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Introduction: Deep brain stimulation (DBS) is approved under a humanitarian device exemption to manage treatment-resistant obsessive-compulsive disorder (TR-OCD) in adults. It is possible that DBS may be trialed or used clinically off-label in children and adolescents with TR-OCD in the future. DBS is already used to manage treatment-resistant childhood dystonia. Evidence suggests it is a safe and effective intervention for certain types of dystonia. Important questions remain unanswered about the use of DBS in children and adolescents with TR-OCD, including whether mental health clinicians would refer pediatric patients for DBS, and who would be a good candidate for DBS., Objectives: To explore mental health clinicians' views on what clinical and psychosocial factors they would consider when determining which children with OCD would be good DBS candidates., Materials and Methods: In depth, semi-structured interviews were conducted with n  = 25 mental health clinicians who treat pediatric patients with OCD. The interviews were transcribed, coded, and analyzed using thematic content analysis. Three questions focused on key, clinical, and psychosocial factors for assessing candidacy were analyzed to explore respondent views on candidacy factors. Our analysis details nine overarching themes expressed by clinicians, namely the patient's previous OCD treatment, OCD severity, motivation to commit to treatment, presence of comorbid conditions, family environment, education on DBS, quality of life, accessibility to treatment, and patient age and maturity., Conclusions: Clinicians generally saw considering DBS treatment in youth as a last resort and only for very specific cases. DBS referral was predominantly viewed as acceptable for children with severe TR-OCD who have undertaken intensive, appropriate treatment without success, whose OCD has significantly reduced their quality of life, and who exhibit strong motivation to continue treatment given the right environment. Appropriate safeguards, eligibility criteria, and procedures should be discussed and identified before DBS for childhood TR-OCD becomes practice.

Introduction: While the ethical significance of caregivers in neurological research has increasingly been recognized, the role of caregivers in brain-computer interface (BCI) research has received relatively less attention., Objectives: This report investigates the extent to which caregivers are mentioned in publications describing implantable BCI (iBCI) research for individuals with motor dysfunction, communication impairment, and blindness., Methods: The scoping review was conducted in June 2024 using the PubMed and Web of Science bibliographic databases. The articles were systematically searched using query terms for caregivers, family members, and guardians, and the results were quantitatively and qualitatively analyzed., Results: Our search yielded 315 unique studies, 78 of which were included in this scoping review. Thirty-four (43.6%) of the 78 articles mentioned the study participant's caregivers. We sorted these into 5 categories: Twenty-two (64.7%) of the 34 articles thanked caregivers in the acknowledgement section, 6 (17.6%) articles described the caregiver's role with regard to the consent process, 12 (35.3%) described the caregiver's role in the technical maintenance and upkeep of the BCI system or in other procedural aspects of the study, 9 (26.5%) discussed how the BCI enhanced participant communication and goal-directed behavior with the help of a caregiver, and 3 (8.8%) articles included general comments that did not fit into the other categories but still related to the importance of caregivers in the lives of the research participants., Discussion: Caregivers were mentioned in less than half of BCI studies in this review. The studies that offered more robust discussions of caregivers provide valuable insight into the integral role that caregivers play in supporting the study participants and the research process. Attention to the role of caregivers in successful BCI research studies can help guide the responsible development of future BCI study protocols., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wohns, Dorfman and Klein.)

