Evidence of a genetic background predisposing to complex regional pain syndrome type 1.

BACKGROUND: Complex regional pain syndrome type 1 (CRPS-1) is a rare, disabling and sometimes chronic disorder usually arising after a trauma. This exploratory study examined whether patients with chronic CRPS-1 have a different genetic profile compared with those who do not have the condition. METHODS: Exome sequencing was performed to seek altered non-synonymous SNP allele frequencies in a discovery cohort of well-characterised patients with chronic CRPS-1 (n=34) compared with population databases. Identified SNP alleles were confirmed by Sanger sequencing and sought in a replication cohort (n=50). Gene expression of peripheral blood macrophages was assessed. RESULTS: In the discovery cohort, the rare allele frequencies of four non-synonymous SNPs were statistically increased. The replication cohort confirmed this finding. In a chronic pain cohort, these alleles were not overexpressed. In total, 25 out of 84 (29.8%) patients with CRPS-1 expressed a rare allele. The SNPs were rs41289586 in ANO10, rs28360457 in P2RX7, rs1126930 in PRKAG1 and rs80308281 in SLC12A9. Males were more likely than females to have a rare SNP allele, 8 out of 14 (57.1%) vs 17 out of 70 (24.3%) (Fisher's p=0.023). ANO10, P2RX7, PRKAG1 and SLC12A9 were all expressed in macrophages from healthy human controls. CONCLUSION: A single SNP in each of the genes ANO10, P2RX7, PRKAG1 and SLC12A9 was associated with developing chronic CRPS-1, with more males than females expressing these rare alleles. Our work suggests the possibility that a permissive genetic background is an important factor in the development of CRPS-1.

Rechallenges without desensitization following platinum-based chemotherapy reactions.

BACKGROUND: There is increasing interest in non-desensitization protocols as a potential way to reintroduce chemotherapy following hypersensitivity reactions (HSR). OBJECTIVE: To provide insight into the potential utility of non-desensitization reintroduction, particularly at institutions where allergy consultation may not be available. METHODS: For 70 patients with platinum HSR who underwent rechallenge with standard (≤2 hours), extended (1-bag, 1-step, 4-6 hours), or titrated (4-to-5-bag and -step, 6-7.5 hours) infusions between 1/2014 and 7/2019, demographics and clinical characteristics were reviewed and initial and breakthrough reactions (BTR) were graded using Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0). Tolerance (no BTR) and completion (dose completed despite BTR) were compared using Fisher's exact test. RESULTS: Patients (mean [standard deviation] age 57 [13] years, initial HSR grade 2 [1]), were rechallenged with standard (n = 8), extended (n = 23), or titrated (n = 22) infusions after oxaliplatin HSR; and standard (n = 5) or titrated (n = 12) after carboplatin HSR. Tolerance and completion were higher for extended versus (vs) standard (tolerance-87%-vs-8%, p < 0.005; completion-96%-vs-38%, p < 0.005) and titrated versus standard (tolerance-76%-vs-8%, p < 0.005; completion-79%-vs-38%, p < 0.05) infusions. CONCLUSIONS: Extended and titrated infusions may increase reintroduction safety compared to standard infusions. Further investigation into extended infusions may provide a safe alternative to standard infusions in patients who may not have access to desensitization at their institution.

Biomimetic Approach to Promote Cellular Uptake and Enhance Photoacoustic Properties of Tumor-Seeking Dyes.

The attachment of glucose to drugs and imaging agents enables cancer cell targeting via interactions with GLUT1 overexpressed on the cell surface. While an added benefit of this modification is the solubilizing effect of carbohydrates, in the context of imaging agents, aqueous solubility does not guarantee decreased π-stacking or aggregation. The resulting broadening of the absorbance spectrum is a detriment to photoacoustic (PA) imaging since the signal intensity, accuracy, and image quality all rely on reliable spectral unmixing. To address this major limitation and further enhance the tumor-targeting ability of imaging agents, we have taken a biomimetic approach to design a multivalent glucose moiety (mvGlu). We showcase the utility of this new group by developing aza-BODIPY-based contrast agents boasting a significant PA signal enhancement greater than 11-fold after spectral unmixing. Moreover, when applied to targeting cancer cells, effective staining could be achieved with ultra-low dye concentrations (50 nM) and compared to a non-targeted analogue, the signal intensity was >1000-fold higher. Lastly, we employed the mvGlu technology to develop a logic-gated acoustogenic probe to detect intratumoral copper (i.e., Cu(I)), which is an emerging cancer biomarker, in a murine model of breast cancer. This exciting application was not possible using other acoustogenic probes previously developed for copper sensing.

