Concomitant bedaquiline and delamanid therapy in patients with drug-resistant extra-pulmonary tuberculosis in Mumbai, India.

Background: World Health Organization suggests concurrent bedaquiline-delamanid (BDQ-DLM) as part of individualised regimens for eligible patients with pulmonary drug-resistant tuberculosis (DR-TB); however, data for patients with drug-resistant extrapulmonary tuberculosis (EPTB) is extremely limited. This study documents the treatment outcomes and adverse events associated with concurrent BDQ-DLM-based regimens in patients with drug-resistant EPTB at a Médecins Sans Frontières clinic in Mumbai, India. Methods: Retrospective cohort study based on routinely collected programmatic data. Individualised regimens were based on drug-susceptibility testing and previous drug exposure. Drug-resistant EPTB patients initiated on regimens containing concurrent BDQ and DLM from April 2016 to October 2019 were included. Patients who completed treatment were followed up at 12 months. Results: Of 17 patients, median age was 23 years (IQR = 21-30 years) and 12/17 (71 %) were female. Pre-extensively drug-resistant tuberculosis and extensively drug-resistant TB was reported in 13/17 (76.4 %) and 2/17 (11.7 %) patients respectively. Microbiological reports were unavailable for two patients with central nervous system TB. Lymph node TB was the commonest form of EPTB in 9/17 (53 %) of patients. Median duration of treatment was 18.9 months. At least one grade three or four severe adverse event (SAE) was reported by 13/17 (76.4 %) patients. Thirteen (76.4 %) patients had favourable outcomes. None of the patients relapsed or died in the one-year period of post-treatment follow-up. Conclusion: Concurrent BDQ-DLM-based regimens in drug-resistant EPTB were effective and associated with manageable adverse events.

Hippocampal Involvement in Safety Signal Learning Varies With Anxiety Among Healthy Adults.

Background: Safety signal learning (SSL), based on conditioned inhibition of fear in the presence of learned safety, can effectively attenuate threat responses in animal models and humans. Difficulty regulating threat responses is a core feature of anxiety disorders, suggesting that SSL may provide a novel mechanism for fear reduction. Cross-species evidence suggests that SSL involves functional connectivity between the anterior hippocampus and the dorsal anterior cingulate cortex. However, the neural mechanisms supporting SSL have not been examined in relation to trait anxiety or while controlling for the effect of novelty. Methods: Here, we investigated the neural mechanisms involved in SSL and associations with trait anxiety in a sample of 64 healthy (non-clinically anxious) adults (ages 18-30 years; 43 female, 21 male) using physiological, behavioral, and neuroimaging (functional magnetic resonance imaging) data collected during an SSL task. Results: During SSL, compared with individuals with lower trait anxiety, individuals with higher trait anxiety showed less fear reduction as well as altered hippocampal activation and hippocampal-dorsal anterior cingulate cortex functional connectivity, and lower inferior frontal gyrus and ventrolateral prefrontal cortex activation. Importantly, the findings show that SSL reduces threat responding, across learning and over and above the effect of novelty, and involves hippocampal activation. Conclusions: These findings provide new insights into the nature of SSL and suggest that there may be meaningful variation in SSL and related neural correlates as a function of trait anxiety, with implications for better understanding fear reduction and optimizing interventions for individuals with anxiety disorders.

Responding to threat: Associations between neural reactivity to and behavioral avoidance of threat in pediatric anxiety.

