Pediatricians' Reports of Interaction with Infant Formula Companies.

Introduction: Seventy percent of countries follow the World Health Organization International Code of Marketing Breast Milk Substitutes that prohibits infant formula companies (IFC) from providing free products to health care facilities, providing gifts to health care staff, or sponsoring meetings. The United States rejects this code, which may impact breastfeeding rates in certain areas. Objective: We aimed at gathering exploratory data about interactions between IFC and pediatricians. Methods: We distributed an electronic survey to U.S. pediatricians asking about practice demographics, interactions with IFC, and breastfeeding practices. Using the zip code of the practice, we obtained additional information from the 2018 American Communities Survey, including median income, percent of mothers who had graduated college, percent of mothers working, and racial and ethnic identity. We compared demographic data for those pediatricians who had a formula company representative visit versus not and those who had a sponsored meal versus not. Results: Of 200 participants, the majority reported a formula company representative visit to their clinic (85.5%) and receiving free formula samples (90%). Representatives were more likely to visit areas with higher-income patients (median = $100K versus $60K, p < 0.001). They tended to visit and sponsor meals for pediatricians at private practices and in suburban areas. Most of the reported conferences attended (64%) were formula company-sponsored. Conclusion: Interactions between IFC and pediatricians are prevalent and occur in many forms. Future studies may reveal whether these interactions influence the advice of pediatricians or the behavior of mothers who had planned to exclusively breastfeed.

D-bifunctional protein deficiency caused by splicing variants in a neonate with severe peroxisomal dysfunction and persistent hypoglycemia.

D-bifunctional protein (DBP) deficiency is a rare, autosomal recessive peroxisomal enzyme deficiency resulting in a high burden of morbidity and early mortality. Patients with DBP deficiency resemble those with a severe Zellweger phenotype, with neonatal hypotonia, seizures, craniofacial dysmorphisms, psychomotor delay, deafness, blindness, and death typically within the first 2 years of life, although patients with residual enzyme function can survive longer. The clinical severity of the disease depends on the degree of enzyme deficiency. Loss-of-function variants typically result in no residual enzyme activity; however, splice variants may result in protein with residual function. We describe a full-term newborn presenting with hypotonia, seizures, and unexplained hypoglycemia, who was later found to have rickets at follow up. Rapid whole genome sequencing identified two HSD17B4 variants in trans; one likely pathogenic variant and one variant of uncertain significance (VUS) located in the polypyrimidine tract of intron 13. To determine the functional consequence of the VUS, we analyzed RNA from the patient's father with RNA-seq which showed skipping of Exon 14, resulting in a frameshift mutation three amino acids from the new reading frame. This RNA-seq analysis was correlated with virtually absent enzyme activity, elevated very-long-chain fatty acids in fibroblasts, and a clinically severe phenotype. Both variants are reclassified as pathogenic. Due to the clinical spectrum of DBP deficiency, this provides important prognostic information, including early mortality. Furthermore, we add persistent hypoglycemia to the clinical spectrum of the disease, and advocate for the early management of fat-soluble vitamin deficiencies to reduce complications.

Ethical considerations in the use of artificial womb/placenta technology.

Despite improvements in survival over the past few decades, pulmonary immaturity and the use of mechanical ventilation have stunted reduction in short- and long-term morbidities for infants at the borderline of viability (22-24 weeks of gestation). It has long been suspected that the use of an artificial womb or artificial placenta to preserve native fetal physiology and maintain fluid- rather than air-filled lungs would help to improve outcomes for these infants. As such, several institutions have ongoing efforts to develop this technology, bringing the field of neonatology within sight of clinical trials. Prior to use in humans, several important ethical issues should be considered and discussed, including the moral status of these patients and the term used to describe them, whether neonate, fetus, or another term entirely. These determinations will guide when it is appropriate to use the technology and when it is permissible to withdraw this support, as well as how to ascribe parental rights and the legal status of these patients.

Safety and Effectiveness of Weekly Carfilzomib, Lenalidomide, Dexamethasone, and Daratumumab Combination Therapy for Patients With Newly Diagnosed Multiple Myeloma: The MANHATTAN Nonrandomized Clinical Trial.