Repurposing Cyanine Photoinstability To Develop Near-Infrared Light-Activatable Nanogels for In Vivo Cargo Delivery.

The favorable properties of cyanines (e.g., near-infrared (NIR) absorbance and emission) have made this class of dyes popular for a wide variety of biomedical applications. However, many cyanines are prone to rapid photobleaching when irradiated with light. In this study, we have exploited this undesirable trait to develop NIR-nanogels for NIR light-mediated cargo delivery. NIR-nanogels feature a photolabile cyanine cross-linker (Cy780-Acryl) that can cleave via dioxetane chemistry when irradiated. This photochemical process results in the formation of two carbonyl fragments and concomitant NIR-nanogel degradation to facilitate cargo release. In contrast to studies where cyanines are utilized as photocages, our approach does not require direct chemical attachment to the cargo, thus expanding our ability to deliver molecules that cannot be covalently modified. We showcase this feature by encapsulating a palette of small-molecule chemotherapeutics that feature a structurally diverse chemical architecture. To demonstrate site-selective release in vivo, we generated a murine model of breast cancer. Relative to nonlight irradiated and drug-free controls, treatment with NIR-nanogels loaded with paclitaxel (a potent cytotoxic agent) and NIR light resulted in significant attenuation of tumor growth. Moreover, we show via histological staining of the vital organs that minimal off-target effects are observed.

Hippocampus mediates nocebo impairment of opioid analgesia through changes in functional connectivity.

The neural mechanisms underlying placebo analgesia have attracted considerable attention over the recent years. In contrast, little is known about the neural underpinnings of a nocebo-induced increase in pain. We previously showed that nocebo-induced hyperalgesia is accompanied by increased activity in the hippocampus that scaled with the perceived level of anxiety. As a key node of the neural circuitry of perceived threat and fear, the hippocampus has recently been proposed to coordinate defensive behaviour in a context-dependent manner. Such a role requires close interactions with other regions involved in the detection of and responses to threat. Here, we investigated the functional connectivity of the hippocampus during nocebo-induced hyperalgesia. Our results show an increase in functional connectivity between hippocampus and brain regions implicated in the processing of sensory-discriminative aspects of pain (posterior insula and primary somatosensory/motor cortex) as well as the periaqueductal grey. This nocebo-induced increase in connectivity scaled with an individual's increase in anxiety. Moreover, hippocampus connectivity with the amygdala was negatively correlated with the pain intensity reported during nocebo hyperalgesia relative to the placebo condition. Our findings suggest that the hippocampus links nocebo-induced anxiety to a heightened responsiveness to nociceptive input through changes in its crosstalk with pain-modulatory brain areas.

How is pain associated with pelvic mesh implants measured? Refinement of the construct and a scoping review of current assessment tools.

BACKGROUND: Recommendations for the management of pain related to pelvic mesh implants are still under development. One limitation that has impeded progress in this area is that mesh-related pain has not been consistently defined or measured. Here, we reviewed the ways in which pain associated with pelvic mesh implants has been measured, and mapped the ways in which these existing measures capture the construct. METHODS: First, we reviewed existing accounts of the pain associated with pelvic mesh implants to develop a multifaceted construct definition, which includes aspects related to pain intensity, timing, body location, phenomenological qualities, impact/interference with daily living, and patient expectations and beliefs. Next, we reviewed the ways that the construct has been measured in the extant literature. RESULTS: Within 333 eligible studies, 28 different assessments of pain associated with pelvic mesh were identified, and 61% of studies reported using more than one measurement tool. Questionnaire measures included measures designed to assess urological and/or pelvic symptoms, generic measures and unvalidated measures. We did not identify any validated questionnaire measures designed to assess pain associated with pelvic mesh implants. The phenomenological, location, and expectation/belief components of the construct were not captured well by the identified questionnaire measures, and there is no evidence that any of the identified measures have appropriate psychometric properties for the assessment of pain related to pelvic mesh implants. CONCLUSIONS: We recommend further qualitative research regarding women's experiences of pelvic mesh-related pain assessment, and the development of a condition-specific patient reported outcome measure.

