Search

The effect of experiencing multiple close losses on a variety of psychological symptoms was examined in a sample of HIV positive and HIV negative gay men over 1 year. Symptoms assessed included depression, intrusive and avoidant thoughts and images, anxiety, and general distress. It was found that on average, experiencing two or more losses in the year prior to the initial interview was associated with significantly higher levels of distress in follow-up assessment over 1 year. Comparisons between subjects with two or fewer losses versus three or more losses produced the largest differences in emotional symptoms. HIV positive subjects showed higher levels of distress symptoms on all measures, except for intrusive and avoidant thoughts and images. These findings indicate that the experience of multiple close losses, which is rather common among HIV-infected gay men, chronically exacerbates their emotional distress. [ABSTRACT FROM AUTHOR]

This study, with the objective of examining voluntary self-disclosure of HIV infection after repeated counseling, was conducted in a private setting, and designed to operate in conjunction with HIV testing. Counseling was provided at entry, and then at 3 months, 6 months, and every six months thereafter. The study was conducted among 129 HIV-positive adults; the primary risk factor was history of: males having sex with males (n = 104); injection drug use (n = 19); or heterosexual contact (n = 6). Results showed that after a mean of 2.3 years since initial HIV-positive notification, 29 percent of subjects had not disclosed the HIV infection to any present partner, and 30 percent to any past sex partner. Casual sex and lower perceived social support were significantly associated with nondisclosure. The authors conclude that even after repeated individual counseling and at least several months to inform others, about one-third of the sexually active subjects did not disclose their HIV infection to any present sex partner. Clinical and public health implications are covered. [ABSTRACT FROM AUTHOR]

Recent advances in haptic technology could allow haptic hearing aids, which convert audio to tactile stimulation, to become viable for supporting people with hearing loss. A tactile vocoder strategy for audio-to-tactile conversion, which exploits these advances, has recently shown significant promise. In this strategy, the amplitude envelope is extracted from several audio frequency bands and used to modulate the amplitude of a set of vibro-tactile tones. The vocoder strategy allows good consonant discrimination, but vowel discrimination is poor and the strategy is susceptible to background noise. In the current study, we assessed whether multi-band amplitude envelope expansion can effectively enhance critical vowel features, such as formants, and improve speech extraction from noise. In 32 participants with normal touch perception, tactile-only phoneme discrimination with and without envelope expansion was assessed both in quiet and in background noise. Envelope expansion improved performance in quiet by 10.3% for vowels and by 5.9% for consonants. In noise, envelope expansion improved overall phoneme discrimination by 9.6%, with no difference in benefit between consonants and vowels. The tactile vocoder with envelope expansion can be deployed in real-time on a compact device and could substantially improve clinical outcomes for a new generation of haptic hearing aids., (© 2024. The Author(s).)

Introduction: US child firearm fatality rates have risen since 2013. Child Access Prevention (CAP) laws aimed at reducing minors' access to firearms have existed since the 1980s. However, specific requirements for safe storage of firearms, standards of negligence, and penalties for offenders vary significantly by state, yielding a heterogeneous body of CAP legislation. A few studies have investigated the relative impacts of these laws on child firearm injury rates, with sometimes conflicting results. Here, we present a rapid review of the existing literature on CAP laws and their apparent impact on firearm-related injuries among US children, to assess whether CAP laws are an effective tool for reducing child firearm injuries., Methods: We conducted a rapid review of published reports that evaluated the impact of CAP laws on pediatric firearm injuries and/or deaths in the United States. We extracted target population data and outcomes of each study. The data are presented narratively., Results: A total of 14 articles met criteria for evaluation. Taken together, these studies showed that implementation of CAP legislation was associated with reduced pediatric firearm injuries and fatalities. Moreover, longitudinal or time-series studies that examined changes in pediatric firearm injuries pre/post-CAP legislation yielded the most consistent and robust findings., Conclusion: CAP laws were found to be associated with reduced pediatric firearm injuries and deaths, with the magnitude of effect being proportional to CAP law stringency., Competing Interests: Conflict Disclosure: The authors declare that they have no competing interests regarding this paper., (© 2024 by the Society of Teachers of Family Medicine.)

Background: This scoping review aimed to characterise near-death experiences in the setting of cardiac arrest, a phenomenon that is poorly understood and may have clinical consequences., Method: PubMed/MEDLINE was searched to 23 July 2023 for prospective studies describing near-death experiences in cardiac arrest. PRISMA-ScR guidelines were adhered to. Qualitative and quantitative data were synthesised. Meta-analysis was precluded due to data heterogeneity., Results: 60 records were identified, of which 11 studies involving interviews were included from various countries. Sample size ranged from 28-344, and proportion of female patients (when reported) was 0-50%, with mean age (when reported) ranging 54-64 years. Comorbidities and reasons for cardiac arrest were heterogeneously reported. Incidence of near-death experiences in the included studies varied from 6.3% to 39.3%; with variation between in-hospital (6.3-39.3%) versus out-of-hospital (18.9-21.2%) cardiac arrest. Individual variables regarding patient characteristics demonstrated statistically significant association with propensity for near-death experiences. Reported content of near-death experiences tended to reflect the language of the questionnaires used, rather than the true language used by individual study participants. Three studies conducted follow-up, and all suggested a positive life attitude change, however one found significantly higher 30-day all-cause mortality in patients with near-death experiences versus those without, in non-controlled analysis., Conclusions: From prospective studies that have investigated the phenomenon, near-death experiences may occur in as frequent as over one-third of patients with cardiac arrest. Lasting effects may follow these events, however these could also be confounded by clinical characteristics., (© 2024. The Author(s).)