BACKGROUND: Despite broad recognition of the central role of avoidance in anxiety, a lack of specificity in its operationalization has hindered progress in understanding this clinically significant construct. The current study uses a multimodal approach to investigate how specific measures of avoidance relate to neural reactivity to threat in youth with anxiety disorders. METHODS: Children with anxiety disorders (ages 6-12 years; n = 65 for primary analyses) completed laboratory task- and clinician-based measures of avoidance, as well as a functional magnetic resonance imaging task probing neural reactivity to threat. Primary analyses examined the ventral anterior insula (vAI), amygdala, and ventromedial prefrontal cortex (vmPFC). RESULTS: Significant but distinct patterns of association with task- versus clinician-based measures of avoidance emerged. Clinician-rated avoidance was negatively associated with right and left vAI reactivity to threat, whereas laboratory-based avoidance was positively associated with right vAI reactivity to threat. Moreover, left vAI-right amygdala and bilateral vmPFC-right amygdala functional connectivity were negatively associated with clinician-rated avoidance but not laboratory-based avoidance. LIMITATIONS: These results should be considered in the context of the restricted range of our treatment-seeking sample, which limits the ability to draw conclusions about these associations across children with a broader range of symptomatology. In addition, the limited racial and ethnic diversity of our sample may limit the generalizability of findings. CONCLUSION: These findings mark an important step towards bridging neural findings and behavioral patterns using a multimodal approach. Advancing understanding of behavioral avoidance in pediatric anxiety may guide future treatment optimization by identifying individual-specific targets for treatment.

Affective language spreads between anxious children and their mothers during a challenging puzzle task.

Humans influence each other's emotions. The spread of emotion is well documented across behavioral, psychophysiological, and neuroscientific levels of analysis, but might this influence also be evident in language (e.g., are people more likely to use emotion words after hearing someone else use them)? The current study tests whether mothers and children influence each other's use of affective language. From 2018 to 2020, children aged 6-12 who met diagnostic criteria for anxiety disorders and their mothers (N = 93 dyads) completed a challenging puzzle task while being video recorded. Analyses of transcriptions revealed that mothers and children indeed influenced each other's language. Bidirectional influence was observed for use of negative affect words: Mothers were more likely to use negative affect words if their child had just used negative affect words (over and above mothers' own language on their previous turn), and children were similarly influenced by mother affect word use. A similar bidirectional relation emerged for linguistic distance, a measure related to effective emotion regulation and mental health. However, the significance of the child-to-mother direction of influence for these two variables varied depending on correction threshold and should thus be verified in future research. Nonetheless, these findings extend understanding of emotional influence by showing turn-by-turn relations between the use of affective language. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Preliminary data on oxytocin modulation of neural reactivity in women to emotional stimuli of children depending on childhood emotional neglect.

Sensitivity for rewarding cues and distress signals from children is fundamental to human caregiving and modulated by the neuropeptide oxytocin. In a functional magnetic resonance imaging study, we investigated whether oxytocin regulates neural responses to reward or distress cues form children. In a placebo-controlled, within-subject design, we measured neural responses to positive, negative, and neutral cues from children in 22 healthy female subjects who received oxytocin (24 IU) versus placebo. Further, based on current literature, we hypothesized that oxytocin effects are modulated by experiences of childhood trauma. The task elicited valence-specific effects-positive images activated the ventromedial prefrontal cortex, left anterior cingulate cortex, and right putamen, and images of children in distress activated the bilateral amygdala, hippocampus, and right medial superior frontal cortex. The effects of oxytocin depended on subjective reports of childhood emotional neglect. Self-reported neglect interacted with oxytocin administration in the amygdala, hippocampus, and prefrontal areas. In individuals with higher scores of emotional neglect, oxytocin increased neural reactivity of limbic structures to positive and neutral images. Our findings need replication in larger samples and can therefore be considered preliminary but are in line with the recent literature on the modulating effect of childhood adversity on the sensitivity to oxytocin administration.

Oxytocin system gene methylation is associated with empathic responses towards children.

Empathy is an essential component of sensitive caregiving behavior, which in turn is an important predictor of children's healthy social-emotional development. The oxytocin (OXT) system plays a key role in promoting sensitive parenting and empathy. In this study, we investigated how OXT system gene methylation was associated with empathic processes in nulliparous women (M age = 23.60, SD =0.44)-measuring both physiological facial muscle responses and ratings of compassion and positive affect to affective images depicting children. Linear mixed effects analyses demonstrated that lower methylation levels in the OXT and OXTR genes were related to enhanced empathic responses. The effect of OXT system gene methylation on empathic processes was partly qualified by an interaction with individual variations in women's care motivation. Our findings provide experimental evidence for an association between the methylation of OXT system genes and empathy.