Development of NIR-II Photoacoustic Probes Tailored for Deep-Tissue Sensing of Nitric Oxide.

Photoacoustic (PA) imaging has emerged as a reliable in vivo technique for diverse biomedical applications ranging from disease screening to analyte sensing. Most contemporary PA imaging agents employ NIR-I light (650-900 nm) to generate an ultrasound signal; however, there is significant interference from endogenous biomolecules such as hemoglobin that are PA active in this window. Transitioning to longer excitation wavelengths (i.e., NIR-II) reduces the background and facilitates the detection of low abundance targets (e.g., nitric oxide, NO). In this study, we employed a two-phase tuning approach to develop APNO-1080, a NIR-II NO-responsive probe for deep-tissue PA imaging. First, we performed Hammett and Brønsted analyses to identify a highly reactive and selective aniline-based trigger that reacts with NO via N-nitrosation chemistry. Next, we screened a panel of NIR-II platforms to identify chemical structures that have a low propensity to aggregate since this can diminish the PA signal. In a head-to-head comparison with a NIR-I analogue, APNO-1080 was 17.7-fold more sensitive in an in vitro tissue phantom assay. To evaluate the deep-tissue imaging capabilities of APNO-1080 in vivo, we performed PA imaging in an orthotopic breast cancer model and a heterotopic lung cancer model. Relative to control mice not bearing tumors, the normalized turn-on response was 1.3 ± 0.12 and 1.65 ± 0.07, respectively.

Comparison of Skin Antiseptic Agents and the Role of 0.01% Hypochlorous Acid.

BACKGROUND: Hypochlorous acid (HA) has both anti-microbial and wound-healing properties with a growing role for utilization in pre-procedural care on the face. OBJECTIVES: The authors sought to compare the antiseptic property of 0.01% HA solution, 5% povidone iodine (PI), 4% chlorhexidine gluconate (CHG), and 70% isopropyl alcohol (IPA) antiseptic on facial skin. METHODS: This was a prospective single-center clinical trial. RESULTS: A total of 21 participants were recruited. Bacterial growth was seen in CHG (10%), IPA (71%), PI (81%), and HA (95%) of specimens (P < 0.001). CHG had less growth compared with HA (P = <0.001), IPA (P = <0.001), and PI (P = <0.001). No difference in bacterial growth was noted between HA and IPA (P = 0.063) or HA and PI (P = 0.25). Significant differences in mono-microbial and poly-microbial growth were seen between HA and IPA (P = 0.046) and HA and CHG (P = <0.001). Staphylococcus epidermidis grew less frequently in CHG (10%), followed by IPA (29%), PI (71%), and HA (71%). Staphylococcus capitis grew less frequently in CHG (0%), followed by PI (14%), HA (24%), and IPA (29%). CONCLUSIONS: CHG reduced the bacterial growth compared with HA, PI, and IPA. However, HA, PI, and IPA had insignificant differences in bactericidal effects. Our study provides a supporting role of HA to be considered as an antiseptic.

0.01% Hypochlorous Acid as an Alternative Skin Antiseptic: An In Vitro Comparison.

