Zika Virus Structure Reported.

Paywalled in Science journal here. Yep, it's a flavivirus.

Causal Exclusion

"Causal analysis as presented
here endorses both supervenience (no extra causal ingredients at
the macro level) and causal exclusion [for a given system at
a given time, causation occurs at one level only, otherwise causes
would be double counted (4)]. However, causal analysis also
demonstrates that EI can actually be maximal at a macro level,
depending on the system’s architecture. In such cases, causal exclusion
turns the reductionist assumption on its head, because to
avoid double-counting causes, optimal macro causation must
exclude micro causation. In other words, macro mechanisms can
always be decomposed to their constituting micro mechanisms
(supervenience); however, if there is emergence, macro causation
does not reduce to micro causation, in which case the macro wins
causally against the micro and takes its place (supersedence). The
notion of irreducibility among levels (does the macro beat the
micro?) is complemented by the notion of irreducibility among
subsets of elements within a level [is the whole more than its
parts (15, 25)?]. From the perspective of a system, emergence
(CE > 0) implies causal “self-definition” at the optimal macro
level—the one at which its causal interactions “come into focus”
(30) and “the action happens.”"

Hoel, E.P. et al. 2013. Quantifying causal emergence shows that macro can beat micro. Proceedings of the National Academy of Sciences USA 110: 19790–19795.

Happy Easter 2016

Here's a hula. Johnny Lon Ho sings the traditional favorite hymn He Nani No (literally, Hawaiian, "You [are] glorious indeed").

Jabuticaba

Jabuticaba (Plinia cauliflora, or, in South America, the jabuticabeira tree which bears jabuticaba fruit), is a medium sized fruit tree native to Brazil. This ornamental, understory rainforest tree has small white flowers and sweet, deep purple (when ripe) fruit resembling in taste and appearance purple Concord grapes. Flowers and subsequent fruit are born on old wood and bud directly from the trunks and branches (referred to as a cauliflorous habit), rather than from younger, smaller twigs as in most other fruit trees.

I first planted this tree as a 6 inch sapling four years ago, but the salt air where it was first planted burned the leaves, so it was moved three years ago to a side of our lot blocked from the salt spray by a large mango tree, where it is beginning to take off this year.

More on the CDC Opiate 2016 Guidelines: Calculated Dosing Recommendations, by Opiate Type

Here is a table. Note the fentanyl doses are micrograms total in a day-- the rest are milligrams total in a a day.

Type of Opioid	MME Conversion Factor	CDC max starting daily mg	CDC maximum daily mg
Buprenorphine patch	12.6	4	7
Buprenorphine tab or film	10	5	9
Butorphanol	7	7	13
Codeine	0.15	330	600
Dihydrocodeine	0.25	200	360
Fentanyl sublingual (mcg)	0.13	380	690
Fentanyl film or oral spray (mcg)	0.18	280	500
Fentanyl nasal spray (mcg)	0.16	310	560
Fentanyl patch (mcg)	7.2	7	12.5
Hydrocodone	1	50	90
Hydromorphone	4	13	23
Levorphanol tartrate	11	4.6	8.2
Meperidine hydrochloride	0.1	500	900
Methadone	3	17	30
Morphine	1	50	90
Nalbuphine	1	50	90
Opium	1	50	90
Oxycodone	1.5	33	60
Oxymorphone	3	17	30
Pentazocine	0.37	135	243
Tapentadol	0.4	125	225
Tramadol	0.1	500	900

New 2016 CDC Guidelines for Opioids in Chronic Pain

Here.

Really Brief Summary:

1. Nonpharmacologic therapy and nonopioid pharmacologic therapy are preferred for chronic pain. Clinicians should consider opioid therapy only if expected benefits for both pain and function are anticipated to outweigh risks to the patient. If opioids are used, they should be combined with nonpharmacologic therapy and nonopioid pharmacologic therapy, as appropriate (recommendation category: A, evidence type: 3).

2. Before starting opioid therapy for chronic pain, clinicians should establish treatment goals with all patients, including realistic goals for pain and function, and should consider how opioid therapy will be discontinued if benefits do not outweigh risks. Clinicians should continue opioid therapy only if there is clinically meaningful improvement in pain and function that outweighs risks to patient safety (recommendation category: A, evidence type: 4).

3. Before starting and periodically during opioid therapy, clinicians should discuss with patients known risks and realistic benefits of opioid therapy and patient and clinician responsibilities for managing therapy (recommendation category: A, evidence type: 3).