Preliminary data on increased reactivity towards children in distress after testosterone administration in women: A matter of protection?

Emotional reactivity to others' distress is a vital prerequisite for a caring response. Testosterone, in contrast, is mostly associated with protection of personal dominance and decreased responsiveness to others' needs. However, experimental work also indicates that rising testosterone levels in response to infant distress can potentially facilitate protection. We assessed the impact of testosterone administration on participants' emotional reactivity to infants in distress, measuring their facial responses on the corrugator supercilii forehead muscle ('frowning') and the zygomaticus major ('smiling') as an index of emotional responses towards children. Moreover, we probed whether the effect of testosterone is moderated by participants' self-reported nurturance and protective tendencies. Our preliminary results showed that testosterone not only increased emotional reactivity to empathy eliciting images of children, but that this increase was strongest in participants with strong protective tendencies. Our administration study is the first to link testosterone to infant protection.

Real-world SARS CoV-2 testing in Northern England during the first wave of the COVID-19 pandemic.

OBJECTIVES: SARS-CoV-2 emerged in South Asia in 2019 and has resulted in a global pandemic. Public Health England (PHE) Manchester rapidly escalated testing for SARS-CoV-2 in the highest COVID-19 incidence location in England. The results of the PHE Manchester SARS-CoV-2 surveillance during the first wave are presented. METHODS: Retrospective data were collected for patients fitting the PHE SARS-CoV-2 case definition from 11th February to 31st August 2020. Respiratory tract, tissue, faecal, fluid and cerebrospinal (CSF) samples were tested for SARS-CoV-2 by a semi-quantitative real-time reverse-transcription PCR. RESULTS: Of the 204,083 tests for SARS-CoV-2, 18,011 were positive demonstrating a positivity of 8.90%. Highest positivity was in nasal swabs (20.99%) followed by broncheo-alveolar lavage samples (12.50%). None of the faecal, fluid or CSF samples received were positive for SARS-CoV-2. CONCLUSIONS: There was a high incidence of SARS-CoV-2 patients in the North-West of England during the first UK wave of the Covid-19 pandemic. Highest positivity rate was in nasal specimens suggesting this is the optimum sample type within this dataset for detecting SARS-CoV-2. Further studies are warranted to assess the utility of testing faecal, fluid and CSF samples. Rapid escalation of testing via multiple platforms was required to ensure prompt diagnosis and isolate infected cases to reduce transmission of the virus.

When mummy and daddy get under your skin: A new look at how parenting affects children's DNA methylation, stress reactivity, and disruptive behavior.

Child maltreatment is a global phenomenon that affects the lives of millions of children. Worldwide, as many as one in three to six children encounter physical, sexual, or emotional abuse from their caregivers. Children who experience abuse often show alterations in stress reactivity. Although this alteration may reflect a physiological survival response, it can nevertheless be harmful in the long run-increasing children's disruptive behavior and jeopardizing their development in multiple domains. But can we undo this process in at-risk children? Based on several lines of pioneering research, we hypothesize that we indeed can. Specifically, we hypothesize that highly dysfunctional parenting leads to an epigenetic pattern in children's glucocorticoid genes that contributes to stress dysregulation and disruptive behavior. However, we also hypothesize that it is possible to "flip the methylation switch" by improving parenting with known-effective parenting interventions in at-risk families. We predict that improved parenting will change methylation in genes in the glucocorticoid pathway, leading to improved stress reactivity and decreased disruptive behavior in children. Future research testing this theory may transform developmental and intervention science, demonstrating how parents can get under their children's skins-and how this mechanism can be reversed.

Methylation of oxytocin related genes and early life trauma together shape the N170 response to human faces.