Background: Personalized risk (PR) estimates may enhance clinical decision making and risk communication by providing individualized estimates of patient outcomes. We explored stakeholder attitudes toward the utility, acceptability, usefulness and best-practices for integrating PR estimates into patient education and decision making about Left Ventricular Assist Device (LVAD)., Methods and Results: As part of a 5-year multi-institutional AHRQ project, we conducted 40 interviews with stakeholders (physicians, nurse coordinators, patients, and caregivers), analyzed using Thematic Content Analysis. All stakeholder groups voiced positive views towards integrating PR in decision making. Patients, caregivers and coordinators emphasized that PR can help to better understand a patient's condition and risks, prepare mentally and logistically for likely outcomes, and meaningfully engage in decision making. Physicians felt it can improve their decision making by enhancing insight into outcomes, enhance tailored pre-emptive care, increase confidence in decisions, and reduce bias and subjectivity. All stakeholder groups also raised concerns about accuracy, representativeness and relevance of algorithms; predictive uncertainty; utility in relation to physician's expertise; potential negative reactions among patients; and overreliance., Conclusion: Stakeholders are optimistic about integrating PR into clinical decision making, but acceptability depends on prospectively demonstrating accuracy, relevance and evidence that benefits of PR outweigh potential negative impacts on decision making quality., Competing Interests: Declaration of Competing Interest Thank you for your time and consideration. This article has not been published previously and is not under consideration elsewhere. There are no conflicts of interests to report. All authors agree with the content of the manuscript., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The ongoing debate within neuroethics concerning the degree to which neuromodulation such as deep brain stimulation (DBS) changes the personality, identity, and agency (PIA) of patients has paid relatively little attention to the perspectives of prospective patients. Even less attention has been given to pediatric populations. To understand patients' views about identity changes due to DBS in obsessive-compulsive disorder (OCD), the authors conducted and analyzed semistructured interviews with adolescent patients with OCD and their parents/caregivers. Patients were asked about projected impacts to PIA generally due to DBS. All patient respondents and half of caregivers reported that DBS would impact patient self-identity in significant ways. For example, many patients expressed how DBS could positively impact identity by allowing them to explore their identities free from OCD. Others voiced concerns that DBS-related resolution of OCD might negatively impact patient agency and authenticity. Half of patients expressed that DBS may positively facilitate social access through relieving symptoms, while half indicated that DBS could increase social stigma. These views give insights into how to approach decision-making and informed consent if DBS for OCD becomes available for adolescents. They also offer insights into adolescent experiences of disability identity and "normalcy" in the context of OCD.

Approximately 10-20% of children with obsessive-compulsive disorder (OCD) have treatment-resistant presentations, and there is likely interest in developing interventions for this patient group, which may include deep brain stimulation (DBS). The World Society for Stereotactic and Functional Neurosurgery has argued that at least two successful randomized controlled trials should be available before DBS treatment for a psychiatric disorder is considered "established." The FDA approved DBS for adults with treatment-resistant OCD under a humanitarian device exemption (HDE) in 2009, which requires that a device be used to manage or treat a condition impacting 8,000 or fewer patients annually in the United States. DBS is currently offered to children ages 7 and older with treatment-resistant dystonia under an HDE. Ethical and empirical work are needed to evaluate whether and under what conditions it might be appropriate to offer DBS for treatment-resistant childhood OCD. To address this gap, we report qualitative data from semi-structured interviews with 25 clinicians with expertise in this area. First, we report clinician perspectives on acceptable levels of evidence to offer DBS in this patient population. Second, we describe their perspectives on institutional policies or protocols that might be needed to effectively provide care for this patient population.

Introduction: Deep brain stimulation (DBS) is utilized to treat pediatric refractory dystonia and its use in pediatric patients is expected to grow. One important question concerns the impact of hope and unrealistic optimism on decision-making, especially in "last resort" intervention scenarios such as DBS for refractory conditions., Objective: This study examined stakeholder experiences and perspectives on hope and unrealistic optimism in the context of decision-making about DBS for childhood dystonia and provides insights for clinicians seeking to implement effective communication strategies., Materials and Methods: Semi-structured interviews with clinicians ( n = 29) and caregivers ( n = 44) were conducted, transcribed, and coded., Results: Using thematic content analysis, four major themes from clinician interviews and five major themes from caregiver interviews related to hopes and expectations were identified. Clinicians expressed concerns about caregiver false hopes (86%, 25/29) and desperation (68.9%, 20/29) in light of DBS being a last resort. As a result, 68.9% of clinicians (20/29) expressed that they intentionally tried to lower caregiver expectations about DBS outcomes. Clinicians also expressed concern that, on the flip side, unrealistic pessimism drives away some patients who might otherwise benefit from DBS (34.5%, 10/29). Caregivers viewed DBS as the last option that they had to try (61.3%, 27/44), and 73% of caregivers (32/44) viewed themselves as having high hopes but reasonable expectations. Fewer than half (43%, 19/44) expressed that they struggled setting outcome expectations due to the uncertainty of DBS, and 50% of post-DBS caregivers (14/28) expressed some negative feelings post treatment due to unmet expectations. 43% of caregivers (19/44) had experiences with clinicians who tried to set low expectations about the potential benefits of DBS., Conclusion: Thoughtful clinician-stakeholder discussion is needed to ensure realistic outcome expectations., Competing Interests: Conflicts of Interest The authors have no conflicts of interest to disclose.