IMPORTANCE: Recently, the benefit of adding daratumumab to the proteasome inhibitor-based, 3-drug combination of bortezomib, lenalidomide, and dexamethasone for patients with newly diagnosed multiple myeloma who underwent high-dose melphalan chemotherapy and autologous hemopoietic cell transplant was assessed. Here, we examine the addition of daratumumab to the second-generation proteasome inhibitor-based, 3-drug combination of carfilzomib, lenalidomide, and dexamethasone. OBJECTIVE: To assess the safety and effectiveness of carfilzomib-lenalidomide-dexamethasone-daratumumab combination therapy for patients with newly diagnosed multiple myeloma, in the absence of high-dose melphalan chemotherapy and autologous hemopoietic cell transplant. DESIGN, SETTING, AND PARTICIPANTS: Clinical and correlative pilot study at the Memorial Sloan Kettering Cancer Center in New York, New York. Patients with newly diagnosed multiple myeloma were enrolled between October 1, 2018, and November 15, 2019. The median follow-up from start of treatment was 20.3 months (95% CI, 19.2-21.9 months). INTERVENTIONS: Eight 28-day cycles with intravenous carfilzomib, 20/56 mg/m2 (days 1, 8, and 15); oral lenalidomide, 25 mg, (days 1-21); dexamethasone, 40 mg weekly, orally or intravenously (cycles 1-4), and 20 mg after cycle 4; and intravenous daratumumab, 16 mg/kg (days 1, 8, 15, and 22 [cycles 1-2]; days 1 and 15 [cycles 3-6]; and day 1 [cycles 7 and 8]). MAIN OUTCOMES AND MEASURES: The primary end point was the minimal residual disease (MRD) rate, in the absence of high-dose melphalan chemotherapy and autologous hemopoietic cell transplant. Secondary end points included determining safety and tolerability, evaluating rates of clinical response per the International Myeloma Working Group, and estimating progression-free survival (PFS) and overall survival (OS) rates. RESULTS: Forty-one evaluable patients were enrolled (median age, 59 years; range, 30-70 years); 25 (61%) were female, and 20 (49%) had high-risk multiple myeloma. The primary end point (MRD negativity in the bone marrow; 10-5 sensitivity) was achieved in 29 of 41 patients (71%; 95% CI, 54%-83%), and therefore the trial was deemed successful. Median time to MRD negativity was 6 cycles (range, 1-8 cycles). Secondary end points of the overall response rate and the very good partial response or complete response rate were 100% (41 of 41 patients) and 95% (39 of 41 patients), respectively. At 11 months of the median follow-up, the 1-year PFS rate and the OS rate were 98% (95% CI, 93%-100%) and 100%, respectively. Most common (≥2 patients) grade 3 or 4 adverse events were neutropenia (12 patients [27%]), rash (4 patients [9%]), lung infection (3 patients [7%]), and increased alanine aminotransferase level (2 patients [4%]). There were no deaths. CONCLUSIONS AND RELEVANCE: In this nonrandomized clinical trial, carfilzomib-lenalidomide-dexamethasone-daratumumab combination therapy was associated with high rates of MRD negativity in patients with newly diagnosed multiple myeloma and high rates of PFS.

Using MALDI-TOF mass spectrometry in peripheral blood for the follow up of newly diagnosed multiple myeloma patients treated with daratumumab-based combination therapy.

BACKGROUND: Daratumumab-based combination therapies have shown high rates of complete response (CR) and minimal residual disease negativity in patients with multiple myeloma. However, daratumumab, an IgGκ monoclonal antibody, interferes with electrophoretic techniques making it difficult to reliably define residual disease versus CR, especially in patients with IgGκ multiple myeloma. METHODS: Enrichment with polyclonal sheep antibody-coated magnetic microparticles combined with MALDI-TOF mass spectrometry (MALDI-TOF MS) analysis was used to detect M-proteins in serial samples from newly diagnosed multiple myeloma patients treated with daratumumab-based therapy. The performance of the MALDI-TOF MS assay was compared to that of a routine test panel (serum protein electrophoresis (SPEP), immunofixation (IFE) and serum free light chain (FLC)). RESULTS: Comparison of MALDI-TOF MS to SPEP/IFE/FLC showed a concordance of 84.9% (p < 0.001). When MALDI-TOF MS and FLC results were combined, the M-protein detection rate was the same or better than the routine test panel. For the 9 patients who obtained CR during follow-up, MALDI-TOF MS detected an M-protein in 46% of subsequent samples. Daratumumab could be distinguished from the M-protein in 215/222 samples. CONCLUSION: MALDI-TOF MS is useful in assessing CR in patients treated with monoclonal antibody-based therapies.