Childhood trauma fundamentally shapes social cognition and basic processing of social cues, which frequently cascade into adverse behavioral outcomes. Recent studies indicate that epigenetic changes in oxytocin functioning might contribute to these long-term effects, although a deeper understanding of the underlying mechanisms is still lacking. The electroencephalographic N170 response to faces might capture a neural response at the core of these interactive effects of oxytocin gene methylation and childhood adversity, given that this response is considered to reflect fundamental face processing, to be susceptible to oxytocin administration and also to be a biomarker of various psychiatric disorders. We assessed the N170 response to neutral faces in relation to participant's (81, women) recalled childhood trauma, methylation of their oxytocin structural (OXTg) and oxytocin receptor (OXTRg) genes, and endogenous levels of cortisol and testosterone. Additionally, we investigated the interactive effect of OXTg methylation and CTQ across three face sets of varying maturity. Methylation of OXTg relates to a weakened N170 response towards adults, children and infants. Moreover, methylation of both OXTRg and OXTg shaped the directionality of adversity effects, predicting a weakened N170 response in those with high methylation and hyper-vigilance with participants with low methylation. Our results are the first to relate OXT(R)g methylation to the N170 response. They shed light on biological processes linking childhood adversity and epigenetic marks to altered behavior and potentially psychopathologies.

An Overview of the Treatment of Less Common Non-Lactose-Fermenting Gram-Negative Bacteria.

Stenotrophomonas maltophilia, Burkholderia cepacia complex, Elizabethkingia spp., Chryseobacterium spp., Achromobacter spp., and Alcaligenes spp. are less-common non-lactose-fermenting bacteria that have emerged as important opportunistic pathogens. Patients at the highest risk for these infections include the immunocompromised, those with cystic fibrosis, and the critically ill. These opportunistic pathogens are frequently drug resistant through the expression of ß-lactamases, multidrug efflux pumps, aminoglycoside-modifying enzymes, and target site alterations discussed in detail throughout this review. As a result, treatment is extremely challenging. For each pathogen, this review will examine the epidemiology, mechanisms of resistance, and in vitro and in vivo data including that for novel ß-lactam/ß-lactamase inhibitors and cefiderocol. Treatment recommendations are provided based on the available literature.

Fast, Facile and Solvent-Free Dry-Melt Synthesis of Oxovanadium(IV) Complexes: Simple Design with High Potency towards Cancerous Cells.

A range of oxobis(phenyl-1,3-butanedione) vanadium(IV) complexes have been successfully synthesized from cheap starting materials and a simple and solvent-free one-pot dry-melt reaction. This direct, straightforward, fast and alternative approach to inorganic synthesis has the potential for a wide range of applications. Analytical studies confirm their successful synthesis, purity and solid-state coordination, and we report the use of such complexes as potential drug candidates for the treatment of cancer. After a 24 hour incubation of A549 lung carcinoma cells with the compounds, they reveal cytotoxicity values elevenfold greater than cisplatin and remain non-toxic towards normal cell types. Additionally, the complexes are stable over a range of physiological pH values and show the potential for interactions with bovine serum albumin.

Modeling Glycan Processing Reveals Golgi-Enzyme Homeostasis upon Trafficking Defects and Cellular Differentiation.

The decoration of proteins by carbohydrates is essential for eukaryotic life yet heterogeneous due to a lack of biosynthetic templates. This complex carbohydrate mixture-the glycan profile-is generated in the compartmentalized Golgi, in which level and localization of glycosylation enzymes are key determinants. Here, we develop and validate a computational model for glycan biosynthesis to probe how the biosynthetic machinery creates different glycan profiles. We combined stochastic modeling with Bayesian fitting that enables rigorous comparison to experimental data despite starting with uncertain initial parameters. This is an important development in the field of glycan modeling, which revealed biological insights about the glycosylation machinery in altered cellular states. We experimentally validated changes in N-linked glycan-modifying enzymes in cells with perturbed intra-Golgi-enzyme sorting and the predicted glycan-branching activity during osteogenesis. Our model can provide detailed information on altered biosynthetic paths, with potential for advancing treatments for glycosylation-related diseases and glyco-engineering of cells.