4. When starting opioid therapy for chronic pain, clinicians should prescribe immediate-release opioids instead of extended-release/long-acting (ER/LA) opioids (recommendation category: A, evidence type: 4).

ER/LA opioids include methadone, transdermal fentanyl, and extended-release versions of opioids such as oxycodone, oxymorphone, hydrocodone, and morphine.

5. When opioids are started, clinicians should prescribe the lowest effective dosage. Clinicians should use caution when prescribing opioids at any dosage, should carefully reassess evidence of individual benefits and risks when considering increasing dosage to ≥50 morphine milligram equivalents (MME)/day, and should avoid increasing dosage to ≥90 MME/day or carefully justify a decision to titrate dosage to ≥90 MME/day (recommendation category: A, evidence type: 3).

6. Long-term opioid use often begins with treatment of acute pain. When opioids are used for acute pain, clinicians should prescribe the lowest effective dose of immediate-release opioids and should prescribe no greater quantity than needed for the expected duration of pain severe enough to require opioids. Three days or less will often be sufficient; more than seven days will rarely be needed (recommendation category: A, evidence type: 4).

7. Clinicians should evaluate benefits and harms with patients within 1 to 4 weeks of starting opioid therapy for chronic pain or of dose escalation. Clinicians should evaluate benefits and harms of continued therapy with patients every 3 months or more frequently. If benefits do not outweigh harms of continued opioid therapy, clinicians should optimize other therapies and work with patients to taper opioids to lower dosages or to taper and discontinue opioids (recommendation category: A, evidence type: 4).

8. Before starting and periodically during continuation of opioid therapy, clinicians should evaluate risk factors for opioid-related harms. Clinicians should incorporate into the management plan strategies to mitigate risk, including considering offering naloxone when factors that increase risk for opioid overdose, such as history of overdose, history of substance use disorder, higher opioid dosages (≥50 MME/day), or concurrent benzodiazepine use, are present (recommendation category: A, evidence type: 4).

9. Clinicians should review the patient’s history of controlled substance prescriptions using state prescription drug monitoring program (PDMP) data to determine whether the patient is receiving opioid dosages or dangerous combinations that put him or her at high risk for overdose. Clinicians should review PDMP data when starting opioid therapy for chronic pain and periodically during opioid therapy for chronic pain, ranging from every prescription to every 3 months (recommendation category: A, evidence type: 4).

10. When prescribing opioids for chronic pain, clinicians should use urine drug testing before starting opioid therapy and consider urine drug testing at least annually to assess for prescribed medications as well as other controlled prescription drugs and illicit drugs (recommendation category: B, evidence type: 4).

11. Clinicians should avoid prescribing opioid pain medication and benzodiazepines concurrently whenever possible (recommendation category: A, evidence type: 3).

12. Clinicians should offer or arrange evidence-based treatment (usually medication-assisted treatment with buprenorphine or methadone in combination with behavioral therapies) for patients with opioid use disorder (recommendation category: A, evidence type: 2).

Asymptomatic MRI Abnormalities: A European Study

The HUNT study is a continuing multipart survey of health in a Norwegian county. Part of the study included brain MRI scan of the normal population, done on a population of 50 to 66 year old men and women in that European region. The study demonstrated a large percentage of asymptomatic MRI anomalies, generally minor ones: 32% of the MRI scans were abnormal. Of these, the findings were felt to be of some clinical revelance in about half the abnormal scans (15.1% of individuals), but, although almost 10% of the abnormalities were found to be intracranial tumors, mostly incidental meningiomas, only 1.4% of the study participants eventually had surgery or radiotherapy.

Thus, in persons aged 50 to 66, MRI's are abnormal 1/3 of the time, but less than 2% of MRI's will show a brain tumor requiring treatment. I also note that about 2% of the scans showed incidental circle of Willis aneurysms, none of which required catheter or surgical intervention.

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ABSTRACT

Incidental Intracranial Findings and Their Clinical Impact; The HUNT MRI Study in a General Population of 1006 Participants between 50-66 Years

Authors: Asta Kristine Håberg , Tommy Arild Hammer , Kjell Arne Kvistad , Jana Rydland , Tomm B. Müller, Live Eikenes , Mari Gårseth , Lars Jacob Stovner

Published: March 7, 2016DOI: 10.1371/journal.pone.0151080

Objectives

Evaluate types and prevalence of all, incidental, and clinically relevant incidental intracranial findings, i.e. those referred to primary physician or clinical specialist, in a cohort between 50 and 66 years from the Nord-Trøndelag Health (HUNT) study. Types of follow-up, outcome of repeated neuroimaging and neurosurgical treatment were assessed.

