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Efficient computation and cue integration with noisy population codes.

The brain represents sensory and motor variables through the activity of large populations of neurons. It is not understood how the nervous system computes with these population codes, given that individual neurons are noisy and thus unreliable. We focus here on two general types of computation, function approximation and cue integration, as these are powerful enough to handle a range of tasks, including sensorimotor transformations, feature extraction in sensory systems and multisensory integration. We demonstrate that a particular class of neural networks, basis function networks with multidimensional attractors, can perform both types of computation optimally with noisy neurons. Moreover, neurons in the intermediate layers of our model show response properties similar to those observed in several multimodal cortical areas. Thus, basis function networks with multidimensional attractors may be used by the brain to compute efficiently with population codes.

Action Potentials↗

CoxFormer enables spatial omics inference with multimodal generative modeling.

Gene co-expression maps transcriptome-wide gene-gene relationships, yet high-quality estimates cover less than half the genome. Meanwhile, spatial omics either profiles restricted in situ panels or lacks cellular resolution. Extending co-expression transcriptome-wide could overcome these limitations by inferring unassayed gene expression at subcellular resolution. Here we show that CoxFormer integrates literature-derived gene knowledge with co-expression networks from bulk tissues and large-scale single-cell atlases to learn 512-dimensional representations for 32,016 human genes. These embeddings capture functional gene relationships and serve as a generative prior for spatial inference across platforms and modalities. Without requiring a matched single-cell RNA-sequencing reference, CoxFormer supports four applications beyond measured genes: histology-based expression imputation, gene activity prediction from chromatin accessibility, subcellular super-resolution inference, and pathological region detection. Together, CoxFormer extends gene embedding from gene- and cell-level tasks to whole-transcriptome spatial inference, providing a unified framework for biological analysis beyond the limited gene coverage of current spatial omics technologies.

Humans↗

Towards multimodal atlases of the human brain.

Atlases of the human brain have an important impact on neuroscience. The emergence of ever more sophisticated imaging techniques, brain mapping methods and analytical strategies has the potential to revolutionize the concept of the brain atlas. Atlases can now combine data describing multiple aspects of brain structure or function at different scales from different subjects, yielding a truly integrative and comprehensive description of this organ. These integrative approaches have provided significant impetus for the human brain mapping initiatives, and have important applications in health and disease.

Anatomy, Artistic↗

Personalizing endometrial cancer care beyond histology: clinical applications and limits of molecular classification.

Endometrial cancer is a biologically heterogeneous disease whose management has been reshaped by molecular classification. This review summarizes the current evidence supporting the integration of molecular subgroups into prognostic assessment and treatment personalization across stages of disease. The Cancer Genome Atlas classification and its clinically applicable surrogates identify four major molecular categories: POLE-mutated, mismatch repair-deficient, p53-abnormal, and no specific molecular profile tumors. These groups differ substantially in biology, prognosis, treatment sensitivity, and areas of unmet need. POLE-mutated tumors have an excellent prognosis and represent the clearest candidates for adjuvant treatment de-escalation, particularly in early-stage disease. Mismatch repair-deficient tumors show intermediate prognosis but strong sensitivity to immune checkpoint inhibition, which has transformed the management of advanced and recurrent disease and is now being tested in earlier settings. p53-abnormal tumors represent the highest-risk subgroup, requiring multimodal treatment and offering opportunities for biomarker-driven strategies including HER2-directed therapy and DNA damage repair targeting. No specific molecular profile tumors remain the most heterogeneous category, increasingly refined by estrogen receptor status, grade, L1 cell adhesion molecule overexpression, and other biomarkers. Mismatch repair-proficient advanced/recurrent disease should be interpreted as a composite clinical trial population rather than a molecular class. Molecular classification should be integrated with traditional clinicopathologic factors, emerging biomarkers, and local implementation strategies to support equitable, biologically informed treatment selection in endometrial cancer.

Humans↗

Assessing children for the effects of sexual victimization.