OBJECTIVE: Compare the in vitro efficacy of hypochlorous acid 0.01% (HA), povidone iodine 5% (PI), chlorhexidine gluconate 4% (CHG), and isopropyl alcohol 70% (IPA) against common skin microorganisms. MATERIALS AND METHODS: Time-kill studies were conducted against methicillin-susceptible Staphylococcus aureus (MSSA) and Staphylococcus epidermidis (MSSE), methicillin-resistant S. aureus (MRSA) and S. epidermidis (MRSE), Candida albicans, Corynebacterium species (striatum and amycolatum), Propionibacterium acnes, Pseudomonas aeruginosa, Streptococcus pyogenes, Staphylococcus capitis, and Staphylococcus xylosus. RESULTS: Methicillin-resistant S. aureus: Bactericidal effect was immediate for HA and IPA. For PI and CHG, the effect occurred at 1 and 10 minutes, respectively. Methicillin-resistant S. epidermidis: Hypochlorous acid, IPA, and PI had immediate bactericidal effects, whereas CHG required 1 minute. Methicillin-susceptible Staphylococcus aureus: All agents had bactericidal effects at 1 minute. C. species, S. pyogenes, P. aeruginosa, and P. acnes: All antiseptics demonstrated immediate bactericidal effects. Methicillin-susceptible Staphylococcus epidermidis and S. capitis: Hypochlorous acid and IPA had immediate effect, whereas PI and CHG required 1 minute. C. albicans: Hypochlorous acid, IPA, and PI were immediately bactericidal, whereas CHG required 1 minute. S. xylosus: Hypochlorous acid and CHG were immediately bactericidal, whereas IPA and PI required 1 and 2 minutes, respectively. CONCLUSION: In vitro studies of HA 0.01% were observed to have equal or more efficacious antiseptic properties compared with IPA, CHG, and PI. Future studies will be needed to investigate its role in periocular use.

Childhood maltreatment moderates the effect of combat exposure on cingulum structural integrity.

Limbic white matter pathways link emotion, cognition, and behavior and are potentially malleable to the influences of traumatic events throughout development. However, the impact of interactions between childhood and later life trauma on limbic white matter pathways has yet to be examined. Here, we examined whether childhood maltreatment moderated the effect of combat exposure on diffusion tensor imaging measures within a sample of military veterans (N = 28). We examined five limbic tracts of interest: two components of the cingulum (cingulum, cingulate gyrus, and cingulum hippocampus [CGH]), the uncinate fasciculus, the fornix/stria terminalis, and the anterior limb of the internal capsule. Using effect sizes, clinically meaningful moderator effects were found only within the CGH. Greater combat exposure was associated with decreased CGH fractional anisotropy (overall structural integrity) and increased CGH radial diffusivity (perpendicular water diffusivity) among individuals with more severe childhood maltreatment. Our findings provide preliminary evidence of the moderating effect of childhood maltreatment on the relationship between combat exposure and CGH structural integrity. These differences in CGH structural integrity could have maladaptive implications for emotion and memory, as well as provide a potential mechanism by which childhood maltreatment induces vulnerability to later life trauma exposure.

Generation of a KOR-Cre knockin mouse strain to study cells involved in kappa opioid signaling.

The kappa opioid receptor (KOR) has numerous important roles in the nervous system including the modulation of mood, reward, pain, and itch. In addition, KOR is expressed in many non-neuronal tissues. However, the specific cell types that express KOR are poorly characterized. Here, we report the development of a KOR-Cre knockin allele, which provides genetic access to cells that express KOR. In this mouse, Cre recombinase (Cre) replaces the initial coding sequence of the Opkr1 gene (encoding the kappa opioid receptor). We demonstrate that the KOR-Cre allele mediates recombination by embryonic day 14.5 (E14.5). Within the brain, KOR-Cre shows expression in numerous areas including the cerebral cortex, nucleus accumbens and striatum. In addition, this allele is expressed in epithelium and throughout many regions of the body including the heart, lung, and liver. Finally, we reveal that KOR-Cre mediates recombination of a subset of bipolar and amacrine cells in the retina. Thus, the KOR-Cre mouse line is a valuable new tool for conditional gene manipulation to enable the study of KOR.

Baseline reward circuitry activity and trait reward responsiveness predict expression of opioid analgesia in healthy subjects.