Bioethicists today are taking a greater role in the design and implementation of emerging technologies by "embedding" within the development teams and providing their direct guidance and recommendations. Ideally, these collaborations allow ethical considerations to be addressed in an active, iterative, and ongoing process through regular exchanges between ethicists and members of the technological development team. This article discusses a challenge to this embedded ethics approach-namely, that bioethical guidance, even if embraced by the development team in theory, is not easily actionable in situ. Many of the ethical problems at issue in emerging technologies are associated with preexisting structural, socioeconomic, and political factors, making compliance with ethical recommendations sometimes less a matter of choice and more a matter of feasibility. Moreover, incentive structures within these systemic factors maintain them against reform efforts. The authors recommend that embedded bioethicists utilize principles from behavioral science (such as behavioral economics) to better understand and account for these incentive structures so as to encourage the ethically responsible uptake of technological innovations.

Rapid developments in the fields of learning and object recognition have been obtained by successfully developing and using methods for learning from a large number of labeled image examples. However, such current methods cannot explain infants' learning of new concepts based on their visual experience, in particular, the ability to learn complex concepts without external guidance, as well as the natural order in which related concepts are acquired. A remarkable example of early visual learning is the category of 'containers' and the notion of 'containment'. Surprisingly, this is one of the earliest spatial relations to be learned, starting already around 3 month of age, and preceding other common relations (e.g., 'support', 'in-between'). In this work we present a model, which explains infants' capacity of learning 'containment' and related concepts by 'just looking', together with their empirical development trajectory. Learning occurs in the model fast and without external guidance, relying only on perceptual processes that are present in the first months of life. Instead of labeled training examples, the system provides its own internal supervision to guide the learning process. We show how the detection of so-called 'paradoxical occlusion' provides natural internal supervision, which guides the system to gradually acquire a range of useful containment-related concepts. Similar mechanisms of using implicit internal supervision can have broad application in other cognitive domains as well as artificial intelligent systems, because they alleviate the need for supplying extensive external supervision, and because they can guide the learning process to extract concepts that are meaningful to the observer, even if they are not by themselves obvious, or salient in the input., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Rats move their whiskers to acquire information about their environment. It has been observed that they palpate novel objects and objects they are required to localize in space. We analyze whisker-based object localization using two complementary paradigms, namely, active learning and intrinsic-reward reinforcement learning. Active learning algorithms select the next training samples according to the hypothesized solution in order to better discriminate between correct and incorrect labels. Intrinsic-reward reinforcement learning uses prediction errors as the reward to an actor-critic design, such that behavior converges to the one that optimizes the learning process. We show that in the context of object localization, the two paradigms result in palpation whisking as their respective optimal solution. These results suggest that rats may employ principles of active learning and/or intrinsic reward in tactile exploration and can guide future research to seek the underlying neuronal mechanisms that implement them. Furthermore, these paradigms are easily transferable to biomimetic whisker-based artificial sensors and can improve the active exploration of their environment., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Early in development, infants learn to solve visual problems that are highly challenging for current computational methods. We present a model that deals with two fundamental problems in which the gap between computational difficulty and infant learning is particularly striking: learning to recognize hands and learning to recognize gaze direction. The model is shown a stream of natural videos and learns without any supervision to detect human hands by appearance and by context, as well as direction of gaze, in complex natural scenes. The algorithm is guided by an empirically motivated innate mechanism--the detection of "mover" events in dynamic images, which are the events of a moving image region causing a stationary region to move or change after contact. Mover events provide an internal teaching signal, which is shown to be more effective than alternative cues and sufficient for the efficient acquisition of hand and gaze representations. The implications go beyond the specific tasks, by showing how domain-specific "proto concepts" can guide the system to acquire meaningful concepts, which are significant to the observer but statistically inconspicuous in the sensory input.