In summary, the psychological assessment of sexually abused children is complicated significantly by the fact that there is no single syndrome that reflects the impact of sexual abuse (Kendall-Tackett, Williams, and Finkelhor, 1993). A number of generic measures of psychopathology in children continue to find large percentages of children relatively asymptomatic. This is due to the variability in impact of sexual abuse, but also reflects the need to develop abuse-specific outcome measures. Because we are discussing the evaluation of children, psychological assessment must be developmentally sensitive and reflect the context of the child (Stewart, Bussey, Goodman, and Saywitz, 1993). Consequently, information should be obtained not only from parents and children, but from the entire family. Unless an evaluation includes some abuse-specific measures and examines findings about the child in the context of the larger family environment, it is not likely to be valid. The interrelationship of abuse impact on parental perception and subsequent parental accuracy in reporting also must be examined in more detail. Not surprisingly, maternal reports of their sexually abused child's emotional states are strongly correlated with their own distress (Newberger, Geremy, Waternaux, and Newberger, 1993). This confound necessitates input from teachers or other objective observers of the child. The evaluation of sexually abused children should be theoretically driven. I strongly recommend assessing both the child and the parents with regard to attachment quality, difficulties with self-regulation, and an impaired sense of self. There are a number of measures pertinent to both parents and children across each of these domains. However, measures must be developed and validated that allow for parent, child, and teacher report in the areas of sexual behavior, sexual concerns, sexual meaning, body integrity, abuse-specific aspects of self (such as blame, shame, and dissociation), PTSD, abuse-specific fears, and family-related variables of rejection and role reversal. There is a developing literature that supports the need to assess each of these domains in a multimodal manner.

Adolescent↗

Management of chronic pain. Part II.

Chronic pain is associated with substantial psychosocial and economic stress coupled with functional loss and various levels of vocational dysfunction. The role of a pain center is to focus on chronic pain in a multidisciplinary, comprehensive manner, providing the patient with the most effective opportunity to manage his or her chronic disease syndrome. This article focuses on methods to manage many types of chronic pain and describes a broad range of pharmacologic and non-pharmacologic interventions and options available to the patient. Part I of this two-part monograph described pharmacotherapeutic interventions and regional nerve blocks. Part II focuses on psychologic assessment and treatment and physical therapy. A multimodal management strategy offers patients the greatest improvement potential for specific chronic pain syndromes. Cognitive and behavioral therapies and physical therapies are described. This combination of therapies may provide patients with the skills and knowledge needed to increase their sense of control over pain. The integration of appropriate pharmacotherapeutic regimens, neural blockades, physical therapy, and psychologic techniques maximizes the patient's effectiveness in dealing with chronic pain. Three case studies are presented in Part II.

Adaptation, Psychological↗

Management of chronic pain. Part I.

Chronic pain is associated with substantial psychosocial and economic stress, coupled with functional loss and various levels of vocational dysfunction. The role of a pain center is to focus on chronic pain in a multidisciplinary, comprehensive manner, providing the patient with the most effective opportunity to manage his or her chronic disease syndrome. This article focuses on methods to manage many types of chronic pain and describes a broad range of pharmacologic and nonpharmacologic interventions and options available to the patient. Part I of this two-part monograph describes pharmacotherapeutic interventions and regional nerve blocks. Part II focuses on psychologic assessment and treatment and physical therapy. A multimodal management strategy offers patients the greatest improvement potential for specific chronic pain syndromes. Cognitive and behavioral therapies and physical therapies are described. This combination of therapies may provide patients with the skills and knowledge needed to increase their sense of control over pain. The integration of appropriate pharmacotherapeutic regimens, neural blockades, physical therapy, and psychologic techniques maximizes a patient's effectiveness in dealing with chronic pain. Three case studies are presented in Part II.

Analgesics↗

[The significance of clinical guidelines for rehabilitation].