Conflicts of interest policies for authors, peer reviewers, and editors of bioethics journals.

BACKGROUND: In biomedical research, there have been numerous scandals highlighting conflicts of interest (COIs) leading to significant bias in judgment and questionable practices. Academic institutions, journals, and funding agencies have developed and enforced policies to mitigate issues related to COI, especially surrounding financial interests. After a case of editorial COI in a prominent bioethics journal, there is concern that the same level of oversight regarding COIs in the biomedical sciences may not apply to the field of bioethics. In this study, we examined the availability and comprehensiveness of COI policies for authors, peer reviewers, and editors of bioethics journals. METHODS: After developing a codebook, we analyzed the content of online COI policies of 63 bioethics journals, along with policy information provided by journal editors that was not publicly available. RESULTS: Just over half of the bioethics journals had COI policies for authors (57%), and only 25% for peer reviewers and 19% for editors. There was significant variation among policies regarding definitions, the types of COIs described, the management mechanisms, and the consequences for noncompliance. Definitions and descriptions centered on financial COIs, followed by personal and professional relationships. Almost all COI policies required disclosure of interests for authors as the primary management mechanism. Very few journals outlined consequences for noncompliance with COI policies or provided additional resources. CONCLUSION: Compared to other studies of biomedical journals, a much lower percentage of bioethics journals have COI policies and these vary substantially in content. The bioethics publishing community needs to develop robust policies for authors, peer reviewers, and editors and these should be made publicly available to enhance academic and public trust in bioethics scholarship.

Mitochondrial Protein Interaction Mapping Identifies Regulators of Respiratory Chain Function.

Mitochondria are essential for numerous cellular processes, yet hundreds of their proteins lack robust functional annotation. To reveal functions for these proteins (termed MXPs), we assessed condition-specific protein-protein interactions for 50 select MXPs using affinity enrichment mass spectrometry. Our data connect MXPs to diverse mitochondrial processes, including multiple aspects of respiratory chain function. Building upon these observations, we validated C17orf89 as a complex I (CI) assembly factor. Disruption of C17orf89 markedly reduced CI activity, and its depletion is found in an unresolved case of CI deficiency. We likewise discovered that LYRM5 interacts with and deflavinates the electron-transferring flavoprotein that shuttles electrons to coenzyme Q (CoQ). Finally, we identified a dynamic human CoQ biosynthetic complex involving multiple MXPs whose topology we map using purified components. Collectively, our data lend mechanistic insight into respiratory chain-related activities and prioritize hundreds of additional interactions for further exploration of mitochondrial protein function.

Cognitive reappraisal self-efficacy mediates the effects of individual cognitive-behavioral therapy for social anxiety disorder.

OBJECTIVE: To examine whether changes in cognitive reappraisal self-efficacy (CR-SE) mediate the effects of individually administered cognitive-behavioral therapy (I-CBT) for social anxiety disorder (SAD) on severity of social anxiety symptoms. METHOD: A randomized controlled trial in which 75 adult patients (21-55 years of age; 53% male; 57% Caucasian) with a principal diagnosis of generalized SAD were randomly assigned to 16 sessions of I-CBT (n = 38) or a wait-list control (WL) group (n = 37). All patients completed self-report inventories measuring CR-SE and social anxiety symptoms at baseline and post-I-CBT/post-WL, and I-CBT completers were also assessed at 1-year posttreatment. RESULTS: Compared with WL, I-CBT resulted in greater increases in CR-SE and greater decreases in social anxiety. Increases in CR-SE during I-CBT mediated the effect of I-CBT on social anxiety. Gains achieved by patients receiving I-CBT were maintained 1-year posttreatment, and I-CBT-related increases in CR-SE were also associated with reduction in social anxiety at the 1-year follow-up. CONCLUSIONS: Increasing CR-SE may be an important mechanism by which I-CBT for SAD produces both immediate and long-term reductions in social anxiety.

