Design and Preliminary Evaluation of a Wearable Passive Cam-Based Shoulder Exoskeleton.

Mechanically passive exoskeletons may be a practical and affordable solution to meet a growing clinical need for continuous, home-based movement assistance. We designed, fabricated, and preliminarily evaluated the performance of a wearable, passive, cam-driven shoulder exoskeleton (WPCSE) prototype. The novel feature of the WPCSE is a modular spring-cam-wheel module, which generates an assistive force that can be customized to compensate for any proportion of the shoulder elevation moment due to gravity. We performed a benchtop experiment to validate the mechanical output of the WPCSE against our theoretical model. We also conducted a pilot biomechanics study (eight able-bodied subjects) to quantify the effect of a WPCSE prototype on muscle activity and shoulder kinematics during three shoulder movements. The shoulder elevation moment produced by the spring-cam-wheel module alone closely matched the desired theoretical moment. However, when measured from the full WPCSE prototype, the moment was lower (up to 30%) during positive shoulder elevation and higher (up to 120%) during negative shoulder elevation compared to the theoretical moment, due primarily to friction. Even so, a WPCSE prototype, compensating for about 25% of the shoulder elevation moment due to gravity, showed a trend of reducing root-mean-square electromyogram magnitudes of several muscles crossing the shoulder during shoulder elevation and horizontal adduction/abduction movements. Our results also showed that the WPCSE did not constrain or impede shoulder movements during the tested movements. The results provide proof-of-concept evidence that our WPCSE can potentially assist shoulder movements against gravity.

Amplitude modulation coding in awake mice and squirrel monkeys.

Both mice and primates are used to model the human auditory system. The primate order possesses unique cortical specializations that govern auditory processing. Given the power of molecular and genetic tools available in the mouse model, it is essential to understand the similarities and differences in auditory cortical processing between mice and primates. To address this issue, we directly compared temporal encoding properties of neurons in the auditory cortex of awake mice and awake squirrel monkeys (SQMs). Stimuli were drawn from a sinusoidal amplitude modulation (SAM) paradigm, which has been used previously both to characterize temporal precision and to model the envelopes of natural sounds. Neural responses were analyzed with linear template-based decoders. In both species, spike timing information supported better modulation frequency discrimination than rate information, and multiunit responses generally supported more accurate discrimination than single-unit responses from the same site. However, cortical responses in SQMs supported better discrimination overall, reflecting superior temporal precision and greater rate modulation relative to the spontaneous baseline and suggesting that spiking activity in mouse cortex was less strictly regimented by incoming acoustic information. The quantitative differences we observed between SQM and mouse cortex support the idea that SQMs offer advantages for modeling precise responses to fast envelope dynamics relevant to human auditory processing. Nevertheless, our results indicate that cortical temporal processing is qualitatively similar in mice and SQMs and thus recommend the mouse model for mechanistic questions, such as development and circuit function, where its substantial methodological advantages can be exploited. NEW & NOTEWORTHY To understand the advantages of different model organisms, it is necessary to directly compare sensory responses across species. Contrasting temporal processing in auditory cortex of awake squirrel monkeys and mice, with parametrically matched amplitude-modulated tone stimuli, reveals a similar role of timing information in stimulus encoding. However, disparities in response precision and strength suggest that anatomical and biophysical differences between squirrel monkeys and mice produce quantitative but not qualitative differences in processing strategy.

Strand Displacement Probes Combined with Isothermal Nucleic Acid Amplification for Instrument-Free Detection from Complex Samples.

Sensitive and specific detection of pathogens via nucleic acid amplification is currently constrained to laboratory settings and portable equipment with costly fluorescent detectors. Nucleic acid-detecting lateral flow immunoassay strips (LFIAs) offer a low-cost visual transduction strategy at points of need. Unfortunately, these LFIAs frequently detect amplification byproducts that can yield spurious results which can only be deciphered through statistical analysis. We integrated customizable strand displacement probes into standard loop mediated isothermal amplification (LAMP) assays to prevent byproduct capture on commercial LFIAs. We find that combining strand displacement with LAMP (SD-LAMP) yields LFIA test band intensities that can be unequivocally interpreted by human subjects without additional instrumentation, thereby alleviating the need for a portable reader's analysis. Using SD-LAMP, we capture target amplicons on commercially available LFIAs from as few as 3.5 Vibrio cholerae and 2 750 Escherichia coli bacteria without false positive or false negative interpretation. Moreover, we demonstrate that LFIA capture of SD-LAMP products remain specific even in the presence of complex sample matrixes, providing a significant step toward reliable instrument-free pathogen detection outside of laboratories.