Clinical practice guidelines are relevant to all parties involved in the health system. For rehabilitation under the German pension insurance scheme, there are two main aspects: the integration of rehabilitation into the curative guidelines in terms of "local tailoring" on the one hand and the development of guidelines for rehabilitative processes, demand-oriented control of rehabilitation access, and rehabilitative aftercare on the other hand. The elaboration of effective standards is aimed at avoiding over-provision, under-provision or misdirected provision of care and, simultaneously, at ensuring that quality assured treatment is offered to the rehabilitees. Also, it is intended to increasingly implement evidence-based medicine in a sector of the health system in which research has so far been underrepresented. Implementation of guidelines in the rehabilitative sector will allow to disseminate existing knowledge in targeted manner, to systematically fill the gaps and to broaden the knowledge base as a whole. Furthermore, guidelines can facilitate integration of the different sectors in health care provision by operationalising the interfaces both with curative medicine and primary prevention. Throughout the process of guideline development for rehabilitation the specific characteristics of this sector must be kept in mind. Since therapeutic interventions are multidisciplinary and multimodal in nature guidelines have to be comprehensible and applicable for all members of the multiprofessional team. Corresponding to the relative paucity in rehabilitation research there is no sufficient evidence base for numerous therapeutic interventions. Accordingly, guidelines in rehabilitation will--initially--consist of a mixture of evidence- and consensus-based recommendations. Also, the specific goal of rehabilitation under the German pension insurance scheme, namely maintenance or recovery of the capacity at work, has to be borne in mind. There are many initiatives by the providers of rehabilitation as well as the scientific medical societies to develop and implement rehabilitative clinical practice guidelines, e. g. the guidelines programme of the BfA (Federal Insurance Institute for Salaried Employees), which is aimed at developing rehabilitation process guidelines for selected indications, the guidelines activities of the VDR (Federation of German Pension Insurance Institutes), and the input of the "Guidelines" commission of the DGRW (German Society of Rehabilitation Science). It is hoped that in the years to come the parties involved in German health care provision will be open to the advantages of clinical practice guidelines. Rehabilitation under the German pension insurance scheme, with respect to its experience with quality assurance, its responsibilities for structure and concept and a growing acceptance on the part of care providers, already holds a well-founded starting position.

Combined Modality Therapy↗

Application of the resistive sheet in finite element microwave heating systems.

The use of the resistive sheet for characterizing thin metallic films is presented in a microwave heating context. A finite edge element formulation is used to include the resistive sheet surface integral in both the frequency and time domains. The properties of the resistive sheet are compared with analytical expressions for the reflection, transmission and absorption coefficients and a correction factor is suggested to improve the accuracy of the numerical implementation. Results are presented for single and multimode systems.

Computer Simulation↗

The directional tuning of the barber-pole illusion.

In order to study the integration of local motion signals in the human visual system, we measured directional tuning curves for the barber-pole illusion by varying two crucial aspects of the stimulus layout independently across a wide a range in the same experiment. These were the orientation of the grating presented behind the rectangular aperture and the aspect ratio of the aperture, which in combination determine the relative contributions of local motion signals perpendicular to the gratings and parallel to the aperture borders, respectively. The strength of the illusion, ie the tendency to perceive motion along the major axis of the aperture, obviously depends on the spatial layout of the aperture, but also on grating orientation. Subjects were asked which direction they perceived and how compelling their motion percept was, revealing different strategies of the visual system to deal with the barber-pole stimulus. Some individuals respond strongly to the unambiguous motion information at the boundaries, leading to multistable percepts and multimodal distributions of responses. Others tend to report intermediate directions, apparently being less influenced by the actual boundaries. The general pattern of deviations from the motion direction perpendicular to grating orientation--a decrease with aspect ratio approaching unity (ie square-shaped apertures) and with gratings approaching parallel orientation to the shorter aperture boundary--is discussed in the context of simple phenomenological models of motion integration. The best fit between model predictions and experimental data is found for an interaction between two stimulus parameters: (i) cycle ratio, which is the sine-wave gratings equivalent of the terminator ratio for line gratings, describing the effects from the aperture boundaries, and (ii) the grating orientation, responsible for perpendicular motion components, which describes the influence of motion signals from inside the aperture. This suggests that the most simple cycle (terminator) ratio explanation cannot fully account for the quantitative properties of the barber-pole illusion.

Adult↗

An integrated fluorescence detection system in poly(dimethylsiloxane) for microfluidic applications.

This paper describes a prototype of an integrated fluorescence detection system that uses a microavalanche photodiode (microAPD) as the photodetector for microfluidic devices fabricated in poly(dimethylsiloxane) (PDMS). The prototype device consisted of a reusable detection system and a disposable microfluidic system that was fabricated using rapid prototyping. The first step of the procedure was the fabrication of microfluidic channels in PDMS and the encapsulation of a multimode optical fiber (100-microm core diameter) in the PDMS; the tip of the fiber was placed next to the side wall of one of the channels. The optical fiber was used to couple light into the microchannel for the excitation of fluorescent analytes. The photodetector, a prototype solid-state microAPD array, was embedded in a thick slab (1 cm) of PDMS. A thin (80 microm) colored polycarbonate filter was placed on the top of the embedded microAPD to absorb scattered excitation light before it reached the detector. The microAPD was placed below the microchannel and orthogonal to the axis of the optical fiber. The close proximity (approximately 200 microm) of the microAPD to the microchannel made it unnecessary to incorporate transfer optics; the pixel size of the microAPD (30 microm) matched the dimensions of the channels (50 microm). A blue light-emitting diode was used for fluorescence excitation. The microAPD was operated in Geiger mode to detect the fluorescence. The detection limit of the prototype (approximately 25 nM) was determined by finding the minimum detectable concentration of a solution of fluorescein. The device was used to detect the separation of a mixture of proteins and small molecules by capillary electrophoresis; the separation illustrated the suitability of this integrated fluorescence detection system for bioanalytical applications.

