Rates of convergence for regression with the graph poly-Laplacian.

In the (special) smoothing spline problem one considers a variational problem with a quadratic data fidelity penalty and Laplacian regularization. Higher order regularity can be obtained via replacing the Laplacian regulariser with a poly-Laplacian regulariser. The methodology is readily adapted to graphs and here we consider graph poly-Laplacian regularization in a fully supervised, non-parametric, noise corrupted, regression problem. In particular, given a dataset {xi}i=1n and a set of noisy labels {yi}i=1n⊂R we let un:{xi}i=1n→R be the minimizer of an energy which consists of a data fidelity term and an appropriately scaled graph poly-Laplacian term. When yi=g(xi)+ξi, for iid noise ξi, and using the geometric random graph, we identify (with high probability) the rate of convergence of un to g in the large data limit n→∞. Furthermore, our rate is close to the known rate of convergence in the usual smoothing spline model.

Congenital Vertical Talus: An Updated Review.

Congenital vertical talus (CVT) is the presence of rigid flatfoot deformity characterized by hindfoot valgus and equinus. This foot deformity is associated with midfoot dorsiflexion and forefoot abduction due to a fixed dorsal dislocation of the navicular relative to the head of the talus. It is often underdiagnosed in children due to its similarity to other disorders of the foot. Misdiagnosis of CVT and subsequent failure to address it leads to significant disability and pain. While past surgical management consisted of soft tissue releases that produced varying efficacy, current management of CVT consists of serial casting and minimally invasive procedures that have yielded excellent long-term outcomes. This review provides insight into the diagnosis and treatment of CVT with the intention of highlighting the importance of promptness of intervention to prevent further disability.

Amygdala subdivisions exhibit aberrant whole-brain functional connectivity in relation to stress intolerance and psychotic symptoms in 22q11.2DS.

The amygdala is a key region in emotional regulation, which is often impaired in psychosis. However, it is unclear if amygdala dysfunction directly contributes to psychosis, or whether it contributes to psychosis through symptoms of emotional dysregulation. We studied the functional connectivity of amygdala subdivisions in patients with 22q11.2DS, a known genetic model for psychosis susceptibility. We investigated how dysmaturation of each subdivision's connectivity contributes to positive psychotic symptoms and impaired tolerance to stress in deletion carriers. Longitudinally-repeated MRI scans from 105 patients with 22q11.2DS (64 at high-risk for psychosis and 37 with impaired tolerance to stress) and 120 healthy controls between the ages of 5 to 30 years were included. We calculated seed-based whole-brain functional connectivity for amygdalar subdivisions and employed a longitudinal multivariate approach to evaluate the developmental trajectory of functional connectivity across groups. Patients with 22q11.2DS presented a multivariate pattern of decreased basolateral amygdala (BLA)-frontal connectivity alongside increased BLA-hippocampal connectivity. Moreover, associations between developmental drops in centro-medial amygdala (CMA)-frontal connectivity to both impaired tolerance to stress and positive psychotic symptoms in deletion carriers were detected. Superficial amygdala hyperconnectivity to the striatum was revealed as a specific pattern arising in patients who develop mild to moderate positive psychotic symptoms. Overall, CMA-frontal dysconnectivity was found as a mutual neurobiological substrate in both impaired tolerance to stress and psychosis, suggesting a role in prodromal dysregulation of emotions in psychosis. While BLA dysconnectivity was found to be an early finding in patients with 22q11.2DS, which contributes to impaired tolerance to stress.

Mixed emotions to social situations: An fMRI investigation.

BACKGROUND: Neuroscience research has generally studied emotions each taken in isolation. However, mixed emotional states (e.g., the co-occurrence of amusement and disgust, or sadness and pleasure) are common in everyday life. Psychophysiological and behavioral evidence suggests that mixed emotions may have response profiles that are distinguishable from their constituent emotions. Yet, the brain bases of mixed emotions remain unresolved. METHODS: We recruited 38 healthy adults who viewed short, validated film clips, eliciting either positive (amusing), negative (disgusting), neutral, or mixed (a mix of amusement and disgust) emotional states, while brain activity was assessed by functional magnetic resonance imaging (fMRI). We assessed mixed emotions in two ways: first by comparing neural reactivity to ambiguous (mixed) with that to unambiguous (positive and negative) film clips and second by conducting parametric analyses to measure neural reactivity with respect to individual emotional states. We thus obtained self-reports of amusement and disgust after each clip and computed a minimum feeling score (shared minimum of amusement and disgust) to quantify mixed emotional feelings. RESULTS: Both analyses revealed a network of the posterior cingulate (PCC), medial superior parietal lobe (SPL)/precuneus, and parieto-occipital sulcus to be involved in ambiguous contexts eliciting mixed emotions. CONCLUSION: Our results are the first to shed light on the dedicated neural processes involved in dynamic social ambiguity processing. They suggest both higher-order (SPL) and lower-order (PCC) processes may be needed to process emotionally complex social scenes.