We measured long-term memory for a narrative film. During the study session, participants watched a 27-min movie episode, without instructions to remember it. During the test session, administered at a delay ranging from 3 h to 9 mo after the study session, long-term memory for the movie was probed using a computerized questionnaire that assessed cued recall, recognition, and metamemory of movie events sampled approximately 20 sec apart. The performance of each group of participants was measured at a single time point only. The participants remembered many events in the movie even months after watching it. Analysis of performance, using multiple measures, indicates differences between recent (weeks) and remote (months) memory. While high-confidence recognition performance was a reliable index of memory throughout the measured time span, cued recall accuracy was higher for relatively recent information. Analysis of different content elements in the movie revealed differential memory performance profiles according to time since encoding. We also used the data to propose lower limits on the capacity of long-term memory. This experimental paradigm is useful not only for the analysis of behavioral performance that results from encoding episodes in a continuous real-life-like situation, but is also suitable for studying brain substrates and processes of real-life memory using functional brain imaging.

Recent reports have revitalized the debate on whether, for each item in memory, consolidation occurs just once, or whether, upon their activation in retrieval, items in memory undergo reconsolidation. Further, it has been recently reported that following retrieval in the absence of reinforcer, the activated memory can either reconsolidate or extinguish, depending on the training history. This raises the question whether consolidation, extinction and reconsolidation share neuronal mechanisms, and moreover, whether reconsolidation recapitulates consolidation. In conditioned taste aversion (CTA), consolidation depends on protein synthesis in the central nucleus of the amygdala, whereas extinction depends on protein synthesis in the basolateral nuclei of the amygdala. Here we show that inhibition of protein synthesis in either of these nuclei has no effect on CTA memory under conditions that initiate reconsolidation. This implies that reconsolidation does not recapitulate consolidation, and that consolidation, reconsolidation and extinction are different processes.

We describe here a two-phase approach for the development of high-affinity human anti-HIV immunoglobulin Fab domains in a bacterial expression system. The first phase of this technique involves the generation of human hybridoma cell lines producing high-affinity antibodies (MAbs). Anti-HIV-1 human MAbs from peripheral blood lymphocytes (PBLs) were prepared from an HIV-1-seropositive patient and from an HIV-1-seronegative volunteer immunized with HIV-1 rgp160. One MAb (T15G1), derived from the blood of the seropositive donor, was specific for HIV-1 gp41, recognized gp41 on the surface of HIV-1-infected cells and bound this antigen with an apparent dissociation constant of 4 x 10(-10) M. A second MAb (M7B5), developed from the immunized volunteer, was specific for HIV-1 gp120 with a dissociation constant on the order of 8 x 10(-10) M, but was unable to recognize cell surface antigen. In the second phase of this technique the Fab domains of these two MAbs were molecularly cloned into a bacterial expression vector. mRNA was isolated from the M7B5 and T15G1 hybridoma cell lines and used as a template for the production of cDNA. The cDNA was amplified using the polymerase chain reaction (PCR) technique, and then fused, in frame, into a bacterial expression vector. The recombinant Fabs (rFabM7B5 and rFabT15G1) were expressed as dicistronic messages in bacteria using the IPTG-inducible lactose promoter (LacZ). DNA sequencing was used to define the gamma chain isotypes and the VH and VL chain gene usage. The binding specificities of rFabM7B5 and rFabT15G1 were indistinguishable from their respective intact MAbs.(ABSTRACT TRUNCATED AT 250 WORDS)

