Two-photon imaging of cortical neurons in vivo has provided unique insights into the structure, function, and plasticity of cortical networks, but this method does not currently allow simultaneous ...imaging of neurons in the superficial and deepest cortical layers. Here, we describe a simple modification that enables simultaneous, long-term imaging of all cortical layers. Using a chronically implanted glass microprism in barrel cortex, we could image the same fluorescently labeled deep-layer pyramidal neurons across their entire somatodendritic axis for several months. We could also image visually evoked and endogenous calcium activity in hundreds of cell bodies or long-range axon terminals, across all six layers in visual cortex of awake mice. Electrophysiology and calcium imaging of evoked and endogenous activity near the prism face were consistent across days and comparable with previous observations. These experiments extend the reach of in vivo two-photon imaging to chronic, simultaneous monitoring of entire cortical columns.
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•Microprisms allow simultaneous chronic subcellular imaging across all cortical layers•Histology, imaging, and electrophysiology confirm viability of neurons near the prism•In mouse V1, retinotopy has columnar organization but orientation preference does not•Diverse effects of locomotion on endogenous neural activity across layers of mouse V1
Two-photon microscopy has accelerated the study of neurons in living animals, but does not allow simultaneous imaging across cortical layers. Here, Andermann et al. describe a simple modification that enables simultaneous, long-term imaging across all cortical layers in awake mice.
Recent literature shows that aggregating across multiple symptom validity test (SVT) failures increases the probability of malingering over use of one indicator alone, supporting the criteria ...proposed by Slick, Sherman, and Iverson (1999) that require multiple sources of evidence for diagnosis of malingering. The present study reanalyzes with likelihood ratios data previously published by Larrabee (
2003a
) on litigants with definite malingering, contrasted with non-malingering patients with moderate and severe traumatic brain injury. Chaining of likelihood ratios demonstrated an increase in probability of malingering when multiple test scores were positive, with values ranging from. 713 to. 837 for one failed SVT,. 936 to. 973 for two failed SVTs, and. 989 to. 995 for three failed SVTs. Posterior probabilities of malingering derived from chaining of likelihood ratios closely approximated those obtained by direct computation of Positive Predictive Power, particularly when three SVTs were failed. Moreover, the five SVTs employed in these analyses did not intercorrelate significantly, satisfying the assumption that the tests be independent for chaining of likelihood ratios. Posterior probabilities derived from chaining of likelihood ratios, holding sensitivity and specificity constant at. 50 and. 90, respectively, and varying the malingering base rate from. 10 to. 90, showed a wide range of values,. 357 to. 978, for failure of one SVT. Failure of two SVTs yielded probabilities ranging from. 735 to. 996. Failure of three SVTs yielded values ranging from. 933 to. 999, demonstrating high probabilities of malingering irrespective of the base rate. These data support the Slick
et al
. recommendation that multiple positive findings are necessary for diagnosis of malingering. Suggestions are made for modification of the Slick
et al
. criteria based on the current results.
To describe the effects of treatment for 1 year with ranibizumab or bevacizumab on macular morphology and the association of macular morphology with visual acuity (VA) in eyes with neovascular ...age-related macular degeneration (AMD).
Prospective cohort study within a randomized clinical trial.
Participants in the Comparison of Age-related Macular Degeneration Treatments Trials.
Participants were assigned randomly to treatment with ranibizumab or bevacizumab on a monthly or as-needed schedule. Optical coherence tomography (OCT), fluorescein angiography (FA), color fundus photography (FP), and VA testing were performed periodically throughout 52 weeks. Masked readers graded images. General linear models were applied to evaluate effects of time and treatment on outcomes.
Fluid type and location and thickness by OCT, size, and lesion composition on FP, FA, and VA.
Intraretinal fluid (IRF), subretinal fluid (SRF), subretinal pigment epithelium fluid, and retinal, subretinal, and subretinal tissue complex thickness decreased in all treatment groups. A higher proportion of eyes treated monthly with ranibizumab had fluid resolution at 4 weeks, and the difference persisted through 52 weeks. At 52 weeks, there was little association between the presence of fluid of any type (without regard to fluid location) and the mean VA. However, at all time points, eyes with residual IRF, especially foveal IRF, had worse mean VA (9 letters) than those without IRF. Eyes with abnormally thin (<120 μm) or thick (>212 μm) retinas had worse VA than those with normal thickness (120-212 μm). At week 52, eyes with larger neovascular lesions or with foveal scar had worse VA than eyes without these features.