Material and Methods

1006 participants (530 women) underwent MRI of the head at 1.5T consisting of T1 weighted sagittal IR-FSPGR volume, axial T2 weighted, gradient echo T2* weighted and FLAIR sequences plus time of flight cerebral angiography covering the circle of Willis. The nature of a finding and if it was incidental were determined from previous radiological examinations, patient records, phone interview, and/or additional neuroimaging. Handling and outcome of the clinically relevant incidental findings were prospectively recorded. True and false positives were estimated from the repeated neuroimaging.

Results

Prevalence of any intracranial finding was 32.7%. Incidental intracranial findings were present in 27.1% and clinically relevant findings in 15.1% of the participants in the HUNT MRI cohort. 185 individuals (18.4%) were contacted by phone about their findings. 40 participants (6.2%) underwent ≥ 1 additional neuroimaging session to establish etiology. Most false positives were linked to an initial diagnosis of suspected glioma, and overall positive predictive value of initial MRI was 0.90 across different diagnoses. 90.8% of the clinically relevant incidental findings were developmental and acquired cerebrovascular pathologies, the remaining 9.2% were intracranial tumors, of which extra-axial tumors predominated. In total, 3.9% of the participants were referred to a clinical specialist, and 11.7% to their primary physician. 1.4% underwent neurosurgery/radiotherapy, and 1 (0.1%) experienced a procedure related postoperative deficit.

Conclusions

In a general population between 50 and 66 years most intracranial findings on MRI were incidental, and >15% of the cohort was referred to clinical-follow up. Hence good routines for handling of findings need to be in place to ensure timely and appropriate handling.

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The above study's statistical outcome data can be usefully compared to other studies performed more typically in that population for health screening reasons, such as colonoscopy for cancer screening. So, let's compare that with the situation with colonoscopy in this population, as shown in the study following the MRI study. That study showed, in a similarly aged population of Austrians aged an average of 61 years, that the incidental finding of ordinary adenomas was 19.7%, with advanced stage adenomas in 6.3% and actual colorectal carcinomas found in 1.1%.

ABSTRACT

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Sex-Specific Prevalence of Adenomas, Advanced Adenomas, and Colorectal Cancer in Individuals Undergoing Screening Colonoscopy

Monika Ferlitsch, MD; Karoline Reinhart, MD; Sibylle Pramhas, MD; Caspar Wiener, MD; Orsolya Gal, MD; Christina Bannert, MD; Michaela Hassler; Karin Kozbial; Daniela Dunkler, PhD; Michael Trauner, MD; Werner Weiss, MD

JAMA. 2011;306(12):1352-1358. doi:10.1001/jama.2011.1362. Text Size: A A A

Context

Although some studies have shown that men are at greater age-specific risk for advanced colorectal neoplasia than women, the age for referring patients to screening colonoscopy is independent of sex and usually recommended to be 50 years.

Objective

To determine and compare the prevalence and number needed to screen (NNS) for adenomas, advanced adenomas (AAs), and colorectal carcinomas (CRCs) for different age groups in men and women.

Design, Setting, and Patients

Cohort study of 44 350 participants in a national screening colonoscopy program over a 4-year period (2007 to 2010) in Austria.

Main Outcome Measures

Prevalence and NNS of adenomas, AAs, and CRCs in different age groups for men and women.

Results

The median ages were 60.7 years (interquartile range [IQR], 54.5-67.5 years) for women and 60.6 years (IQR, 54.3-67.6 years) for men, and the sex ratio was nearly identical (51.0% [22 598] vs 49.0% [21 572]). Adenomas were found in 19.7% of individuals screened (95% CI, 19.3%-20.1%; n = 8743), AAs in 6.3% (95% CI, 6.1%-6.5%; n = 2781), and CRCs in 1.1% (95% CI, 1.0%-1.2%; n = 491); NNS were 5.1 (95% CI, 5.0-5.2), 15.9 (95% CI, 15.4-16.5), and 90.9 (95% CI, 83.3-100.0), respectively. Male sex was significantly associated with a higher prevalence of adenomas (24.9% [95% CI, 24.3%-25.4%] vs 14.8% [95% CI, 14.3%-15.2%]; P < .001; unadjusted odds ratio [OR], 1.9 [95% CI, 1.8-2.0]), AAs (8.0% [95% CI, 7.6%-8.3%] vs 4.7% [95% CI, 4.4%-4.9%]; P < .001; unadjusted OR, 1.8 [95% CI, 1.6-1.9]), and CRCs (1.5% [95% CI, 1.3%-1.7%] vs 0.7% [95% CI, 0.6%-0.9%]; P < .001; unadjusted OR, 2.1 [95% CI, 1.7-2.5]). The prevalence of AAs in 50- to 54-year-old individuals was 5.0% (95% CI, 4.4%-5.6%) in men but 2.9% (95% CI, 2.5%-3.4%) in women (adjusted P = .001); the NNS in men was 20 (95% CI, 17.8-22.6) vs 34 in women (95% CI, 29.1-40; adjusted P = .001). There was no statistical significance between the prevalence and NNS of AAs in men aged 45 to 49 years compared with women aged 55 to 59 years (3.8% [95% CI, 2.3%-6.1%] vs 3.9% [95% CI, 3.3%-4.5%] and 26.1 [95% CI, 16.5-44.4] vs 26 [95% CI, 22.5-30.2]; P = .99).