Polydisperse emulsion digital assay to enhance time to detection and extend dynamic range in bacterial cultures enabled by a statistical framework.

Microbiological culture remains the most sensitive method for detecting viable and infectious bacteria, but these methods often require at least 24 hours to visibly identify bacterial growth. Lab-on-a-chip applications have utilized methods to isolate bacteria in picoliter-sized reaction vessels, resulting in digitized signals that offer improved time-to-detection and improved quantification. Although a great improvement, these approaches typically require expensive and specialized equipment, trained laboratory personnel, and maximum addressable volumes that can be orders of magnitude less than needed for clinically relevant limits of detection. To address these limitations, we have developed a simple method for preparing and semi-quantitatively analyzing small-volume droplets for performing digital culture, allowing for the detection of bacteria. This work includes a description of the method, characterization of resulting droplet sizes, comparison to traditional culture, and a statistical framework to quantify results. Though polydisperse, the droplet size distribution was consistent over different experiments, and there was a correlation between the observed number of positive droplets and the bulk concentration that can serve as a calibration curve for samples with unknown droplet size distributions. This statistical framework enables the simplification of droplet preparation and allows for accurate quantification even with polydisperse droplet sizes. The application of this method can also be extended to a variety of settings for the detection or quantification of bacteria in complex samples.

Diverse effects of stimulus history in waking mouse auditory cortex.

Responses to auditory stimuli are often strongly influenced by recent stimulus history. For example, in a paradigm called forward suppression, brief sounds can suppress the perception of, and the neural responses to, a subsequent sound, with the magnitude of this suppression depending on both the spectral and temporal distances between the sounds. As a step towards understanding the mechanisms that generate these adaptive representations in awake animals, we quantitatively characterize responses to two-tone sequences in the auditory cortex of waking mice. We find that cortical responses in a forward suppression paradigm are more diverse in waking mice than previously appreciated, that these responses vary between cells with different firing characteristics and waveform shapes, but that the variability in these responses is not substantially related to cortical depth or columnar location. Moreover, responses to the first tone in the sequence are often not linearly related to the suppression of the second tone response, suggesting that spike-frequency adaptation of cortical cells is not a large contributor to forward suppression or its variability. Instead, we use a simple multilayered model to show that cell-to-cell differences in the balance of intracortical inhibition and excitation will naturally produce such a diversity of forward interactions. We propose that diverse inhibitory connectivity allows the cortex to encode spectro-temporally fluctuating stimuli in multiple parallel ways.NEW & NOTEWORTHY Behavioral and neural responses to auditory stimuli are profoundly influenced by recent sounds, yet how this occurs is not known. Here, the authors show in the auditory cortex of awake mice that the quality of history-dependent effects is diverse and related to cell type, response latency, firing rates, and receptive field bandwidth. In a cortical model, differences in excitatory-inhibitory balance can produce this diversity, providing the cortex with multiple ways of representing temporally complex information.

Multicenter Investigation of the Micro-Organisms Involved in Penile Prosthesis Infection: An Analysis of the Efficacy of the AUA and EAU Guidelines for Penile Prosthesis Prophylaxis.