Anti-vascular endothelial growth factor (VEGF) therapy reduced lesion activity and improved VA in all treatment groups. At all time points, eyes with residual IRF had worse VA than those without. Eyes with abnormally thin or thick retinas, residual large lesions, and scar also had worse VA. Monthly ranibizumab dosing yielded more eyes with no fluid and an abnormally thin retina, although the long-term significance is unknown. These results have important treatment implications in eyes undergoing anti-VEGF therapy for neovascular AMD.
Proprietary or commercial disclosure may be found after the references.
Ferroelectric/antiferroelectric thin/thick films with large positive or negative electrocaloric (EC) effects could be very useful in designing commercial refrigeration devices. Here, a giant negative ...EC effect (maximum Δ
T
∼ −42.5 K with Δ
S
∼ −29.3 J K
−1
kg
−1
) comparable to the best positive EC effects reported so far is demonstrated for 0.5(Ba
0.8
Ca
0.2
)TiO
3
-0.5Bi(Mg
0.5
Ti
0.5
)O
3
(BCT-BMT) lead-free relaxor ferroelectric thin films prepared on Pt(111)/TiO
x
/SiO
2
/Si substrates using a sol-gel method. An electric-field induced structural phase transition (nanoscale tetragonal and orthorhombic to rhombohedral) along the out-of-plane 111 direction plays a very key role in developing the giant negative EC effect. This breakthrough will pave the way for practical applications of next-generation refrigeration devices with high cooling efficiency in one cycle by ingeniously utilizing and combining both the giant negative and positive EC effects. Moreover, a large energy density of 51.7 J cm
−3
with a high power density of 1.15 × 10
10
W kg
−1
at room temperature is also achieved in the thin film, indicating that it is also an attractive multifunctional material for energy storage.
Ferroelectric/antiferroelectric thin/thick films with large positive or negative electrocaloric (EC) effects could be very useful in designing commercial refrigeration devices.
To compare the efficacy and safety of brolucizumab with aflibercept to treat neovascular age-related macular degeneration (AMD).
Prospective, randomized, double-masked, multicenter, 2-arm, phase 2 ...study.
Eighty-nine treatment-naïve participants, aged ≥50 years, with active choroidal neovascularization secondary to AMD.
Eligible participants were randomized 1:1 to intravitreal brolucizumab (6 mg/50 μl) or aflibercept (2 mg/50 μl). Both groups received 3 monthly loading doses and were then treated every 8 weeks (q8) with assessment up to week 40. In the brolucizumab group, the final q8 cycle was extended to enable 2 cycles of treatment every 12 weeks (q12; to week 56); participants on aflibercept continued on q8. Unscheduled treatments were allowed at the investigator's discretion.
The primary and secondary hypotheses were noninferiority (margin: 5 letters at a 1-sided alpha level 0.1) in best-corrected visual acuity (BCVA) change from baseline of brolucizumab versus aflibercept at weeks 12 and 16, respectively. BCVA, central subfield thickness (CSFT), and morphologic features were assessed throughout the study.
The mean BCVA change from baseline (letters) with brolucizumab was noninferior to aflibercept at week 12 (5.75 and 6.89, respectively 80% confidence interval for treatment difference, -4.19 to 1.93) and week 16 (6.04 and 6.62 -3.72 to 2.56), with no notable differences up to week 40. Outcomes exploring disease activity during the q8 treatment cycles suggest greater stability of the brolucizumab participants, supported by receipt of fewer unscheduled treatments versus aflibercept (6 vs. 15) and more stable CSFT reductions. In addition, from post hoc analysis, a greater proportion of brolucizumab-treated eyes had resolved intraretinal and subretinal fluid compared with aflibercept-treated eyes. Approximately 50% of brolucizumab-treated eyes had stable BCVA during the q12 cycles. Brolucizumab and aflibercept adverse events were comparable.
During the matched q8 phase, the BCVA in brolucizumab-treated eyes appeared comparable to aflibercept-treated eyes, with more stable CSFT reductions, receipt of fewer unscheduled treatments, and higher rates of fluid resolution. The brolucizumab safety profile was similar to aflibercept over 56 weeks of treatment. A 12-week treatment cycle for brolucizumab may be viable in a relevant proportion of eyes.