Conclusion

Among a cohort of Austrian individuals undergoing screening colonoscopy, the prevalence and NNS of AAs were comparable between men aged 45 to 49 years and women aged 55 to 59 years.

As in many countries, including the United States, the recommended age in Austria for screening colonoscopy for colorectal cancer (CRC) in average-risk patients is 50 years for both men and women1- 4 because of the increase in the prevalence of CRC in the sixth decade of life. The goal of screening colonoscopy is to find and remove adenomas and particularly advanced adenomas (AAs). Although transition rates from AA to CRC are similar for women and men, the prevalences of AA and CRC are higher in men than in women (8% vs 4.3% for AA, 1.4% vs 0.6% for CRC, respectively),5- 8 which may result from a larger number of adenomas present in men in their 40s.7 Based on the results of a national screening program in Poland, Regula et al5 have suggested that the age for starting screening colonoscopy should be sex specific, because the number needed to screen (NNS) to detect an AA among men aged 40 to 49 years was similar to that of women aged 50 to 59 years. A study by Brenner et al6 revealed that the same incidence of CRC and CRC mortality occurred in women 4 to 8 years later than in men, but the patients included in this study were 55 years or older. Nevertheless, a modification of the screening recommendations because of sex has not been implemented because the optimal age for screening has remained insufficiently explored.

In 2007, a national project entitled Quality Management for Colon Cancer Prevention was initiated to define and control standards for quality and documentation of screening colonoscopies in Austria. The objective of our study was to investigate the most appropriate age for initial screening colonoscopy for both male and female patient groups to achieve a higher detection rate of adenoma, AA, and CRC, which could result in a lower CRC mortality rate.

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In summary, brain MRI abnormalities are common in older human age groups, but they need intervention only rarely. The incidence of clinically significant brain tumor is similar to that of carcinoma found by colonoscopy, but, unlike colonoscopy where adenomas and advanced adenomas can often be removed during the procedure which detects them, MRI does not show promise as a tool for preventative health.

Unlike colonoscopy, MRI as a pure screening tool seems to have little reason for implementation as a public health measure to detect tumor or aneurysm. Despite this, MRI's sensitivity when chosen to examine a previously known or suspected structural abnormality, such as with clinically symptomatic stroke or MS, remains excellent.

Sanboukan lemon grafting.

Citrus type: Citrus paradisi Macfad. (sensu Swingle and Reece 1967 sec. Cottin 2002); Citrus sulcata hort. ex Tanaka (sec. Hodgson 1967; sensu Tanaka sec. Cottin 2002).

The two new scions shown above, with taped surfaces, were just bark grafted to an unknown variety of nonproductive citrus tree after a heavy rain this past weekend. The Sanboukan lemon is a very sweet lemon -- it's said it tastes like sweet lemonade -- from Wakayama, Japan. I hope the grafts will both survive. I also plan to bud or bark graft a blood orange to the main trunk of the same tree next month, once the Boukhobza Blood Orange scions arrive in April.

Design controversies again, in biology this time.

Bloggers and others pressured PlosOne to retract an above-average-quality biomechanics paper which suggested in three different phrases that the human hand was designed by a creator.