INTRODUCTION: Penile prosthesis infections remain challenging despite advancements in surgical technique, device improvements, and adoption of antibiotic prophylaxis guidelines. AIM: To investigate penile prosthesis infection microbiology to consider which changes in practice could decrease infection rates, to evaluate current antibiotic prophylaxis guidelines, and to develop a proposed algorithm for penile prosthesis infections. METHODS: This retrospective institutional review board-exempt multi-institutional study from 25 centers reviewed intraoperative cultures obtained at explantation or Mulcahy salvage of infected three-piece inflatable penile prostheses (IPPs). Antibiotic usage was recorded at implantation, admission for infection, and explantation or salvage surgery. Cultures were obtained from purulent material in the implant space and from the biofilm on the device. MAIN OUTCOME MEASURES: Intraoperative culture data from infected IPPs. RESULTS: Two hundred twenty-seven intraoperative cultures (2002-2016) were obtained at salvage or explantation. No culture growth occurred in 33% of cases and gram-positive and gram-negative organisms were found in 73% and 39% of positive cultures, respectively. Candida species (11.1%), anaerobes (10.5%) and methicillin-resistant Staphylococcus aureus (9.2%) constituted nearly one third of 153 positive cultures. Multi-organism infections occurred in 25% of positive cultures. Antibiotic regimens at initial implantation were generally consistent with American Urological Association (AUA) and European Association of Urology (EAU) guidelines. However, the micro-organisms identified in this study were covered by these guidelines in only 62% to 86% of cases. Antibiotic selection at admissions for infection and salvage or explantation varied widely compared with those at IPP implantation. CONCLUSION: This study documents a high incidence of anaerobic, Candida, and methicillin-resistant S aureus infections. In addition, approximately one third of infected penile prosthesis cases had negative cultures. Micro-organisms identified in this study were not covered by the AUA and EAU antibiotic guidelines in at least 14% to 38% of cases. These findings suggest broadening antibiotic prophylaxis guidelines and creating a management algorithm for IPP infections might lower infection rates and improve salvage success. Gross MS, Phillips EA, Carrasquillo RJ, et al. Multicenter Investigation of the Micro-Organisms Involved in Penile Prosthesis Infection: An Analysis of the Efficacy of the AUA and EAU Guidelines for Penile Prosthesis Prophylaxis. J Sex Med 2017;14:455-463.

The Malleable Implant Salvage Technique: Infection Outcomes after Mulcahy Salvage Procedure and Replacement of Infected Inflatable Penile Prosthesis with Malleable Prosthesis.

PURPOSE: Since its introduction in 1996 Mulcahy salvage has significantly improved outcomes for the removal and replacement of infected inflatable penile prostheses. Long-term followup data of Mulcahy salvage show an infection-free rate of 82%. A multicenter retrospective analysis of the malleable implant salvage technique was conducted to assess infection outcomes and the feasibility of conversion from malleable device back to inflatable penile prosthesis. MATERIALS AND METHODS: This is a retrospective, institutional review board exempt, multi-institution study of 58 patients who underwent Mulcahy salvage with inflatable penile prosthesis removal and replacement with malleable prosthesis. Patient operative notes and charts were extensively reviewed to compile study data. RESULTS: Between 2002 and 2014 a total of 58 patients underwent infected inflatable penile prosthesis removal and replacement with a malleable prosthesis via Mulcahy salvage. Of these patients 54 (93%) have remained infection-free postoperatively. Average patient age was 56.4 years and average operative time was 148 minutes. Postoperative followup (as of May 2015) ranged from 1 month to 84 months. Of the 54 patients 37 retained the malleable prosthesis and 17 (31%) subsequently underwent replacement with an inflatable penile prosthesis. This occurred on average 6.7 months after Mulcahy salvage. Four patients had persistent infection after Mulcahy salvage with the malleable prosthesis and underwent explantation. CONCLUSIONS: This retrospective analysis of Mulcahy salvage procedure and replacement of inflatable penile prosthesis with malleable prosthesis shows a high infection-free rate. Additionally, 17 of the 54 patients who remained infection-free were able to successfully undergo subsequent removal of the malleable prosthesis and replacement with an inflatable penile prosthesis. Further prospective studies are needed to compare salvage with malleable vs inflatable penile prosthesis.

Use of High-Dose Phenylephrine in the Treatment of Ischemic Priapism: Five-Year Experience at a Single Institution.