Carbonic Anhydrases↗

[Salvage of exposed alloplastic materials in irradiated wounds - a case report].

BACKGROUND: Modern multimodal concepts of complex reconstructions and advanced wound management enlarge strategies for surgical oncological therapies. One of the mainstays of classical surgical therapy in case of exposed alloplastic materials in irradiated wounds was to remove the foreign body due to the risk of infection. This loss of integrity and function of the contaminated host bed was to allow wound healing and closure. METHOD: We report the management of a 56-year-old female patient who developed a lyomyosarcoma at her left shoulder girdle 8 years after radiation of the left thorax because of breast cancer. After radical tumor resection and exarticulation of her left arm in the shoulder joint a necrosis of the soft tissue envelope developed, leading to an exposed alloplastic mesh. Staged debridement and continuous application of negative pressure was performed three times. Ultimate plastic coverage was performed by means of a pectoralis myocutaneous island flap from the other breast. RESULTS: After staged debridement and repeated vacuum application excellent wound cleaning, neovascularisation, wound contraction and formation of granulation tissue within the previously irradiated tissue zone was observed. Until fourteen months postoperative wound coverage remained stable and no signs of infection were observed. DISCUSSION: By means of negative pressure therapy even in radiated wounds excellent wound cleaning and sufficient formation of granulation tissue can be achieved. In some cases negative pressure therapy together with staged debridement allows reintegration of exposed and therefore potentially contaminated alloplastic meshes into new formed granulation tissue in radiated wounds respectively radiation ulcers. Thus leading to the possibility of ultimate plastic coverage.

Breast Neoplasms↗

Integrated pharmacologic treatment of attention-deficit hyperactivity disorder (ADHD).

This article is a review of what is currently known about optimal treatments for patients with attention-deficit hyperactivity disorder (ADHD). It begins with a description of assessment techniques and the differential diagnosis, which includes learning disorders, anxiety disorders, and bipolar disorder. The high rate of comorbidity in patients with ADHD and the impact of comorbidity on treatment decisions are also discussed. Detailed descriptions of various pharmacologic treatments are provided, including a description of the role of combination pharmacotherapy and the integration of nonpharmacologic therapy. A decision-making model for selecting the most appropriate pharmacologic therapy versus combining pharmacotherapy with psychosocial interventions is described. The advantages and disadvantages of various pharmacologic agents--including long-acting stimulants and atomoxetine--are examined. Particular attention is paid to the recent Multimodal Treatment Study of Attention-Deficit Hyperactivity Disorder, sponsored by the National Institute of Mental Health, which includes a comparison of long-term pharmacotherapy, behavioral therapy, or a combination thereof, as well as an evaluation of the role of community-based therapy (i.e., treatment as usual). This article focuses on children and adolescents, because most of the research on ADHD has been conducted in this age group. However, a brief section on adults is also provided.

Adrenergic alpha-Agonists↗

Next-Generation Disease Profiling by Integrating Histopathology with Spatial Multi-Omics Data.

The field of pathology has experienced several transformative changes in recent years with the advent of digital pathology and spatial multi-omics. These technologies have enhanced every aspect of pathology practice, from streamlining daily workflows to generating high-fidelity multi-omics data that provide pathologists with novel tools to refine disease profiling and clinical diagnosis. Each layer of multimodal data (genomic, metabolomic, proteomic, or transcriptomic) has uncovered a distinct facet of disease pathologies, and combined with machine learning/artificial intelligence-based data analysis and pattern recognition models, has provided holistic understanding of regulatory mechanisms underpinning them. However, high-dimensional data have far exceeded the volume, scale, and complexity of immunostaining methods implemented by pathologists and, thus, have generated significant challenges related to deconvolution, interpretation, and clinical translation. Furthermore, these multimodal studies have predominantly relied on computational methods to process data and extract disease-relevant insights, thus raising questions around relevance or role of a pathologist in this new era of multi-omics. This review will provide a perspective on the evolving fields of molecular histopathology and spatial -omics, leveraging them to approach disease profiling, and redefining the role of a pathologist during this process.