A total of nine human monoclonal antibodies (MAbs) to rabies virus were generated from peripheral B lymphocytes of subjects immunized with human diploid cell rabies vaccine by somatic cell hybridization. The MAbs were analyzed for their antigen-binding specificities using ELISA, Western blot, and immunoprecipitation assays. The different assays made it possible to identify MAbs directed to the surface glycoprotein, nucleoprotein, nominal phosphoprotein, and matrix protein. One of the MAbs that recognized the surface glycoprotein neutralized rabies virus.

Monoclonal antibodies that bound to HIV gp41 and cross-reacted with astrocytes were recovered from the blood of three patients infected with HIV-1. Mapping of the specificity of these monoclonal antibodies, using synthetic gp41 peptides, located their epitope to amino acids 644-663 and established their conformation dependence. Six other human monoclonal anti-HIV antibodies were found to bind to HIV gp41 or gp120 but not to reactive astrocytes in brain tissue. Sharing of linear or conformational protein determinants between disparate viral and host proteins is termed molecular mimicry. The consequences of such mimicry by anti-viral antibodies interacting with astrocytes may play a role in the dementia of AIDS patients since a major function of astrocytes is to maintain the appropriate milieu for neuronal function. The finding of such cross-reactive antibodies adds to the evidence for a possible autoimmune pathogenesis in some of the disease manifestations accompanying HIV infection.

Patients infected with HIV-1 experience several hyperproliferative skin disorders, including seborrheic dermatitis, ichthyosis, and psoriasis. Transgenic mice carrying a subgenomic HIV-1 proviral construct lacking the gag and pol genes were found to develop proliferative epidermal lesions, manifested as diffuse epidermal hyperplasia in homozygous transgenic mice and benign papillomas in heterozygous transgenic mice. Nonpapillomatous skin from both homozygotes and heterozygotes expressed viral RNA, and the viral envelope protein gp120 was localized to the suprabasal keratinocyte. Papillomas contained increased amounts of both viral mRNA and envelope glycoprotein. Exposure of transgenic mice to doses of ultraviolet B (UV-B) irradiation that induced cutaneous injury increased viral gene expression and resulted in the development of papillomas within 14-21 days. Cutaneous injury induced by phenol and liquid nitrogen had similar effects. These data support a role for HIV-1 gene products in the pathogenesis of proliferative epidermal disorders associated with HIV-1 infection. Further, they suggest that the process of wound repair increases HIV-1 gene expression in this transgenic mouse model.

Sarcomas were induced in C57BL/6 mice by using 3-methylcholanthrene. Spleen cells taken from these mice bearing primary, chemically induced tumors and from matched control mice were assessed for the capacity to generate cell-mediated cytotoxic cell activity after in vitro sensitization. Spleen cells from tumor-bearing mice generated strong cell-mediated cytotoxic responses against alloantigens and antigens on syngeneic cells.

Mouse spleen cells became cytotoxic in short-term 51Cr-release assays for a wide variety of target cells after 5 days of culture in vitro with polyinosinic acid in a system that was otherwise entirely syngeneic. This study characterizes these effector cells with respect to target specificity, effect of donor age, time course of their appearance, mouse strain differences, and expression of differentiation antigens Thy-1, Lyt-1, Lyt-2, NK-1, and asialo GM1. The combination of properties of this cytotoxic cell response that make it unique are that a) the broadly reactive cytotoxic activity developed from unprimed spleen cells in the absence of either foreign cells or foreign serum; b) the response did not peak until 4 to 5 days of culture in vitro; c) the broad reactivity pattern included freshly dispersed primary syngeneic sarcoma cells and cultured syngeneic fibroblasts but did not include syngeneic lymphoblast target cells; d) the response was largely monoclonal as defined by target cell binding; and e) cytotoxic cell activity was sensitive in complement-mediated treatments to both anti-NK and anti-theta but not to anti-Lyt-2, anti-Lyt-1, or anti-asialo GM1. Both high- and low-responding mouse strains have been identified.