Neural processing of gendered information is more robustly associated with mothers' gendered communication with children than mothers' implicit and explicit gender stereotypes.

Processes like gender socialization (the ways in which parents convey information to their children about how girls and boys should behave) often happen unconsciously and might therefore be studied best with neuroscientific measures. We examined whether neural processing of gender-stereotype-congruent and incongruent information is more robustly related to mothers' gendered socialization of their child than mothers' implicit and explicit gender stereotypes. To this end, we examined event-related potentials (ERPs) of mothers (N = 35) completing an implicit gender-stereotype task and mothers' gender stereotypes in relation to observed gendered communication with their child (2-6 years old) in a naturalistic picture-book-reading setting. Increased N2 activity (previously related to attentional processes) to gender stimuli in the implicit gender-stereotype task was associated with mothers' positive evaluation of similar gendered behaviors and activities in the picture book they read with their child. Increased P300 activity (previously related to attention to unexpected events) to incongruent trials in the gender-stereotype task was associated with a more positive evaluation of congruent versus incongruent pictures. Compared to mothers' gender stereotypes, neural processing of gendered information was more robustly related to how mothers talk to their children about boys' and girls' stereotype-congruent and incongruent behavior, and masculine and feminine activities.

Touch-induced pupil size reflects stimulus intensity, not subjective pleasantness.

Interpersonal touch is known to influence human communication and emotion. An important system for interpersonal touch is the C-tactile (CT) system, which is activated by a soft stroke on hairy skin with a velocity of 1-10 cms-1. This system been proposed to play a unique role in hedonic valence and emotion of touch. For other sensory modalities, hedonic processing has been associated with pupil dilation. However, it is unclear whether pupil dilation can be modulated by hedonic touch. The current study investigated in two experiments how pupil size reacts to both affective and non-affective stroking. Pupil-size data were obtained to investigate differences between stroking conditions. In addition, an adjusted version of the Touch Perception Task (TPT) was used to assess subjective touch pleasantness ratings. In Experiment 1, affective (3 cms-1) and non-affective (0.3 and 30 cms-1) stroking was applied to the dorsal side of the right hand. Results revealed that stroking velocity had a significant effect on TPT-item scores, showing higher that affective touch was rated as more pleasant compared to non-affective touch, thereby replicating the previous studies. Results, however, revealed no specific pupil dilation for the 3 cms-1 condition; instead, a logarithmic relation was found between pupil-size dilation and stroking velocity. This relation was confirmed in a second experiment. Furthermore, the palm of the hand was used as a control site for tactile stimulation, for which similar findings were obtained as for the dorsal side of the hand. In addition, skin conductance recordings showed a pattern of response to different stroking velocities similar to pupil dilation. These results suggest that pupil-size dilation does respond to tactile input, but that this response is related to arousal caused by changes in stimulus intensity (e.g., stroking velocity) rather than specific C-tactile stimulation.

Epigenetic variability in the human oxytocin receptor (OXTR) gene: A possible pathway from early life experiences to psychopathologies.

The human oxytocin (OXT) system is implicated in the regulation of complex social behaviors, as well as in psychopathologies characterized by social deficits. Emerging evidence suggests that variation in epigenetic regulation of the oxytocin receptor gene (OXTR) provides the oxytocin system with flexibility in response to environmental events, especially those occurring during early childhood. Changes in DNA methylation patterns of OXTR associated with these events may reflect biological alterations of social sensitivity. This is often related to an increased risk of developing mental disorders later in life. Here, we systematically reviewed all human studies (n = 30) discussing OXTR methylation in relation to socio-behavioral phenotypes. As such, we provide a complete and up-to-date overview of the literature that will aid future research in the interdisciplinary field of epigenetics and socio-behavioral sciences.

Assessment of fever in the returning traveller.