Intraoperative Intra-articular Antibiotic Injection Reduces Infection in Shoulder Arthroplasty.

Deep infection is a debilitating complication after shoulder arthroplasty. The authors hypothesized that an intra-articular, intraoperative injection of antibiotics would result in a lower infection rate compared with intravenous antibiotics alone. Before 2007, 164 patients (group A) did not receive intra-articular antibiotics. From 2007 to 2018, 1324 patients (group B) received intra-articular antibiotics. Patients received intra-articular gentamicin at the end of surgery with the addition of 1 g of cefazolin in January 2014. Records were retrospectively reviewed for comorbidities, type of surgery, and infection. The cohort that received intra-articular antibiotics was compared with the cohort that did not to determine the effect of prophylactic intra-articular antibiotic administration in preventing infection. There was 1 deep infection in the antibiotic group compared with 5 in the non-antibiotic group (P<.001). Superficial infections developed in 2 cases of patients treated with antibiotics; there were no superficial infections in patients treated without antibiotics (P=.62). One previous study evaluated intra-articular injection of antibiotics for shoulder arthroplasty and found significantly lower rates of infection with the injection of intra-articular gentamicin. In this retrospective follow-up study, the injection of intra-articular gentamicin or gentamicin and cefazolin effectively decreased rates of postoperative infection. At mean follow-up of 399 days, intra-articular antibiotics at the time of surgery resulted in significantly fewer deep infections. Given the minimal risk of adverse events and minimal cost, this is a valid method of reducing infections in total shoulder arthroplasty. [Orthopedics. 2023;46(5):310-314.].

Neural Basis of Internal Attention in Adults with Pure and Comorbid ADHD.

OBJECTIVE: To examine whether putatively atypical neuronal activity during internal attention in ADHD yields insights into processes underlying emotion dysregulation. METHODS: We used a word processing paradigm to assess neural activations in adults with ADHD (N = 46) compared to controls (N = 43). We measured effects of valence, applied partial-least squares correlation analysis to assess multivariate brainbehavior relationships and ran subgroup analyses to isolate results driven by pure ADHD (N = 18). RESULTS: During internal attention, ADHD, compared to controls, have (1) increased activation in the right angular gyrus (rAG), which appears driven by pure, not comorbid, ADHD and (2) diminished activation in the insula and fronto-striatal circuitry. Diminished activations were driven by negatively-valenced internal attention and negatively correlated with increased affective lability within the ADHD group. CONCLUSION: Internal attention in ADHD is associated with increased rAG activation, possibly reflecting difficulty converging external and internal information, and diminished activation within emotion regulation circuitry.

Distribution of the reef manta ray Mobula alfredi and the oceanic manta ray Mobula birostris in the Philippines: a collaborative effort for conservation.

Little is known about manta ray population size, structure and connectivity in the Philippines. In collaboration with dive operators, non-governmental organizations and authorities, sightings of manta rays were collated into a single national database. Using in-water photographs and videos gathered through citizen science and dedicated research efforts, this study compiled sightings between 2004 and 2020, showing 22 separate sites throughout the archipelago with manta rays present. A total of 392 individual reef manta rays (Mobula alfredi) and 107 oceanic manta rays (Mobula birostris) were identified from the collected footage. Four specific sites in the provinces of Masbate and Palawan together hosted 89% of all identified individuals and accounted for 95% of sightings, highlighting these areas are key aggregation sites. This study also reports the movements of M. birostris within the Philippines, based on photo-identification of three individuals moving 150 km between Cebu and Masbate. Despite the growing number of recreational divers in Daanbantayan and San Jacinto, an 80% decline in M. birostris sightings was observed at these sites. To ensure effective future conservation, it is recommended that efforts focus on the identification and protection of manta ray hotspots and migratory corridors, the creation of a sustainable tourism framework and, most important, the implementation of mitigation strategies to reduce fisheries interactions.

Realizing the Goals of the Advancing American Kidney Health Initiative: Toward a Better Future for Kidney Disease Research Funding.