Pembrolizumab improved survival in patients with recurrent or metastatic head and neck squamous-cell carcinoma (HNSCC). The aims of this study were to determine if pembrolizumab would be safe, result ...in pathologic tumor response (pTR), and lower the relapse rate in patients with resectable human papillomavirus (HPV)-unrelated HNSCC.
Neoadjuvant pembrolizumab (200 mg) was administered and followed 2 to 3 weeks later by surgical tumor ablation. Postoperative (chemo)radiation was planned. Patients with high-risk pathology (positive margins and/or extranodal extension) received adjuvant pembrolizumab. pTR was quantified as the proportion of the resection bed with tumor necrosis, keratinous debris, and giant cells/histiocytes: pTR-0 (<10%), pTR-1 (10%-49%), and pTR-2 (≥50%). Coprimary endpoints were pTR-2 among all patients and 1-year relapse rate in patients with high-risk pathology (historical: 35%). Correlations of baseline PD-L1 and T-cell infiltration with pTR were assessed. Tumor clonal dynamics were evaluated (ClinicalTrials.gov NCT02296684).
Thirty-six patients enrolled. After neoadjuvant pembrolizumab, serious (grades 3-4) adverse events and unexpected surgical delays/complications did not occur. pTR-2 occurred in eight patients (22%), and pTR-1 in eight other patients (22%). One-year relapse rate among 18 patients with high-risk pathology was 16.7% (95% confidence interval, 3.6%-41.4%). pTR ≥10% correlated with baseline tumor PD-L1, immune infiltrate, and IFNγ activity. Matched samples showed upregulation of inhibitory checkpoints in patients with pTR-0 and confirmed clonal loss in some patients.
Among patients with locally advanced, HPV-unrelated HNSCC, pembrolizumab was safe, and any pathologic response was observed in 44% of patients with 0% pathologic complete responses. The 1-year relapse rate in patients with high-risk pathology was lower than historical.
Spondweni virus (SPONV) and Zika virus cause similar diseases in humans. We detected SPONV outside of Africa from a pool of Culex mosquitoes collected in Haiti in 2016. This finding raises questions ...about the role of SPONV as a human pathogen in Haiti and other Caribbean countries.
To compare the efficacy of intravitreal aflibercept and ranibizumab on the exudative activity of neovascular age-related macular degeneration (nAMD) using optical coherence tomography (OCT) and to ...correlate morphologic findings with visual acuity (VA) outcomes.
Post hoc analysis of the prospective VIEW trials.
Data of 1815 patients randomized to 0.5 mg ranibizumab every 4 weeks (Q4wks), 2 mg aflibercept Q4wks, or 2 mg aflibercept every 8 weeks (Q8wks).
Standardized OCT evaluation was performed by masked reading centers for the presence of intraretinal cystoid fluid (IRC), subretinal fluid (SRF), and pigment epithelial detachment (PED). Rates of feature resolution were compared between drugs and regimen. Associations between morphologic features and VA were analyzed using multivariate modeling.
Resolution rates of IRC, SRF, and PED, and associations between morphology and VA.
At baseline, the proportions of eyes with IRC, SRF, and PED were balanced between the aflibercept and ranibizumab groups. At week 12, IRC resolved in 50% of eyes with both agents. Subretinal fluid resolved in 70% of pooled aflibercept-treated eyes and in 59% of ranibizumab-treated eyes, and PED resolved in 29% and 24% of pooled aflibercept-treated eyes and ranibizumab-treated eyes, respectively. At week 52, IRC resolved in 57% (aflibercept Q4wks), 50% (aflibercept Q8wks), and 52% (ranibizumab) of patients; SRF resolved in 75% (both aflibercept Q4wks/Q8wks) and 66% (ranibizumab) of patients; and PED resolved in 40% (aflibercept Q4wks), 34% (aflibercept Q8wks), and 28% (ranibizumab) of patients. During fixed dosing (weeks 12-52) all exudative features showed synchronized fluctuations after treatment-free visits in the Q8wks aflibercept regimen. During pro re nata dosing (weeks 52-96), greater proportions of patients showed recurrent fluid in all treatment arms. Presence of IRC was generally associated with lower VA at baseline, which translated into poorer final VA outcomes.