One wonders if these bloggers would have forced Isaac Newton's publisher to retract his Principia (1729) which says in its General Scholium:

The six primary Planets are revolv’d about the Sun, in circles concentric with the Sun, and with motions directed towards the same parts and almost in the same plane. Ten Moons are revolv’d about the Earth, Jupiter and Saturn, in circles concentric with them, with the same direction of motion, and nearly in the planes of the orbits of those Planets. But it is not to be conceived that mere mechanical causes could give birth to so many regular motions: since the Comets range over all parts of the heavens, in very eccentric orbits. For by that kind of motion they pass easily through the orbs of the Planets, and with great rapidity; and in their aphelions, where they move the slowest, and are detain’d the longest, they recede to the greatest distances from each other, and thence suffer the least disturbance from their mutual attractions. This most beautiful System of the Sun, Planets, and Comets, could only proceed from the counsel and dominion of an intelligent and powerful being.

A good reader should be able to bracket statements that they disagree with and still benefit from new information. Censorship of such minor comments about a personified "Nature" or "Creator," which merely show the writer doing some wider reflection about the investigation and are not specifically religious at all, is out of place in an open scientific forum. This sort of anti-intelligent design witch hunting has got out of hand.

Paukaa Early Spring Tea

Hand rolled this weekend: Camellia sinesis tea, done 金萱 (light oolong) style. Plucked from the two four-year-old small trees in the back yard. About 20 g per bag.

Congenital Zika virus, like rubella virus, infects fetal cortical progenitor cells.

Many viral infections, especially rubella, can affect the developing nervous system. Perhaps one way in which they do so is to cross the placenta from the infected mother to the infant, where they damage the developing cortical layers of the fetal brain's cerebrum. The following recent studies support this hypothesis.

ABSTRACT

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Immunolocalization and Distribution of Rubella Antigen in Fatal Congenital Rubella Syndrome

Mihaela Lazar, Ludmila Perelygina, Roosecelis Martines, Patricia Greer, Christopher D. Paddock, Gheorghe Peltecu, Emilia Lupulescu, Joseph Icenogle, and Sherif R. Zakib

An estimated 100,000 cases of congenital rubella syndrome (CRS) occur worldwide each year. The reported mortality rate for infants with CRS is up to 33%. The cellular mechanisms responsible for the multiple congenital defects in CRS are presently unknown. Here we identify cell types positive for rubella virus (RV) in CRS infants.

Methods

Cells and organs involved in RV replication were identified in paraffin-embedded autopsy tissues from three fatal case-patients by histopathologic examination and immunohistochemical (IHC) staining using a rabbit polyclonal RV antibody. Normal rabbit antisera and RV antisera preabsorbed with highly purified RV served as negative controls.

Results

RV antigen was found in interstitial fibroblasts in the heart, adventitial fibroblasts of large blood vessels, alveolar macrophages, progenitor cells of the outer granular layer of the brain, and in capillary endothelium and basal plate in the placenta. The antibody specificity was verified by IHC staining of multiple tissue sections from other infectious disease cases. RV infection of each cell type is consistent with abnormalities which have been identified in patients with CRS, in the heart, large blood vessels, and brain. Antigen distribution was consistent with inflammatory response to vascular injury and systemic spread of RV.

Conclusions

The identification of RV positive cell types in CRS is important to better understand the pathology and pathogenesis of CRS.

ABSTRACT

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Zika Virus Infects Human Cortical Neural Progenitors and Attenuates Their Growth

Hengli Tang11correspondenceemail, Christy Hammack11, Sarah C. Ogden11, Zhexing Wen11, Xuyu Qian11, Yujing Li, Bing Yao, Jaehoon Shin, Feiran Zhang, Emily M. Lee, Kimberly M. Christian, Ruth A. Didier, Peng Jin, Hongjun Songcorrespondenceemail, Guo-li Ming

Publication stage: In Press Corrected Proof

DOI: http://dx.doi.org/10.1016/j.stem.2016.02.016

Summary

The suspected link between infection by Zika virus (ZIKV), a re-emerging flavivirus, and microcephaly is an urgent global health concern. The direct target cells of ZIKV in the developing human fetus are not clear. Here we show that a strain of the ZIKV, MR766, serially passaged in monkey and mosquito cells efficiently infects human neural progenitor cells (hNPCs) derived from induced pluripotent stem cells. Infected hNPCs further release infectious ZIKV particles. Importantly, ZIKV infection increases cell death and dysregulates cell-cycle progression, resulting in attenuated hNPC growth. Global gene expression analysis of infected hNPCs reveals transcriptional dysregulation, notably of cell-cycle-related pathways. Our results identify hNPCs as a direct ZIKV target. In addition, we establish a tractable experimental model system to investigate the impact and mechanism of ZIKV on human brain development and provide a platform to screen therapeutic compounds.

Received: February 24, 2016; Received in revised form: February 28, 2016; Accepted: February 29, 2016; Published: March 4, 2016