The Executive Order on Advancing American Kidney Health aimed to slow the progression of kidney disease, increase access to kidney transplantation, and expand home dialysis. In order to support the kidney health strategy laid out by the Advancing American Kidney Health, the National Institutes of Health, the National Institute of Diabetes, and Digestive, and Kidney Diseases, as well as other funding agencies must dedicate robust research funding to kidney disease. Currently, federal research investment for kidney health is less than 1% of Medicare fee-for-service expenditures for Americans with kidney disease. To address disparities in federal research funding, nephrology organizations are working together to advocate for increased federal commitment to kidney disease research. Underfunding of kidney disease research impedes scientific opportunities and innovation and prevents the collaboration of young investigators with research faculty that can accelerate the exodus of talent within the nephrology research workforce. This review provides an overview of the current state of federal research funding for kidney disease within the United States. In addition, we discuss ongoing advocacy efforts and programs that aim to increase federal funding for kidney-related research and accelerate the development of new and better therapies.

Cytosine base editing enables quadruple-edited allogeneic CART cells for T-ALL.

Allogeneic chimeric antigen receptor T-cell (CART) therapies require multiple gene edits to be clinically tractable. Most allogeneic CARTs have been created using gene editing techniques that induce DNA double-stranded breaks (DSBs), resulting in unintended on-target editing outcomes with potentially unforeseen consequences. Cytosine base editors (CBEs) install C•G to T•A point mutations in T cells, with between 90% and 99% efficiency to silence gene expression without creating DSBs, greatly reducing or eliminating undesired editing outcomes following multiplexed editing as compared with clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9). Using CBE, we developed 7CAR8, a CD7-directed allogeneic CART created using 4 simultaneous base edits. We show that CBE, unlike CRISPR-Cas9, does not impact T-cell proliferation, lead to aberrant DNA damage response pathway activation, or result in karyotypic abnormalities following multiplexed editing. We demonstrate 7CAR8 to be highly efficacious against T-cell acute lymphoblastic leukemia (T-ALL) using multiple in vitro and in vivo models. Thus, CBE is a promising technology for applications requiring multiplexed gene editing and can be used to manufacture quadruple-edited 7CAR8 cells, with high potential for clinical translation for relapsed and refractory T-ALL.

Randomized controlled trial of a mindfulness-based intervention in adolescents from the general population: The Mindfulteen neuroimaging study protocol.

AIM: Adolescence is a period of vulnerability to stress. Increased anxiety during this period has been associated with the later development of mental disorders, hence the growing interest for interventions that could decrease stress reactivity and improve cognitive control in adolescents. Mindfulness-based interventions have demonstrated their efficacy on stress reactivity and anxiety in adults, but evidence is lacking in youth. METHODS: The Mindfulteen Study is a 3-year longitudinal cohort with a nested randomized controlled trial examining the effectiveness of mindfulness-based interventions for adolescents. Young adolescents from the general population, aged between 13 and 15 years old, with no history of current mental health disorder (apart from past mood disorders or current anxiety disorders) are included and stratified into low or high anxiety based on trait anxiety scores before being randomized to early or late 8-week intervention groups. Primary outcomes are based on neuroimaging data (i.e., structural and functional measures in the cortico-limbic network) while secondary outcomes are psychological (i.e., anxiety and stress-associated dimensions) and biological (i.e., cortisol, inflammatory and redox markers). Assessments are performed at baseline, immediately after intervention or waiting time and after 18 months of intervention. CONCLUSION: To the best of our knowledge, this is the first randomized controlled trail examining the effect of a mindfulness-based intervention in young adolescents from the general population based on the measurement and analyses of psychological, neuroimaging and biological data.

Identifying Disease-Specific Neural Reactivity to Psychosocial Stress in Borderline Personality Disorder.

BACKGROUND: Patients with borderline personality disorder (BPD) typically present emotion dysregulation (ED) when faced with adversity. However, it is argued that altered stress response may be more influenced by ED than BPD-specific traits. Here, we investigated this issue with functional magnetic resonance imaging using another ED condition as clinical control, i.e., bipolar disorder (BD), and controlling for ED traits. METHODS: We recruited 17 patients with BD, 24 patients with BPD, and 32 healthy control (HC) subjects. We adapted a functional magnetic resonance imaging-compatible psychosocial stressor task (Montreal Imaging Stress Task) in which participants are placed under time pressure when performing mental calculations and then receive immediate performance feedback (positive, negative, and neutral). ED traits were measured via self-report questionnaires targeting cognitive emotion dysregulation, affective lability, and trait anger and anxiety. RESULTS: Relative to patients with BD and HC subjects, patients with BPD exhibited overactive corticolimbic reactivity across all conditions, particularly in self-monitoring and emotion regulation regions such as the orbitofrontal cortex and anterior insula, even when controlling for ED. Conversely, patients with BD exhibited hypoactive corticolimbic reactivity to all feedback conditions compared with patients with BPD and HC subjects, even after controlling for ED. HC subjects exhibited significantly lower amygdala/hippocampus activity compared with both clinical groups, although this did not survive when controlling for ED. CONCLUSIONS: This study provides new insight into BPD-specific neural stress responding, suggesting hyperactive self- and emotion-regulatory neural psychosocial stress responding, independent of ED traits. The findings also highlight the importance of considering BPD as a diagnostic profile distinguishable from other ED disorder clinical groups.