Evaluation of people returning from trips abroad with fever is an important skill for all general physicians given the increasing trend in foreign travel. This evaluation should comprise a detailed travel history, thorough clinical examination, appropriate initial tests and a knowledge of when to ask for further advice. An understanding of the incubation periods of common imported infections and a syndromic approach to patients' symptoms is helpful in order to narrow down the likely diagnosis. The need to implement relevant infection control precautions has been highlighted by the recent Middle East respiratory syndrome coronavirus and Ebola virus disease outbreaks.

Oxytocin reduces neural activation in response to infant faces in nulliparous young women.

Infant faces have distinctive features that together are described as baby schema, a configuration that facilitates caregiving motivation and behavior, and increases the perception of cuteness. In the current functional magnetic resonance imaging (fMRI) study, we investigated the effect of a within-subjects intranasal oxytocin administration (24 IU) and caregiving motivation on neural responses to infant faces of varying baby schema in 23 healthy nulliparous women. Overall, infant faces elicited activation in several brain regions involved in reward and salience processing, including the ventral tegmental area (VTA), putamen, amygdala, anterior cingulate cortex (ACC), and insula, and this activation was related to self-reported caregiving motivation. Critically, whereas we hypothesized enhanced neural caregiving-related responses after oxytocin administration, we observed reduced activation in the VTA, putamen and amygdala after oxytocin compared to placebo. In nulliparous women, oxytocin has been shown to reduce neural responses in the same regions in response to social stimuli using other paradigms. Oxytocin might affect neural activation toward social stimuli depending on elicited arousal and personal characteristics. The current study is the first to demonstrate this effect in response to infant faces and thereby adds to specify the role of oxytocin in human social information processing.

Ethnic effects when facing children: An ERP study.

Abundant research has highlighted a disadvantage experienced by children of ethnic minority groups in, for example, educational and health care settings. In order to understand implicit attitudes that contribute to ethnic disparities, underlying neural correlates have been widely studied. However, this has been limited to the context of adults. Using a sample of nulliparous Caucasian females (N = 46), the current study is the first to examine how early attentional and facial perceptual processing stages, assessed with event-related brain potentials (ERPs), differentiate for stimuli of young ingroup (of the same ethnicity) or outgroup (of a different ethnicity) children. Additionally, we assessed how a differentiation in ERPs may relate to subsequent adult responsiveness to children by measuring both cuteness ratings and motivation to view child faces. Similar to previous findings for adult facial stimuli, we found significant differences in attentional (N200) and facial perceptual (N170) processing when adults were faced with children of different ethnicities. Furthermore, increased differentiation in attentional processing (N200) for ingroup and outgroup children was associated with reduced cuteness ratings of outgroup children. Importantly however, participants showed no overall preference for ingroup child faces, as motivation to view child faces was even greater towards outgroup child faces. In addition, increased self-reported motivation for parental care was related to enhanced cuteness appraisals of outgroup child faces. Taken together, these findings reveal how early social categorization processes may lead to biased behavior when interacting with children of ethnic minorities.

Antibiotic functionalised polymers reduce bacterial biofilm and bioburden in a simulated infection of the cornea.

Microbial keratitis can arise from penetrating injuries to the cornea. Corneal trauma promotes bacterial attachment and biofilm growth, which decrease the effectiveness of antimicrobials against microbial keratitis. Improved therapeutic efficacy can be achieved by reducing microbial burden prior to antimicrobial therapy. This paper assesses a highly-branched poly(N-isopropyl acrylamide) with vancomycin end groups (HB-PNIPAM-van), for reducing bacterial attachment and biofilm formation. The polymer lacked antimicrobial activity against Staphylococcus aureus, but significantly inhibited biofilm formation (p = 0.0008) on plastic. Furthermore, pre-incubation of S. aureus cells with HB-PNIPAM-van reduced cell attachment by 50% and application of HB-PNIPAM-van to infected ex vivo rabbit corneas caused a 1-log reduction in bacterial recovery, compared to controls (p = 0.002). In conclusion, HB-PNIPAM-van may be a useful adjunct to antimicrobial therapy in the treatment of corneal infections.