervals. The study protocols were approved by the Albert Einstein College of Medicine institutional review board, and written informed consent was obtained at study visits.

The Big Five Inventory

The Big Five Inventory (BFI) is a 44‐item self‐report measure designed to assess five dimensions of personality25 (neuroticism, extraversion, conscientiousness, agreeableness, and openness).1 Participants were asked by trained research assistants to rate the extent to which they agreed or disagreed with each item using a 5‐point Likert scale where 1 = “Disagree strongly” and 5 = “Agree strongly.” Scores range from 0 to 40 for each of the five personality traits. The scale was shown to have good validity and reliability (α = .83) in previous studies.26

Pre‐Dementia Syndrome Diagnoses

MCI and MCR diagnostic procedures in CCMA were reported,12, 24, 27 based on published guidelines.28 In brief, nondemented participants with subjective cognitive complaints but without a dementia diagnosis or functional limitations were classified as amnestic MCI if they had impairments on tests of the memory domain or non‐amnestic MCI if they had impairments on tests of nonmemory domains. Impairment was defined as 1.5 standard deviations (SDs) below age‐ and education‐adjusted norms on relevant cognitive tests. MCI was diagnosed at consensus case conferences attended by study clinicians and neuropsychologists using DSM‐IV criteria.23
MCR syndrome is defined as the presence of subjective cognitive complaints and slow gait speed in older individuals without dementia or mobility disability.10, 12, 29 Subjective cognitive complaints were assessed by a score of 1 or higher on the AD8‐dementia screener15 or a “yes” response to the memory item on the Geriatric Depression Scale (GDS) (“Do you feel that you have more problems with memory than most?”).30 Gait speed at “normal pace” was measured on a computerized walkway (180 × 35.5 × .25 inches) with embedded pressure sensors (GAITRite; CIR Systems, Franklin, NJ).31 From footfalls recorded on the walkway, the software computes gait parameters including gait speed (cm/s). GAITRite is widely used and has excellent reliability.31 Slow gait was defined as walking speed 1 SD or more below age‐ and sex‐specific means.10, 12, 29
https://onlinelibrary.wiley.com/doi/full/10.1111/jgs.16424

Impact of children’s loneliness today may manifest in depression for years to come

Children and adolescents are likely to experience high rates of depression and anxiety long after current lockdown and social isolation ends and clinical services need to be prepared for a future spike in demand, according to the authors of a new rapid review into the long-term mental health effects of lockdown.

The research, which draws on over 60 pre-existing, peer-reviewed studies into topics spanning isolation, loneliness and mental health for young people aged 4 — 21, is published today (Monday 1 June 2020) in the Journal of the American Academy of Child and Adolescent Psychiatry.
According to the review, young people who are lonely might be as much as three times more likely to develop depression in the future, and that the impact of loneliness on mental health could last for at least 9 years.
The studies highlight an association between loneliness and an increased risk of mental health problems for young people. There is also evidence that duration of loneliness may be more important than the intensity of loneliness in increasing the risk of future depression among young people.
This, say the authors, should act as a warning to policymakers of the expected rise in demand for mental health services from young people and young adults in the years to come — both here in the UK and around the world.
Dr Maria Loades, clinical psychologist from the Department of Psychology at the University of Bath who led the work, explained: “From our analysis, it is clear there are strong associations between loneliness and depression in young people, both in the immediate and the longer-term. We know this effect can sometimes be lagged, meaning it can take up to 10 years to really understand the scale of the mental health impact the covid-19 crisis has created.”
For teachers and policymakers currently preparing for a phased re-start of schools in the UK, scheduled from today, Monday 1 June, Dr Loades suggests the research could have important implications for how this process is managed too.
She adds: “There is evidence that it’s the duration of loneliness as opposed to the intensity which seems to have the biggest impact on depression rates in young people. This means that returning to some degree of normality as soon as possible is of course important. However, how this process is managed matters when it comes to shaping young people’s feelings and experiences about this period.
“For our youngest and their return to school from this week, we need to prioritise the importance of play in helping them to reconnect with friends and adjust following this intense period of isolation.”
Members of the review team were also involved in a recent open letter to UK Education Secretary, Gavin Williamson MP, focusing on support for children’s social and emotional wellbeing during and after lockdown. In their letter they suggested that:
– The easing of lockdown restrictions should be done in a way that provides all children with the time and opportunity to play with peers, in and outside of school, and even while social distancing measures remain in place;
– Schools should be appropriately resourced and given clear guidance on how to support children’s emotional wellbeing during the transition period as schools reopen and that play — rather than academic progress — should be the priority during this time;
– The social and emotional benefits of play and interaction with peers must be clearly communicated, alongside guidance on the objective risks to children.
Acknowledging the trade-offs that need to be struck in terms of restarting the economy and reducing educational disparities, their letter to the Education Secretary concludes: ‘Poor emotional health in children leads to long term mental health problems, poorer educational attainment and has a considerable economic burden.’