High Tibial Osteotomy for Varus Deformity of the Knee.

High tibial osteotomy is a powerful technique to treat symptomatic varus deformity of the knee and is successful when properly indicated and performed. Indications include varus deformity with medial compartment osteoarthritis, cartilage or meniscus pathology. Several techniques exist to correct symptomatic varus malalignment along with concomitant procedures to restore cartilage or meniscus injuries. Evidence supporting high tibial osteotomy for symptomatic medial compartment pathology exists, which provides a durable solution for joint preservation. This review will discuss the indications, techniques, and outcomes for high tibial osteotomies used in the treatment of symptomatic varus deformity of the knee.

Kidney-Related Research in the United States: A Position Statement From the National Kidney Foundation and the American Society of Nephrology.

Kidney disease is an important US public health problem because it affects over 37 million Americans, and Medicare expenditures for patients with chronic kidney disease now alone exceed $130 billion annually. Kidney disease is characterized by strong racial, ethnic, and socioeconomic disparities, and reducing kidney disease incidence will positively impact US health disparities. Due to the aging of the US population and an unabated obesity epidemic, the number of patients receiving treatment for kidney failure is anticipated to increase, which will escalate kidney disease health expenditures. The historical and current investment in kidney-related research via the National Institute of Diabetes and Digestive and Kidney Diseases has severely lagged behind ongoing expenditures for kidney disease care. Increasing research investment will identify, develop, and increase implementation of interventions to slow kidney disease progression, reduce incidence of kidney failure, enhance survival, and improve quality of life. This perspective states the urgent reasons why increasing investment in kidney-related research is important for US public health. The National Kidney Foundation and the American Society of Nephrology are working together to advocate for increased funding for the National Institute of Diabetes and Digestive and Kidney Diseases. The long-term goal is to reduce the burden of kidney disease in the US population and improve the quality of life of patients living with kidney disease.

Under Disclosure of Conflicts of Interest Is Less Frequent in Senior Authors: A Cross-sectional Review of All Authors Submitting to JAAOS Between 2014 and 2018.

The interactions between physicians and industry are necessary for advancement of clinical practice and improvement in medical devices. Physician-industry relationships also introduces financial conflicts of interest into research publications. Payments to physicians do not inherently introduce bias in research, but failure to disclose potential conflicts of interest can negatively impact the perceived integrity of authors, editors, and journals. The conflict of interest disclosure statement in all articles published in the Journal of the American Academy of Orthopaedic Surgery between 2014 and 2018 were compared to the financial payments indexed in the Center for Open Payments Database. Payment type, magnitude, and payer were obtained for each payment meeting inclusion criteria. Statistical comparisons were made using Mann-Whitney comparisons due to non-normal distribution of payment amounts. 704 articles involving 2596 authors were reviewed, with 1268 authors meeting inclusion criteria. 634 authors had accurate disclosure statements. The total amount of disclosed payments was $169 million, whereas undisclosed payments were $14.2 million. The amount of disclosed payments on a per-author basis, $55,844 ($12,559, $186,129), was significantly greater than undisclosed payments, $2,171 ($568, $7,238). The lowest rates of correct disclosure were in education (29.2%), gifts (38.7%) and honoraria (57.8%). First and middle authors disclosed correctly at a significantly lower rate than last authors. The magnitude of undisclosed payments was significantly lower than disclosed payments, indicating that these payments do not register with authors as significant enough to disclose.

Maladaptive emotion regulation traits predict altered corticolimbic recovery from psychosocial stress.