INTRODUCTION: Ischemic priapism is an uncommon urologic emergency characterized by a compartment syndrome-like ischemic insult to the corpora cavernosa of the penis. The goal of treatment in ischemic priapism is rapid detumescence to prevent long-term erectile dysfunction. Non-surgical treatment options include aspiration, irrigation, and intracavernous injections of sympathomimetic agents. At our institution, phenylephrine is used in the treatment of ischemic priapism at concentrations and doses that are higher than those recommended in established guidelines. AIM: To characterize our experience with high-concentration intracavernous phenylephrine in the treatment of ischemic priapism at an urban tertiary care center. METHODS: A retrospective chart review identified 58 unique patients presenting to the emergency department on 136 occasions and receiving the diagnosis of ischemic priapism by urologic physicians. Patients' charts were reviewed to record the dosing of phenylephrine and the outcomes and circumstances of the presentation. MAIN OUTCOME MEASURES: Success rates of different treatment strategies for different circumstances of presentation. RESULTS: Successful detumescence was achieved with non-surgical management in 86% of unique patients and the overall resolution rate when including repeat visits was 94%. All patients presenting within less than 36 hours of priapism were successfully treated with non-surgical management. There were no reported complications or associated symptoms related to the use of intracavernous phenylephrine during the 5-year period. CONCLUSION: The use of high concentration and dosing of intracavernous phenylephrine demonstrates a high success rate in the treatment of ischemic priapism. Future prospective studies are needed to further characterize appropriate phenylephrine dosing for its efficacy and safety.

Active Polysubstance Abuse Concurrent With Surgery as a Possible Newly Identified Infection Risk Factor in Inflatable Penile Prosthesis Placement Based on a Retrospective Analysis of Health and Socioeconomic Factors.

INTRODUCTION: Since the introduction of inflatable penile prostheses (IPPs), risk of infection has decreased. However, concurrent substance abuse has not been investigated in prosthetic urology. AIMS: To determine whether substance abuse would stand out as a relevant risk factor for infection in patients undergoing IPP implantation. METHODS: This retrospective study was conducted on charts from the past 12 years at our institution, where a single surgeon completed 602 primary IPP surgeries, with only 12 cases (2%) resulting in postoperative infection. Five of these patients (42%) were actively misusing at least one substance at the time of operation (ie, alcohol, marijuana, cocaine, heroin, other illicit substances, and prescription narcotics). Substance abuse was identified in the medical chart by International Classification of Diseases, Ninth Revision code or by clear documentation by a provider. Multivariate logistic regression analysis was used to estimate the probability of infection as a function of demographic, physical, and treatment variables. MAIN OUTCOME MEASURES: Logistic regression analysis was used to determine statistically significant correlations between risk factors and IPP infection. RESULTS: Polysubstance abuse, poorly controlled blood sugar, and homelessness at the time of procedure positively correlated with postoperative infection. Use of the mummy wrap correlated with decreased infection. CONCLUSION: Active polysubstance abuse, poor glycemic control, and homelessness increase infection risk at IPP implantation. We encourage other implanters to discuss active polysubstance abuse with their patients and to tread cautiously because of the increased risk of infection.

Sex Offenders Seeking Treatment for Sexual Dysfunction--Ethics, Medicine, and the Law.

INTRODUCTION: The treatment of sexual dysfunction in patients with prior sexual offenses poses ethical and legal dilemmas. Sex offenders are not obligated by law to disclose this history to medical professionals. Over 20% of sex offenders experience sexual dysfunction; however, the number of sex offenders seeking evaluation for sexual dysfunction is unknown. AIMS: The aims of this study were to determine the incidence and characteristics of sex offenders seeking treatment in our clinic; and to review data regarding sex offender recidivism and ethics pertaining to the issue as it relates to treating physicians. METHODS: Sex offenders were identified via three methods: new patient screening in a dedicated sexual medicine clinic, chart review of those on intracavernosal injection (ICI) therapy for erectile dysfunction (ED), and review of patient's status-post placement of penile prosthesis. Charts were cross-referenced with the U.S. Department of Justice National Sex Offender Public Website. Patient characteristics and details of offenses were collected. MAIN OUTCOME MEASURES: The main outcome measures used were a self-reported sexual offense and national registry data. RESULTS: Eighteen male sex offenders were identified: 13 via new patient screening; 3 by review of ICI patients; 1 by review of penile prosthesis data; and 1 prior to penile prosthesis placement. All were primarily referred for ED. Of those with known offenses, 64% were level 3 offenders (most likely to re-offend). The same number had committed crimes against children. All those with complete data had multiple counts of misconduct (average 3.6). Ninety-four percent (17/18) had publicly funded health care. Twelve (67%) were previously treated for sexual dysfunction. CONCLUSIONS: Registered sex offenders are seeking and receiving treatment for sexual dysfunction. It is unknown whether treatment of sexual dysfunction increases the risk of recidivism of sexual offenses. Physicians currently face a difficult choice in deciding whether to treat sexual dysfunction in sex offenders.