Variability in opioid analgesia has been attributed to many factors. For example, genetic variability of the µ-opioid receptor (MOR)-encoding gene introduces variability in MOR function and endogenous opioid neurotransmission. Emerging evidence suggests that personality trait related to the experience of reward is linked to endogenous opioid neurotransmission. We hypothesized that opioid-induced behavioral analgesia would be predicted by the trait reward responsiveness (RWR) and the response of the brain reward circuitry to noxious stimuli at baseline before opioid administration. In healthy volunteers using functional magnetic resonance imaging and the µ-opioid agonist remifentanil, we found that the magnitude of behavioral opioid analgesia is positively correlated with the trait RWR and predicted by the neuronal response to painful noxious stimuli before infusion in key structures of the reward circuitry, such as the orbitofrontal cortex, nucleus accumbens, and the ventral tegmental area. These findings highlight the role of the brain reward circuitry in the expression of behavioral opioid analgesia. We also show a positive correlation between behavioral opioid analgesia and opioid-induced suppression of neuronal responses to noxious stimuli in key structures of the descending pain modulatory system (amygdala, periaqueductal gray, and rostral-ventromedial medulla), as well as the hippocampus. Further, these activity changes were predicted by the preinfusion period neuronal response to noxious stimuli within the ventral tegmentum. These results support the notion of future imaging-based subject-stratification paradigms that can guide therapeutic decisions.

Mapping institution-specific study descriptions to RadLex Playbook entries.

The naming of imaging procedures is currently not standardized across institutions. As a result, it is a challenge to establish national registries, for instance, a national registry of dose to facilitate comparisons among different types of CT procedures. RSNA's RadLex Playbook is an effort towards addressing this gap (by introducing a unique Playbook identifier called an RPID for each procedure), and the current research focuses on semi-automatically mapping institution-specific procedure descriptions to Playbook entries to assist with this standardization effort. We discuss an algorithm we have developed to facilitate the mapping process which first extracts RadLex codes from the procedure description and then uses the definition of an RPID to determine the most suitable RPID(s) for the extracted set of RadLex codes. We also developed a tool that has three modes of operations-a single procedure mapping mode that allows a user to map a single institution-specific procedure description to a Playbook entry, a bulk mode to process large number of descriptions, and an exploratory mode that assists a user to better understand how the selection of values for various Playbook attributes affects the resulting RPID. We validate our algorithms using 166 production CT procedure descriptions and discuss how the tool can be used by administrators to map institution-specific procedure descriptions to RPIDs.

Heightened interoception in adults with fibromyalgia.

Previous research suggests that the processing of internal body sensations (interoception) affects how we experience pain. Some evidence suggests that people with fibromyalgia syndrome (FMS) - a condition characterised by chronic pain and fatigue - may have altered interoceptive processing. However, extant findings are inconclusive, and some tasks previously used to measure interoception are of questionable validity. Here, we used an alternative measure - the Phase Adjustment Task (PAT) - to examine cardiac interoceptive accuracy in adults with FMS. We examined: (i) the tolerability of the PAT in an FMS sample (N = 154); (ii) if there are differences in facets of interoception (PAT performance, PAT-related confidence, and scores on the Private Body Consciousness Scale) between an FMS sample and an age- and gender-matched pain-free sample (N = 94); and (iii) if subgroups of participants with FMS are identifiable according to interoceptive accuracy levels. We found the PAT was tolerable in the FMS sample, with additional task breaks and a recommended hand posture. The FMS sample were more likely to be classified as 'interoceptive' on the PAT, and had significantly higher self-reported interoception compared to the pain-free sample. Within the FMS sample, we identified a subgroup who demonstrated very strong evidence of being interoceptive, and concurrently had lower fibromyalgia symptom impact (although the effect size was small). Conversely, self-reported interoception was positively correlated with FMS symptom severity and impact. Overall, interoception may be an important factor to consider in understanding and managing FMS symptoms. We recommend future longitudinal work to better understand associations between fluctuating FMS symptoms and interoception.

Stimulus site and modality dependence of functional activity within the human spinal cord.