BACKGROUND: Adaptive recovery from stress promotes healthy cognitive affective functioning, whereas maladaptive recovery is linked to poor psychological outcomes. Neural regions, like the anterior cingulate and hippocampus, play critical roles in psychosocial stress responding and serve as hubs in the corticolimbic neural system. To date, however, it is unknown how cognitive emotion regulation traits (cER), adaptive and maladaptive, influence corticolimbic stress recovery. Here, we examined acute psychosocial stress neural recovery, accounting for cER. METHODS: Functional neuroimaging data were collected while forty-seven healthy participants performed blocks of challenging, time-sensitive, mental calculations. Participants immediately received performance feedback (positive/negative/neutral) and their ranking, relative to fictitious peers. Participants rested for 90 seconds after each feedback, allowing for a neural stress recovery period. Collected before scanning, cER scores were correlated with neural activity during each recovery condition. RESULTS: Negative feedback recovery yielded increased activity within the dorsomedial prefrontal cortex and amygdala, but this effect was ultimately explained by maladaptive cER (M-cER), like rumination. Isolating positive after-effects (i.e. positive > negative recovery) yielded a significant positive correlation between M-cER and the anterior cingulate, anterior insula, hippocampus, and striatum. CONCLUSIONS: We provide first evidence of M-cER to predict altered neural recovery from positive stress within corticolimbic regions. Positive feedback may be potentially threatening to individuals with poor stress regulation. Identifying positive stress-induced activation patterns in corticolimbic neural networks linked to M-cER creates the possibility to identify these neural responses as risk factors for social-emotional dysregulation subsequent to rewarding social information, often witnessed in affective disorders, like depression.

Temporal dynamics of amygdala response to emotion- and action-relevance.

It has been proposed that the human amygdala may not only encode the emotional value of sensory events, but more generally mediate the appraisal of their relevance for the individual's goals, including relevance for action or task-based needs. However, emotional and non-emotional/action-relevance might drive amygdala activity through distinct neural signals, and the relative timing of both kinds of responses remains undetermined. Here, we recorded intracranial event-related potentials from nine amygdalae of patients undergoing epilepsy surgery, while they performed variants of a Go/NoGo task with faces and abstract shapes, where emotion- and action-relevance were orthogonally manipulated. Our results revealed early amygdala responses to emotion facial expressions starting ~ 130 ms after stimulus-onset. Importantly, the amygdala responded to action-relevance not only with face stimuli but also with abstract shapes (squares), and these relevance effects consistently occurred in later time-windows (starting ~ 220 ms) for both faces and squares. A similar dissociation was observed in gamma activity. Furthermore, whereas emotional responses habituated over time, the action-relevance effect increased during the course of the experiment, suggesting progressive learning based on the task needs. Our results support the hypothesis that the human amygdala mediates a broader relevance appraisal function, with the processing of emotion-relevance preceding temporally that of action-relevance.

Directed evolution of adenine base editors with increased activity and therapeutic application.

The foundational adenine base editors (for example, ABE7.10) enable programmable A•T to G•C point mutations but editing efficiencies can be low at challenging loci in primary human cells. Here we further evolve ABE7.10 using a library of adenosine deaminase variants to create ABE8s. At NGG protospacer adjacent motif (PAM) sites, ABE8s result in ~1.5× higher editing at protospacer positions A5-A7 and ~3.2× higher editing at positions A3-A4 and A8-A10 compared with ABE7.10. Non-NGG PAM variants have a ~4.2-fold overall higher on-target editing efficiency than ABE7.10. In human CD34+ cells, ABE8 can recreate a natural allele at the promoter of the γ-globin genes HBG1 and HBG2 with up to 60% efficiency, causing persistence of fetal hemoglobin. In primary human T cells, ABE8s achieve 98-99% target modification, which is maintained when multiplexed across three loci. Delivered as messenger RNA, ABE8s induce no significant levels of single guide RNA (sgRNA)-independent off-target adenine deamination in genomic DNA and very low levels of adenine deamination in cellular mRNA.

Neutral competition in a deterministically changing environment: Revisiting continuum approaches.

Environmental variation can play an important role in ecological competition by influencing the relative advantage between competing species. Here, we consider such effects by extending a classical, competitive Moran model to incorporate an environment that fluctuates periodically in time. We adapt methods from work on these classical models to investigate the effects of the magnitude and frequency of environmental fluctuations on two important population statistics: the probability of fixation and the mean time to fixation. In particular, we find that for small frequencies, the system behaves similar to a system with a constant fitness difference between the two species, and for large frequencies, the system behaves similar to a neutrally competitive model. Most interestingly, the system exhibits nontrivial behavior for intermediate frequencies. We conclude by showing that our results agree quite well with recent theoretical work on competitive models with a stochastically changing environment, and discuss how the methods we develop ease the mathematical analysis required to study such models.