The authors obtained artificial lipid vesicles--liposomes containing immunoglobulins. IgG in the complexes with liposomes proved to retain their immunological activity: the liposomes containing rabbit anti-mouse IgG agglutinated in the presence of donkey anti-rabbit IgG or mouse serum. As shown by the use of liposomes containing H3-inulin and immunoglobulins against the cell surface determinants, these immuno-liposomes selectively bound the target, but not the control cells. Specific binding with the antigenic cell surface determinants was also demonstrated in the case of liposomes bearing the nonimmune globulins besides the immunoglobulins. By the indirect immunofluorescence method it was shown that the nonimmune globulins in complex with the immune liposomes were selectively bound by target cells. A possible use of the immuno-liposomes to deliver various substances selectively to the cells of particular types, and to incorporate new antigens into the cell membrane is discussed.

In isoelectric focusing of twofold gradienpturified and Tween 80-ether disrupted RLV the groupspecific antigen (gs-1) was found in 3 pH-zones (4,45-5,5; 5,65-6,0; 6,45-6,6). For the gs-1 from plasma und spleen cells of leukemic mice was shown heterogeneity by several methods: 1. Gs-1 from plasma showed in isoelectric focusing a scattering along the whole elution profile. 2. Agarimmunoelectrophoresis resulted in a longer precipitationline for gs-1 from plasma in comparison with gs-1 from spleen cells. 3. Polyacrylamidgelelectrophoresis with following immunodiffusion made evident the particularly discrete character of this heterogeneity: gs-1 from both materials were found in two main zones.

Mouse thymocytes and spleen cells from unprimed C57BL/6 donors generate broadly reactive cytotoxic cells during 5 days of culture in vitro with polyinosinic acid (5') (poly(I] and/or supernatant from PMA-treated EL4 leukemia cells which contains interleukin 2 (IL-2) activity. We refer here to such cytotoxic cells as "supplement-induced cytotoxic cells" or SICC. Thymocytes are dependent on the supernatant factor(s), whereas spleen cells are usually stimulated by poly(I) alone. Polyinosinic acid acts synergistically with supernatant factor(s) to stimulate generation of SICC by both thymocytes (SICC-T) and spleen cells (SICC-S) when the IL-2 activity of the supernatant is inadequate alone. SICC can be generated by both splenocytes and thymocytes in medium supplemented with fetal calf serum or syngeneic plasma. SICC are active in 4 hr 51Cr-release tests against syngeneic, allogeneic, and xenogeneic tumors but not against lipopolysaccharide-induced lymphoblasts. Embryonic fibroblasts, too, are sensitive to SICC generated by thymocytes. In complement-dependent depletion tests, cytotoxic activity is partially sensitive (SICC-T) or fully sensitive (SICC-S) to anti-Thy-1 and -H-2 but not to anti-Lyt-1, -Lyt-2, or -asialo GM1.

A transmissible syndrome which is characterized by splenomegaly and myeloid metaplasia was induced in BALB/c mice by injections of certain homologous and heterologous antigens and complete Freund's adjuvant or dextransulfate. From the plasma of these animals small viruslike particles (30--50 nm) were isolated.

Preparation of target cells from tissue culture lines which grow adherent to tissue culture vessels is often desirable for tests of cell-mediated cytotoxicity (CMC). In the present study we used cells derived from adherent tissue culture lines to compare the merits of suspension vs. adherent target cells in short-term 51Cr-release assays. Cytotoxic activity of murine spleen cells sensitized in vitro against allogeneic spleen cells or syngeneic sarcoma cells was tested with fibroblast or sarcoma target cells. In parallel tests, aliquots of tissue culture lines were detached and used as either suspension or adherent target cells in CMC assays, matching the concentrations of suspension and adherent target cells. In both allogeneic and syngeneic combinations adherent target cells released less 51Cr spontaneously and were more susceptible to CMC than their suspension counterparts.