Fluid resolution in all compartments was consistently greater for aflibercept Q4wks than for aflibercept Q8wks and ranibizumab. At week 52, Q8wks aflibercept-treated eyes were, on average, as dry as or drier than with ranibizumab despite the extended treatment interval. Independent of agent or regimen, preexisting morphologic features of the retina at baseline markedly influenced VA outcomes.
To describe risk factors for scar in eyes treated with ranibizumab or bevacizumab for neovascular age-related macular degeneration (AMD).
Prospective cohort study within a randomized clinical trial.
...Patients with no scar on color fundus photography (CFP) or fluorescein angiography (FA) at enrollment in the Comparison of Age-related Macular Degeneration Treatments Trials (CATT).
Eyes were assigned to ranibizumab or bevacizumab treatment and to 1 of 3 dosing regimens for 2 years. Masked readers assessed CFP and FA. Baseline demographic characteristics, visual acuity, morphologic features on photography and optical coherence tomography (OCT), and genotypes associated with AMD risk were evaluated as risk factors using adjusted hazard ratios (aHRs) and associated 95% confidence intervals (CIs). Scars were classified as fibrotic with well-demarcated elevated mounds of yellowish white tissue or nonfibrotic with discrete flat areas of hyperpigmentation with varying amounts of central depigmentation.
Scar formation.
Scar developed in 480 of 1059 eyes (45.3%) by 2 years. Baseline characteristics associated with greater risk of scarring were predominantly classic choroidal neovascularization (CNV) (aHR, 3.1; CI, 2.4-3.9) versus occult CNV, blocked fluorescence (aHR, 1.4; CI, 1.1-1.8), foveal retinal thickness >212 μm (aHR, 2.4; CI, 1.7-3.6) versus <120 μm, foveal subretinal tissue complex thickness >275 μm (aHR, 2.4; CI, 1.7-3.6) versus ≤75 μm, foveal subretinal fluid (aHR, 1.5; CI, 1.1-2.0) versus no subretinal fluid, and subretinal hyperreflective material (SHRM) (aHR, 1.7; CI, 1.3-2.3) versus no SHRM. Eyes with elevation of the retinal pigment epithelium had lower risk (aHR, 0.6; CI, 0.5-0.8) versus no elevation. Drug, dosing regimen, and genotype had no statistically significant association with scarring. Fibrotic scars developed in 24.7% of eyes, and nonfibrotic scars developed in 20.6% of eyes. Baseline risk factors for the scar types were similar except that eyes with larger lesion size or visual acuity <20/40 were more likely to develop fibrotic scars.
Approximately half of eyes enrolled in CATT developed scar by 2 years. Eyes with classic neovascularization, a thicker retina, and more fluid or material under the foveal center of the retina are more likely to develop scar.
Itch is an everyday sensation, but when associated with disease or infection it can be chronic and debilitating. Several forms of itch can be blocked using antihistamines, but others cannot and these ...constitute an important clinical problem. Little information is available on the mechanisms underlying itch that is produced by nonhistaminergic mechanisms. We examined the responses of spinothalamic tract neurons to histaminergic and, for the first time, nonhistaminergic forms of itch stimuli. Fifty-seven primate spinothalamic tract (STT) neurons were identified using antidromic activation techniques and examined for their responses to histamine and cowhage, the nonhistaminergic itch-producing spicules covering the pod of the legume Mucuna pruriens. Each examined neuron had a receptive field on the hairy skin of the hindlimb and responded to noxious mechanical stimulation. STT neurons were tested with both pruritogens applied in a random order and we found 12 that responded to histamine and seven to cowhage. Each pruritogen-responsive STT neuron was activated by the chemical algogen capsaicin and two-thirds responded to noxious heat stimuli, demonstrating that these neurons convey chemical, thermal, and mechanical nociceptive information as well. Histamine or cowhage responsive STT neurons were found in both the marginal zone and the deep dorsal horn and were classified as high threshold and wide dynamic range. Unexpectedly, histamine and cowhage never activated the same cell. Our results demonstrate that the spinothalamic tract contains mutually exclusive populations of neurons responsive to histamine or the nonhistaminergic itch-producing agent cowhage.
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