A randomized trial of MBSR versus aerobic exercise for social anxiety disorder.

OBJECTIVE: Effective treatments for social anxiety disorder (SAD) exist, but additional treatment options are needed for nonresponders as well as those who are either unable or unwilling to engage in traditional treatments. Mindfulness-based stress reduction (MBSR) is one nontraditional treatment that has demonstrated efficacy in treating other mood and anxiety disorders, and preliminary data suggest its efficacy in SAD as well. METHOD: Fifty-six adults (52% female; 41% Caucasian; age mean [M] ± standard deviation [SD]: 32.8 ± 8.4) with SAD were randomized to MBSR or an active comparison condition, aerobic exercise (AE). At baseline and post-intervention, participants completed measures of clinical symptoms (Liebowitz Social Anxiety Scale, Social Interaction Anxiety Scale, Beck Depression Inventory-II, and Perceived Stress Scale) and subjective well-being (Rosenberg Self-Esteem Scale, Satisfaction with Life Scale, Self-Compassion Scale, and UCLA-8 Loneliness Scale). At 3 months post-intervention, a subset of these measures was readministered. For clinical significance analyses, 48 healthy adults (52.1% female; 56.3% Caucasian; age [M ± SD]: 33.9 ± 9.8) were recruited. MBSR and AE participants were also compared with a separate untreated group of 29 adults (44.8% female; 48.3% Caucasian; age [M ± SD]: 32.3 ± 9.4) with generalized SAD who completed assessments over a comparable time period with no intervening treatment. RESULTS: A 2 (Group) x 2 (Time) repeated measures analyses of variance (ANOVAs) on measures of clinical symptoms and well-being were conducted to examine pre-intervention to post-intervention and pre-intervention to 3-month follow-up. Both MBSR and AE were associated with reductions in social anxiety and depression and increases in subjective well-being, both immediately post-intervention and at 3 months post-intervention. When participants in the randomized controlled trial were compared with the untreated SAD group, participants in both interventions exhibited improvements on measures of clinical symptoms and well-being. CONCLUSION: Nontraditional interventions such as MBSR and AE merit further exploration as alternative or complementary treatments for SAD.

The role of maladaptive beliefs in cognitive-behavioral therapy: Evidence from social anxiety disorder.

Beliefs that are negatively biased, inaccurate, and rigid are thought to play a key role in the mood and anxiety disorders. Our goal in this study was to examine whether a change in maladaptive beliefs mediated the outcome of individual cognitive-behavioral therapy (CBT) for social anxiety disorder (SAD). In a sample of 47 individuals with SAD receiving CBT, we measured maladaptive interpersonal beliefs as well as emotional and behavioral components of social anxiety, both at baseline and after treatment completion. We found that (a) maladaptive interpersonal beliefs were associated with social anxiety at baseline and treatment completion; (b) maladaptive interpersonal beliefs were significantly reduced from baseline to treatment completion; and (c) treatment-related reductions in maladaptive interpersonal beliefs fully accounted for reductions in social anxiety after CBT. These results extend the literature by providing support for cognitive models of mental disorders, broadly, and SAD, specifically.

Self-compassion and social anxiety disorder.

Self-compassion refers to having an accepting and caring orientation towards oneself. Although self-compassion has been studied primarily in healthy populations, one particularly compelling clinical context in which to examine self-compassion is social anxiety disorder (SAD). SAD is characterized by high levels of negative self-criticism as well as an abiding concern about others' evaluation of one's performance. In the present study, we tested the hypotheses that: (1) people with SAD would demonstrate less self-compassion than healthy controls (HCs), (2) self-compassion would relate to severity of social anxiety and fear of evaluation among people with SAD, and (3) age would be negatively correlated with self-compassion for people with SAD, but not for HC. As expected, people with SAD reported less self-compassion than HCs on the Self-Compassion Scale and its subscales. Within the SAD group, lesser self-compassion was not generally associated with severity of social anxiety, but it was associated with greater fear of both negative and positive evaluation. Age was negatively correlated with self-compassion for people with SAD, whereas age was positively correlated with self-compassion for HC. These findings suggest that self-compassion may be a particularly important target for assessment and treatment in persons with SAD.