Toxicokinetic Model Development for the Insensitive Munitions Component 3-Nitro-1,2,4-Triazol-5-One.

3-Nitro-1,2,4-triazol-5-one (NTO) is a component of insensitive munitions that are potential replacements for conventional explosives. Toxicokinetic data can aid in the interpretation of toxicity studies and interspecies extrapolation, but only limited data on the toxicokinetics and metabolism of NTO are available. To supplement these limited data, further in vivo studies of NTO in rats were conducted and blood concentrations were measured, tissue distribution of NTO was estimated using an in silico method, and physiologically based pharmacokinetic models of the disposition of NTO in rats and macaques were developed and extrapolated to humans. The model predictions can be used to extrapolate from designated points of departure identified from rat toxicology studies to provide a scientific basis for estimates of acceptable human exposure levels for NTO.

Bitter melon extract inhibits proliferation of Trypanosoma brucei bloodstream forms in vitro.

Trypanosoma brucei is the causative agent of sleeping sickness, a fatal disease prevalent in sub-Saharan Africa. The few currently available drug treatments are dated and face problems with toxicity and resistance. For these reasons, there is an urgent need for the development of new chemotherapies for the treatment of sleeping sickness. In this study, we investigated the trypanocidal activity of bitter melon extract. Recently, it has been shown that bitter melon extracts display cytotoxic activity towards different cancer cell lines. However, agents exhibiting anti-tumour activity are usually also inhibiting the growth of T. brucei. Treatment of bloodstream forms of T. brucei with extracts prepared from Chinese and Indian bitter melon varieties resulted in a decrease in cell proliferation. In contrast, human myeloid leukaemia HL-60 cells were 3-6 times less sensitive to the extracts than trypanosomes. Initial fractionation of bitter melon extracts indicated that the trypanocidal activity of the extract is associated with at least two different classes of substances: one class of larger molecular weight compounds (>3 kDa) causing rapid lysis of trypanosomes and one class of smaller molecular weight compounds (<3 kDa) inducing accumulation of the parasites in the G(2)-M phase of the cell cycle. Together, the results suggest that bitter melon is a promising source for trypanocidal agents which could be used as lead compounds for the development of novel anti-sleeping sickness drugs.

Detection of viral RNAs at ambient temperature via reporter proteins produced through the target-splinted ligation of DNA probes.

Nucleic acid assays are not typically deployable in point-of-care settings because they require costly and sophisticated equipment for the control of the reaction temperature and for the detection of the signal. Here we report an instrument-free assay for the accurate and multiplexed detection of nucleic acids at ambient temperature. The assay, which we named INSPECTR (for internal splint-pairing expression-cassette translation reaction), leverages the target-specific splinted ligation of DNA probes to generate expression cassettes that can be flexibly designed for the cell-free synthesis of reporter proteins, with enzymatic reporters allowing for a linear detection range spanning four orders of magnitude and peptide reporters (which can be mapped to unique targets) enabling highly multiplexed visual detection. We used INSPECTR to detect a panel of five respiratory viral targets in a single reaction via a lateral-flow readout and ~4,000 copies of viral RNA via additional ambient-temperature rolling circle amplification of the expression cassette. Leveraging synthetic biology to simplify workflows for nucleic acid diagnostics may facilitate their broader applicability at the point of care.

Current status of robot-assisted laparoscopic ureteral reimplantation and reconstruction.