Chronic pain is thought to arise because of maladaptive changes occurring within the peripheral nervous system and CNS. The transition from acute to chronic pain is known to involve the spinal cord (Woolf and Salter, 2000). Therefore, to investigate altered human spinal cord function and translate results obtained from other species, a noninvasive neuroimaging technique is desirable. We have investigated the functional response in the cervical spinal cord of 18 healthy human subjects (aged 22-40 years) to noxious thermal and non-noxious tactile stimulation of the left and right forearms. Physiological noise, which is a significant source of signal variability in the spinal cord, was accounted for in the general linear model. Group analysis, performed using a mixed-effects model, revealed distinct regions of activity that were dependent on both the side and the type of stimulation. In particular, thermal stimulation on the medial aspect of the wrist produced activity within the C6/C5 segment ipsilateral to the side of stimulation. Similar to data recorded in animals (Fitzgerald, 1982), painful thermal stimuli produced increased ipsilateral and decreased contralateral blood flow, which may reflect, respectively, excitatory and inhibitory processes. Nonpainful punctate stimulation of the thenar eminence provoked more diffuse activity but was still ipsilateral to the side of stimulation. These results present the first noninvasive evidence for a lateralized response to noxious and non-noxious stimuli in the human spinal cord. The development of these techniques opens the path to understanding, at a subject-specific level, central sensitization processes that contribute to chronic pain states.

An ontology-based similarity measure for biomedical data-application to radiology reports.

BACKGROUND: Determining similarity between two individual concepts or two sets of concepts extracted from a free text document is important for various aspects of biomedicine, for instance, to find prior clinical reports for a patient that are relevant to the current clinical context. Using simple concept matching techniques, such as lexicon based comparisons, is typically not sufficient to determine an accurate measure of similarity. METHODS: In this study, we tested an enhancement to the standard document vector cosine similarity model in which ontological parent-child (is-a) relationships are exploited. For a given concept, we define a semantic vector consisting of all parent concepts and their corresponding weights as determined by the shortest distance between the concept and parent after accounting for all possible paths. Similarity between the two concepts is then determined by taking the cosine angle between the two corresponding vectors. To test the improvement over the non-semantic document vector cosine similarity model, we measured the similarity between groups of reports arising from similar clinical contexts, including anatomy and imaging procedure. We further applied the similarity metrics within a k-nearest-neighbor (k-NN) algorithm to classify reports based on their anatomical and procedure based groups. 2150 production CT radiology reports (952 abdomen reports and 1128 neuro reports) were used in testing with SNOMED CT, restricted to Body structure, Clinical finding and Procedure branches, as the reference ontology. RESULTS: The semantic algorithm preferentially increased the intra-class similarity over the inter-class similarity, with a 0.07 and 0.08 mean increase in the neuro-neuro and abdomen-abdomen pairs versus a 0.04 mean increase in the neuro-abdomen pairs. Using leave-one-out cross-validation in which each document was iteratively used as a test sample while excluding it from the training data, the k-NN based classification accuracy was shown in all cases to be consistently higher with the semantics based measure compared with the non-semantic case. Moreover, the accuracy remained steady even as k value was increased - for the two anatomy related classes accuracy for k=41 was 93.1% with semantics compared to 86.7% without semantics. Similarly, for the eight imaging procedures related classes, accuracy (for k=41) with semantics was 63.8% compared to 60.2% without semantics. At the same k, accuracy improved significantly to 82.8% and 77.4% respectively when procedures were logically grouped together into four classes (such as ignoring contrast information in the imaging procedure description). Similar results were seen at other k-values. CONCLUSIONS: The addition of semantic context into the document vector space model improves the ability of the cosine similarity to differentiate between radiology reports of different anatomical and image procedure-based classes. This effect can be leveraged for document classification tasks, which suggests its potential applicability for biomedical information retrieval.

Prestimulus functional connectivity determines pain perception in humans.

Pain is a highly subjective experience that can be substantially influenced by differences in individual susceptibility as well as personality. How susceptibility to pain and personality translate to brain activity is largely unknown. Here, we report that the functional connectivity of two key brain areas before a sensory event reflects the susceptibility to a subsequent noxious stimulus being perceived as painful. Specifically, the prestimulus connectivity among brain areas related to the subjective perception of the body and to the modulation of pain (anterior insular cortex and brainstem, respectively) determines whether a noxious event is perceived as painful. Further, these effects of prestimulus connectivity on pain perception covary with pain-relevant personality traits. More anxious and pain-attentive individuals display weaker descending connectivity to pain modulatory brain areas. We conclude that variations in functional connectivity underlie personality-related differences in individual susceptibility to pain.