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Story Source:
Materials provided by University of Bath. Note: Content may be edited for style and length.

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Journal Reference:

1. M. Loades et al. Rapid Systematic Review: The impact of social isolation and loneliness on the mental health of children and adolescents in the context of COVID-19. Journal of the American Academy of Child and Adolescent Psychiatry, 2020 DOI: 10.1016/j.jaac.2020.05.009

https://www.sciencedaily.com/releases/2020/05/200531200333.htm

Google adds anxiety self-assessment to search

Google is partnering with grassroots organization the National Alliance on Mental Illness to provide access to more mental health resources, including a clinically validated anxiety self-assessment, according to a release on Thursday.

Starting on Thursday, when Google users in the US search for information about anxiety, they will be directed to the self-assessment in Google’s knowledge panel, the box of key facts and information at the top of the search results. Medically validated information about symptoms and common treatments of anxiety will also appear in the box.

The assessment is called the Generalized Anxiety Disorder-7, GAD-7, and will ask seven questions that health care professionals may ask when screening for anxiety. The assessment will also provide access to resources developed by NAMI.
“Anxiety disorders affect 48 million adults in the U.S. Anxiety presents itself as a wide range of symptoms and can be a result of biological factors or triggered by a change in environment or exposure to a stressful event,” said Daniel H. Gillison Jr., CEO of NAMI, in a release. “With COVID-19 introducing new points of stress, communities are seeing a rise in mental health issues and needs.”

New data released by the Census Bureau last week revealed that a third of Americans are showing signs of clinical anxiety or depression.
The anxiety self-assessment is the third mental health screen available on Google Search. NAMI has previous partners with Google to provide clinically validated questionnaires and resources for depression and PTSD.
Google says that it does not collect or share answers of results from the questionnaires to ensure results will be private and secure.
https://www.cnet.com/health/google-adds-anxiety-self-assessment-to-search/

Inside New York City’s not-so-grand coronavirus reopening

New York City is set for its reopening Monday — but there’ll be nothing grand about it.
A number of coronavirus-weary retailers — including Sephora, Coach, Kate Spade and Stuart Weitzman — won’t be opening up, even though in-store pickup or drop-off is OK.
“Phase 1 is only going to have a minor impact on retail and retail employment,” said Stuart Applebaum, president of the 60,000-member Retail, Wholesale and Department Store Union, referring to the state’s four-phase reopening plan. “Most retail workers will remain unemployed.”
He said workers are “frightened” to come back to work over concerns for their health as the city awakens from its coronavirus coma.
Tapestry Inc., the parent company of Coach, Kate Spade and Stuart Weitzman, told Bloomberg News that it would wait longer to reopen its shops in the Big Apple, despite having hundreds of stores already open across the globe.
Business coalitions including the Fifth Avenue Association and Times Square Alliance have no details as to which stores will reopen.

“For Times Square, we don’t expect too dramatic a difference from today,” said Times Square Alliance president Tim Tompkins.
Bloomingdale’s on East 60th Street and Macy’s in Herald Square will open for curbside pickup next week, but reps for both stores warned, “We are taking things day by day.”
Barnes & Noble is planning on a slow rollout, too, opening three shops on Monday and another three the following week.
Meanwhile, more than 33,500 non-essential construction sites — including real-estate and office construction — will come back online Monday in a boost to the workforce.
New York City is the last of the state’s 10 economic regions to open under Phase 1 of the four-phase plan.
https://nypost.com/2020/06/05/inside-new-york-citys-not-so-grand-coronavirus-reopening/

How best to develop a liquid biopsy

Natera’s cancer blood test is couture, but Guardant’s pret-a-porter offering might sell better.