Humans↗

Multimodal information processing in neurons.

Advances in neuroscience research have led to substantial expansion and even revision of many concepts of neuronal structure and function. The essence of this progress is contained in the knowledge that there are multiple modes of information processing in neurons and even subneuronal elements such as the dendrite. The challenge and opportunity of the new findings lies in understanding how the various modes are integrated in complex brain function. Progress in this area should offer new insights into the pathophysiology of neurological disease.

Action Potentials↗

Presurgical evaluation of the liver transplant candidate.

Determination of liver transplant candidacy requires an integrated approach contingent upon clinical, surgical, and radiologic evaluation. Imaging patients with end-stage liver disease is a challenging yet fascinating task. Chest radiographs, ultrasound with Doppler, and unenhanced and biphasic contrast CT provide sufficient preoperative information about the majority of patients. Problematic cases, however, may require a multimodality approach, for which chest CT, invasive abdominal CT techniques, MR imaging, cholangiography, angiography, and biopsy have all been useful adjuncts. In addition to providing important information for surgical planning, the radiologist must carefully look for any evidence of malignancy or other conditions that jeopardize successful OLTX and threaten meaningful postoperative survival.

Humans↗

Postoperative analgesia in infants and children.

PURPOSE OF REVIEW: Although postoperative analgesia in infants and children should be an integral part of the perioperative management, undertreatment of pain is not rare in clinical practice and may influence outcome and long term behaviour. Therefore, this review summarizes results of recent papers and discusses actual trends and future perspectives concerning postoperative pharmacologic pain therapy in infants and children. RECENT FINDINGS: A multimodal approach using locoregional anesthesia and systemic analgesics is a widely accepted technique. New developments include new local anesthetics with a wider margin of safety and more experience with adjuvants, catheter techniques and systemic analgesics. Replacement of bupivacaine with ropivacaine may be prudent especially for prolonged epidural infusion, use in neonates, impaired hepatic metabolic function, and anesthetic techniques requiring large dosage of local anesthetic. The limited duration of analgesia after single blocks can be prolonged by use of adjuvants (clonidine, ketamine), catheter techniques or early use of systemic analgesics. Non-opioids (acetaminophen, non-steroidal anti-inflammatory drugs) are appropriate for patients with mild to moderate pain or as a component of multimodal pain therapy. Patient- and nurse-controlled analgesia are convenient ways for opioid administration in infants and children. SUMMARY: The reviewed studies suggest that there are many reliable agents and techniques available to provide a safe and effective postoperative analgesia even in neonates and small infants.

Journal Article↗

Multimodal intervention raises smoking cessation rate during pregnancy.

BACKGROUND: The aim was to study the effect of a multimodal smoking cessation intervention regimen on a number of pregnant smokers. METHODS: A prospective intervention study was designed where participants were allocated to intervention or control based on their birth date. The study included 647 pregnant smokers. The intervention group (n = 327) received initial individual smoking cessation counseling supplemented by an invitation to join, individually or in a group, a smoking cessation program with nicotine replacement therapy as a voluntary option. Intervention was designed as an integral part of the midwives' prenatal care. All pregnant smokers in the usual care group (n = 320) received standard counseling from a midwife. Outcome was self-reported smoking cessation in the 37th week of pregnancy and the reported cessation was validated by cotinine saliva concentration. RESULTS: Self-reported cessation rates during pregnancy were significantly higher in the intervention group (14%) than in the group receiving usual care (5.0%) (p < 0.0001) (Fisher's exact test). Cotinine-validated cessation rates during pregnancy were significantly higher among the former (7%) than the latter (2%) (p = 0.003). The adjusted odds ratio (OR) for smoking cessation was 4.20 (95% CI 2.13-8.03). Logistic regression analysis showed a significant positive association of smoking cessation with low caffeine consumption in pregnancy, many years in school, no exposure to passive smoking outside the home, and previous attempts to stop smoking. CONCLUSIONS: A multimodal intervention regimen with initial individual counseling supplemented by an invitation to join a smoking cessation program with nicotine replacement therapy as a voluntary option markedly increased cessation rates during pregnancy.

Adult↗