We reviewed the literature on robot-assisted laparoscopic ureteral reimplantation and provide general considerations for indications, perioperative management, and steps of the case. Robot-associated laparoscopic procedures are becoming more common in urologic surgery. The uses of the da Vinci robot (Intuitive Surgical, Sunnyvale, CA) are expanding as well. We examine the use of the robot in distal ureteral reconstruction. A PubMed search was performed using keywords "robot" and "ureter," "distal ureter," "ureteral reimplant," "psoas," and "Boari." Papers that discussed proximal ureteral reconstruction and nephroureterectomy were excluded. A total of nine papers were relevant. Personal experience was also drawn upon. Distal ureteral reconstruction using the robotic technique is feasible, safe, and becoming more and more prevalent as surgeon comfort with the robot increases.

Characterization of wax valving and µPIV analysis of microscale flow in paper-fluidic devices for improved modeling and design.

Paper-fluidic devices are a popular platform for point-of-care diagnostics due to their low cost, ease of use, and equipment-free detection of target molecules. They are limited, however, by their lack of sensitivity and inability to incorporate more complex processes, such as nucleic acid amplification or enzymatic signal enhancement. To address these limitations, various valves have previously been implemented in paper-fluidic devices to control fluid obstruction and release. However, incorporation of valves into new devices is a highly iterative, time-intensive process due to limited experimental data describing the microscale flow that drives the biophysical reactions in the assay. In this paper, we tested and modeled different geometries of thermally actuated valves to investigate how they can be more easily implemented in an LFIA with precise control of actuation time, flow rate, and flow pattern. We demonstrate that bulk flow measurements alone cannot estimate the highly variable microscale properties and effects on LFIA signal development. To further quantify the microfluidic properties of paper-fluidic devices, micro-particle image velocimetry was used to quantify fluorescent nanoparticle flow through the membranes and demonstrated divergent properties from bulk flow that may explain additional variability in LFIA signal generation. Altogether, we demonstrate that a more robust characterization of paper-fluidic devices can permit fine-tuning of parameters for precise automation of multi-step assays and inform analytical models for more efficient design.

Long-term intracavernosal injection therapy: treatment efficacy and patient satisfaction.

Intracavernosal injection therapy (ICI) was the first pharmacologic treatment in the management of erectile dysfunction. ICI allows for customization of medication composition and concentrations, making it a highly effective treatment with an acceptable side effect profile. The objective was to investigate the long-term results of ICI using validated and non-validated instruments. This is a retrospective, single-institution study of 105 patients (mean age 61.6 ± 11.1) patients using ICI. Mean duration of ICI was 8.4 ± 6.25 years. Pre- and post-treatment patient-reported penile rigidity were 41.1% ± 29.3 and 89.6% ± 13.6, respectively (p < 0.05). Statistical changes were also found in the pre and post International Index of Erectile Function (IIEF) scores (33.0 ± 14.4 and 60.0 ± 12.7, p < 0.05), erectile function (11.5 ± 1.3 and 27.3 ± 0.9, p < 0.05) and satisfaction domains (5.3 ± 1.5 and 8.1 ± 1.1, p < 0.05) of the IIEF. There were no statistical differences in questionnaire outcomes between difficult to treat patients (diabetes or radical prostatectomy) and the remainder of queried patients. Complications were rare and included priapism (7.1%), penile curvature (10%; <30°), bruising (7.6%), and mild penile pain (12.4%). Overall, ICI therapy is safe and effective, and compliance may be augmented by patient education, dosing customization, and cost reduction.

Microfluidic rapid and autonomous analytical device (microRAAD) to detect HIV from whole blood samples.