A growing number of companies are developing blood tests for cancer, and many presented data at Asco or will do so at the upcoming AACR meeting. But when assessing how these tests compare, particular attention must be paid to the settings in which they are used.
Broadly, there are three: screening to detect early disease, recurrence monitoring, and tracking response to treatment. Here, Evaluate Vantage looks at two liquid biopsy developers, Guardant Health and Natera, which are taking very different strategic approaches.
Natera made its name with a test to detect foetal abnormalities using circulating foetal DNA in the mother’s blood. It has adapted this technology to pick up DNA shed by tumours into the patient’s blood, and is focusing on detecting cancer recurrence in patients whose tumours have been surgically removed. Its Signatera test is unlike any other in development in that it is custom-made, using the excised cancer tissue as a blueprint.
“We sequence the patient’s tumour,” says Alexey Aleshin, senior medical director at Natera. “We then use that to design a bespoke assay unique to each patient’s tumour that focuses on 16 of the most clonal or truncal mutations.” Clonal mutations are those that occur early in the tumour’s evolution and are consequently present in all the patient’s cancer cells.
Made to measure
This tumour-informed approach, as Natera calls it, is a pretty involved process, but allows high levels of accuracy, Mr Aleshin says. The test avoids picking up mutations that are not related to the tumour, such as those that accrue in the bone marrow with age.
Exquisite accuracy is needed because of the postsurgical setting in which Signatera is used.
“In this space the patient’s cancer has been removed, so the levels of circulating tumour DNA we need to detect are 0.01% up to maybe 1% at the higher range,” Mr Aleshin says. This is one or two orders of magnitude lower than the levels of ctDNA that tend to be seen in advanced or even early-stage cancer patients who have not been treated surgically. It allows the detection of minimal residual disease – the cancer cells that remain after treatment and can cause relapse.
In a trial published last year, in which Signatera was used to detect post-surgical disease recurrence in breast cancer, suggested sensitivity and specificity of 89% and 100% respectively. Data presented at Asco suggested that the test identified patients at high risk of recurrence with near 100% specificity.
The intention here is to help doctors to decide whether to administer adjuvant chemotherapy. The ongoing Bespoke trial is assessing whether Signatera can enable exactly this decision in 1,000 colorectal cancer patients. Results will not emerge for some years.
Signatera is also used in Astrazeneca’s Columbia-2 study. This is enrolling MRD-positive patients to examine whether the addition of Imfinzi and various other therapies to adjuvant chemo can increase cure rates.
Natera clearly believes that this personally tailored approach has its advantages. But it also has a relatively high up-front cost, Mr Aleshin acknowledges – though he adds that because it is used serially to monitor response to treatment it becomes more economical over time.
It is sold as a lab-developed test in the US, and is also available in Europe and beyond. Natera is working with the FDA for formal approval.
Off the peg
If Natera is focused on tailored tests, Guardant Health is chasing a more one-size-fits-all approach. Or rather three sizes, as its chief executive, Helmy Eltoukhy, explains.
“We’re one of the few liquid biopsy companies, maybe the only one, that has active development programmes or products in each of the three buckets of cancer care – early detection, cancer survivors in terms of recurrence monitoring and adjuvant decision-making, and then the late-stage market in terms of treatment selection,” he says.
Guardant’s Lunar-1 test is in the same setting as Signatera. The single-arm Pegasus trial is looking at the feasibility of using Lunar-1 to guide the post-surgical and post-adjuvant clinical management of colon cancer. The phase II/III Cobra study is more significant, evaluating whether using Lunar-1 in 1,400 subjects with resected stage II colon cancer to help decide whether patients get adjuvant chemotherapy improves recurrence-free survival.
Cobra will yield data in a couple of years, and its results in particular could be extremely meaningful for Guardant – and, by extension, for Natera.
Guardant also has the Lunar-2 programme, looking at screening for colon cancer. Data to be presented at AACR this month show the test to have sensitivity of 90.3% and specificity of 96.6%. These figures are pretty good, but with just 162 patients in that cohort larger trials versus active control will be necessary before the test is ready for prime time.
Gold standard
“You have to compare to the existing standard of care,” Mr Eltoukhy says. “It’s very difficult to get a physician to forgo use of a guideline-recommended screening method, whether it’s a stool test, colonoscopy, mammography, PSA, a low-dose CT scan, without seeing head-to-head data with those specific modalities.”
That said, the company’s vast registrational Eclipse trial of Lunar-2 does not include a control group; any comparison with current screening would have to be against published data.
Guardant’s third liquid biopsy, Guardant360, is a pan-cancer assay to help assign targeted therapy to late-stage patients. Data suggesting that its use in detecting ARID1A mutations, found in around 11% of colorectal tumours, could help oncologists decide whether to administer Erbitux has a late-breaker slot at AACR. Studies in which the blood tests are used to guide treatment are vital, Mr Eltoukhy says.
“Prospective, randomised-control trials are the gold standard. Anything retrospective means there may be some cherry-picking – there may be some bias.” Guardant, unlike almost any other developer of cancer blood tests, can afford to run these huge programmes because it is so well funded. It floated in 2018, raising $273m – still one of the 10 largest medtech IPOs in history. Its stock has performed well, though the $315m equity offering it has just closed knocked the shares slightly.
Guardant360 is already sold in the US as a lab-developed test, and is the leading liquid biopsy in the US today, Mr Eltoukhy says, with around 7,000 of the 10,000 oncologists in the US having ordered it.
Ultimately Guardant’s “tumour-naive” assays will likely sell better than Natera’s tailored test. Guardant sold nearly 50,000 tests for clinical use in 2019, plus more than 20,000 to pharma companies for use in drug trials, with its revenues hitting $214m. Natera, and pretty much all the other liquid biopsy developers, will have some catching up to do.
https://www.evaluate.com/vantage/articles/analysis/spotlight/how-best-develop-liquid-biopsy