Childhood trauma and current psychological functioning in adults with social anxiety disorder.

Etiological models of social anxiety disorder (SAD) suggest that early childhood trauma contributes to the development of this disorder. However, surprisingly little is known about the link between different forms of childhood trauma and adult clinical symptoms in SAD. This study (1) compared levels of childhood trauma in adults with generalized SAD versus healthy controls (HCs), and (2) examined the relationship between specific types of childhood trauma and adult clinical symptoms in SAD. Participants were 102 individuals with generalized SAD and 30 HCs who completed measures of childhood trauma, social anxiety, trait anxiety, depression, and self-esteem. Compared to HCs, individuals with SAD reported greater childhood emotional abuse and emotional neglect. Within the SAD group, childhood emotional abuse and neglect, but not sexual abuse, physical abuse, or physical neglect, were associated with the severity of social anxiety, trait anxiety, depression, and self-esteem.

Neural mechanisms of cognitive reappraisal of negative self-beliefs in social anxiety disorder.

BACKGROUND: Social anxiety disorder (SAD) is characterized by distorted negative self-beliefs (NSBs), which are thought to enhance emotional reactivity, interfere with emotion regulation, and undermine social functioning. Cognitive reappraisal is a type of emotion regulation used to alter NSBs, with the goal of modulating emotional reactivity. Despite its relevance, little is known about the neural bases and temporal features of cognitive reappraisal in patients with SAD. METHODS: Twenty-seven patients with SAD and 27 healthy control subjects (HCs) were trained to react and to implement cognitive reappraisal to downregulate negative emotional reactivity to NSBs, while undergoing functional magnetic resonance imaging and providing ratings of negative emotion experience. RESULTS: Behaviorally, compared with HCs, patients with SAD reported greater negative emotion both while reacting to and reappraising NSBs. However, when cued, participants in both groups were able to use cognitive reappraisal to decrease negative emotion. Neurally, reacting to NSBs resulted in early amygdala response in both groups. Reappraising NSBs resulted in greater early cognitive control, language, and visual processing in HCs but greater late cognitive control, visceral, and visual processing in patients with SAD. Functional connectivity analysis during reappraisal identified more regulatory regions inversely related to left amygdala in HCs than in patients with SAD. Reappraisal-related brain regions that differentiated patients and control subjects were associated with negative emotion ratings and cognitive reappraisal self-efficacy. CONCLUSIONS: Findings regarding cognitive reappraisal suggest neural timing, connectivity, and brain-behavioral associations specific to patients with SAD and elucidate neural mechanisms that might serve as biomarkers of interventions for SAD.

A case study of an emerging visual artist with frontotemporal lobar degeneration and amyotrophic lateral sclerosis.

Patients presenting with left-sided FTLD syndromes sometimes develop a new preoccupation with art, greater attention to visual stimuli, and increased visual creativity. We describe the case of a 53-year-old, right-handed man with a history of bipolar disorder who presented with language and behavior impairments characteristic of FTLD, then developed motor symptoms consistent with a second diagnosis of amyotrophic lateral sclerosis. Though the patient had never created visual art before, he developed a compulsion for painting beginning at the earliest stages of his disease, and continued producing art daily until he could no longer lift a paintbrush because of his motor deficits. Upon autopsy, he was found to have ubiquitin and TDP43-positive inclusions with MND pathology. This case study details the patient's longitudinal neuropsychological, emotional, behavioral, and motor symptoms, along with structural imaging, neurologic, and neuropathologic findings. Multiple examples of the patient's art are depicted throughout all stages of his illness, and the possible cognitive, behavioral, and neurologic correlates of his new-onset visual artistry are discussed.