While identifying acute HIV infection is critical to providing prompt treatment to HIV-positive individuals and preventing transmission, existing laboratory-based testing methods are too complex to perform at the point of care. Specifically, molecular techniques can detect HIV RNA within 8-10 days of transmission but require laboratory infrastructure for cold-chain reagent storage and extensive sample preparation performed by trained personnel. Here, we demonstrate our point-of-care microfluidic rapid and autonomous analysis device (microRAAD) that automatically detects HIV RNA from whole blood. Inside microRAAD, we incorporate vitrified amplification reagents, thermally-actuated valves for fluidic control, and a temperature control circuit for low-power heating. Reverse transcription loop-mediated isothermal amplification (RT-LAMP) products are visualized using a lateral flow immunoassay (LFIA), resulting in an assay limit of detection of 100 HIV-1 RNA copies when performed as a standard tube reaction. Even after three weeks of room-temperature reagent storage, microRAAD automatically isolates the virus from whole blood, amplifies HIV-1 RNA, and transports amplification products to the internal LFIA, detecting as few as 3 × 105 HIV-1 viral particles, or 2.3 × 107 virus copies per mL of whole blood, within 90 minutes. This integrated microRAAD is a low-cost and portable platform to enable automated detection of HIV and other pathogens at the point of care.

Ampli: A Construction Set for Paperfluidic Systems.

The design and fabrication of reconfigurable, modular paperfluidics driven by a prefabricated reusable block library, asynchronous modular paperfluidic linear instrument-free (Ampli) block, are reported. The blocks are inspired by the plug-and-play modularity of electronic breadboards that lower prototyping barriers in circuit design. The resulting biochemical breadboard is a paperfluidic construction set that can be functionalized with chemical, biological, and electrical elements. Ampli blocks can form standard paperfluidic devices without any external instrumentation. Furthermore, their modular nature enhances fluidics in ways that fixed devices cannot. The blocks' ability to start, stop, modify, and reverse reaction flows, reagents, and rates in real time is demonstrated. These enhancements allow users to increase colorimetric signals, fine tune reaction times, and counter check multiplexed diagnostics for false positives or negatives. The modular construction demonstrates that field-ready, distributed fabrication of paper analytical systems can be standardized without requiring the "black box" of craft and technique inherent in paper-based systems. Ampli assembly and point-of-care redesign extends the usability of paper analytical systems and invites user-driven prototyping beyond the lab setting demonstrating "Design for Hack" in diagnostics.

Cortical Interneurons Differentially Regulate the Effects of Acoustic Context.

Both behavioral and neural responses to sounds are generally modified by the acoustic context in which they are encountered. As an example, in the auditory cortex, preceding sounds can powerfully suppress responses to later, spectrally similar sounds-a phenomenon called forward suppression (FWS). Whether cortical inhibitory networks shape such suppression or whether it is wholly regulated by common mechanisms such as synaptic depression or spike frequency adaptation is controversial. Here, we show that optogenetically suppressing somatostatin-positive (Sst+) interneurons weakens forward suppression, often revealing facilitation in neurons that are normally forward-suppressed. In contrast, inactivating parvalbumin-positive (Pvalb+) interneurons strengthens forward suppression and alters its frequency dependence. In a simple network model, we show that these effects can be accounted for by differences in short-term synaptic dynamics of inputs onto Pvalb+ and Sst+ interneurons. These results demonstrate separate roles for somatostatin and parvalbumin interneurons in regulating the context dependence of auditory processing.

Thermally actuated wax valves for paper-fluidic diagnostics.

The complexity of current paper-fluidic diagnostic devices is limited by their imperfect control of reagent incubation and delivery. Valves providing complete fluid obstruction and multiple actuation steps within a single paper-fluidic diagnostic would increase the range of diagnostic bioassays in these porous membranes. Here, we report the rapid fabrication of tunable wax-ink valves that are thermally actuated within porous membranes. Varying width bands of wax-ink were printed onto strips of nitrocellulose and cellulose membranes and characterized by their triggered obstruction and release of fluid wicking through the membranes. To demonstrate the utility of these wax-ink valves, we have transformed a traditional lateral flow immunoassay into a multi-step, semi-autonomous assay that enhances bacterial detection signal intensity 6-fold. The wax-ink valves are applicable to other paper fluidic assays by fully obstructing fluid flow for a sustained reaction time and are able to be actuated multiple times for sequential fluid delivery with minimal user involvement. These easily fabricated wax-ink valves are a versatile addition to the toolkit of fluidic control mechanisms required to develop more sensitive paper-based diagnostics.