Economic assessment of home-based COPD management programs.

Home-based exacerbation management programs have been proposed as an approach to reducing the clinical and financial burden of COPD. We demonstrate a framework to evaluate such programs in order to guide program design and performance decisions towards optimizing cost and clinical outcomes. This study models the impact of hypothetical exacerbation management programs through probabilistic Markov simulations. Patients were stratified by risk using exacerbation rates from the ECLIPSE study and expert opinion. Three scenarios were modeled, using base, worst and best case parameters to suggest potential telehealth program performance. In these scenarios, acute exacerbations could be detected early, with sensitivity and specificity ranging from 60-90%. Detected acute exacerbations could be diverted to either a sub-acute pathway (12.5-50% probability), thus entirely avoiding hospitalization, or a lower cost pathway through length-of-stay reduction (14-28% reduction). For a cohort of patients without prior hospitalization, the base case telehealth scenario results in a cumulative per-patient lifetime savings of $2.9 K over ≈ 12 years. For a higher risk cohort of patients with a prior admission and 1 to 2 acute exacerbations per year, a cumulative $16K per patient was saved during the remaining ≈ 3 life-years. Acceptable prices for home-based exacerbation detection testing were highly dependent on patient risk and scenario, but ranged from $290-$1263 per month for the highest risk groups. These results suggest the economic viability of exacerbation management programs and highlight the importance of risk stratification in such programs. The presented model can further be adapted to model specific programs as trial data becomes available.

Comparison of Standard, Cluster, and Rush Allergy Immunotherapy Buildup Protocols.

BACKGROUND: Allergy immunotherapy (AIT) involves a dose-escalation phase following 1 of 3 protocols: standard, cluster, or rush. Although the cluster and rush protocols have been shown to decrease the time to reach maintenance dosing, there is a lack of direct comparison between the protocols. OBJECTIVE: This study aimed to evaluate the differences in time to maintenance dosing and occurrence of adverse reactions among the dose-escalation protocols. METHODS: A retrospective observation study of patients on AIT was conducted. Patients were categorized as participating in the standard, cluster, or rush buildup protocols. Patients on the rush protocol, unlike the standard and cluster protocols, were required to receive prednisone, montelukast, cetirizine, and famotidine on the rush day and first 2 weekly injections thereafter. Variables analyzed include patient demographics, time until maintenance dosing, rate of adverse reactions, treatments required for reactions, and AIT formulation. RESULTS: Data were reviewed on 237 patients on the standard (n = 41), cluster (n = 122), and rush (n = 74) protocols. The maintenance dose was achieved faster with the rush (16.50 weeks) and cluster (19.33 weeks) buildup protocols than the standard (31.09 weeks) protocol (P < .001). There was no statistically significant difference between time to maintenance dosing when comparing the cluster and rush protocols (P = .322). Despite pretreatment with the rush protocol, the rate of systemic reactions was the same for the standard (9.76%), cluster (9.84%), or rush (14.86%) buildup protocols (P = .526). CONCLUSION: Patients on the cluster buildup protocol for AIT achieved maintenance dosing in a comparable time frame as the rush protocol with a similar rate of systemic reactions and without the need for the pretreatment required with rush immunotherapy.

Activity-Based Photoacoustic Probes for Detection of Disease Biomarkers beyond Oncology.

The earliest activity-based photoacoustic (PA) probes were developed as diagnostic agents for cancer. Since this seminal work over a decade ago that specifically targeted matrix metalloproteinase-2, PA instrumentation, dye platforms, and probe designs have advanced considerably, allowing for the detection of an impressive list of cancer types. However, beyond imaging for oncology purposes, the ability to selectively visualize a given disease biomarker, which can range from aberrant enzymatic activity to the overproduction of reactive small molecules, is also being exploited to study a myriad of noncancerous disease states. In this review, we have assembled a collection of recent papers to highlight the design principles that enable activity-based sensing via PA imaging with respect to biomarker identification and strategies to trigger probe activation under specific conditions.