Many people with hearing loss struggle to understand speech in noisy environments, making noise robustness critical for hearing-assistive devices. Recently developed haptic hearing aids, which convert audio to vibration, can improve speech-in-noise performance for cochlear implant (CI) users and assist those unable to access hearing-assistive devices. They are typically body-worn rather than head-mounted, allowing additional space for batteries and microprocessors, and so can deploy more sophisticated noise-reduction techniques. The current study assessed whether a real-time-feasible dual-path recurrent neural network (DPRNN) can improve tactile speech-in-noise performance. Audio was converted to vibration on the wrist using a vocoder method, either with or without noise reduction. Performance was tested for speech in a multi-talker noise (recorded at a party) with a 2.5-dB signal-to-noise ratio. An objective assessment showed the DPRNN improved the scale-invariant signal-to-distortion ratio by 8.6 dB and substantially outperformed traditional noise-reduction (log-MMSE). A behavioural assessment in 16 participants showed the DPRNN improved tactile-only sentence identification in noise by 8.2%. This suggests that advanced techniques like the DPRNN could substantially improve outcomes with haptic hearing aids. Low-cost haptic devices could soon be an important supplement to hearing-assistive devices such as CIs or offer an alternative for people who cannot access CI technology., (© 2024. The Author(s).)

Haptic hearing aids, which provide speech information through tactile stimulation, could substantially improve outcomes for both cochlear implant users and for those unable to access cochlear implants. Recent advances in wide-band haptic actuator technology have made new audio-to-tactile conversion strategies viable for wearable devices. One such strategy filters the audio into eight frequency bands, which are evenly distributed across the speech frequency range. The amplitude envelopes from the eight bands modulate the amplitudes of eight low-frequency tones, which are delivered through vibration to a single site on the wrist. This tactile vocoder strategy effectively transfers some phonemic information, but vowels and obstruent consonants are poorly portrayed. In 20 participants with normal touch perception, we tested (1) whether focusing the audio filters of the tactile vocoder more densely around the first and second formant frequencies improved tactile vowel discrimination, and (2) whether focusing filters at mid-to-high frequencies improved obstruent consonant discrimination. The obstruent-focused approach was found to be ineffective. However, the formant-focused approach improved vowel discrimination by 8%, without changing overall consonant discrimination. The formant-focused tactile vocoder strategy, which can readily be implemented in real time on a compact device, could substantially improve speech perception for haptic hearing aid users., (© 2024. The Author(s).)

Cochlear implants (CIs) have revolutionised treatment of hearing loss, but large populations globally cannot access them either because of disorders that prevent implantation or because they are expensive and require specialist surgery. Recent technology developments mean that haptic aids, which transmit speech through vibration, could offer a viable low-cost, non-invasive alternative. One important development is that compact haptic actuators can now deliver intense stimulation across multiple frequencies. We explored whether these multiple frequency channels can transfer spectral information to improve tactile phoneme discrimination. To convert audio to vibration, the speech amplitude envelope was extracted from one or more audio frequency bands and used to amplitude modulate one or more vibro-tactile tones delivered to a single-site on the wrist. In 26 participants with normal touch sensitivity, tactile-only phoneme discrimination was assessed with one, four, or eight frequency bands. Compared to one frequency band, performance improved by 5.9% with four frequency bands and by 8.4% with eight frequency bands. The multi-band signal-processing approach can be implemented in real-time on a compact device, and the vibro-tactile tones can be reproduced by the latest compact, low-powered actuators. This approach could therefore readily be implemented in a low-cost haptic hearing aid to deliver real-world benefits., (© 2023. Springer Nature Limited.)

Major depressive disorder represents a serious public health challenge worldwide; however, the underlying cellular and molecular mechanisms are mostly unknown. Here, we profile the dorsolateral prefrontal cortex of female cynomolgus macaques with social stress-associated depressive-like behaviors using single-nucleus RNA-sequencing and spatial transcriptomics. We find gene expression changes associated with depressive-like behaviors mostly in microglia, and we report a pro-inflammatory microglia subpopulation enriched in the depressive-like condition. Single-nucleus RNA-sequencing data result in the identification of six enriched gene modules associated with depressive-like behaviors, and these modules are further resolved by spatial transcriptomics. Gene modules associated with huddle and sit alone behaviors are expressed in neurons and oligodendrocytes of the superficial cortical layer, while gene modules associated with locomotion and amicable behaviors are enriched in microglia and astrocytes in mid-to-deep cortical layers. The depressive-like behavior associated microglia subpopulation is enriched in deep cortical layers. In summary, our findings show cell-type and cortical layer-specific gene expression changes and identify one microglia subpopulation associated with depressive-like behaviors in female non-human primates., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Depression is the leading cause of global disability and can develop following the change in body image and functional capacity associated with stoma surgery. However, reported prevalence across the literature is unknown. Accordingly, we performed a systematic review and meta-analysis aiming to characterise depressive symptoms after stoma surgery and potential predictive factors., Methods: PubMed/MEDLINE, Embase, CINAHL and Cochrane Library were searched from respective database inception to 6 March 2023 for studies reporting rates of depressive symptoms after stoma surgery. Risk of bias was assessed using the Downs and Black checklist for non-randomised studies of interventions (NRSIs), and Cochrane RoB2 tool for randomised controlled trials (RCTs). Meta-analysis incorporated meta-regressions and a random-effects model., Registration: PROSPERO, CRD42021262345., Results: From 5,742 records, 68 studies were included. According to Downs and Black checklist, the 65 NRSIs were of low to moderate methodological quality. According to Cochrane RoB2, the three RCTs ranged from low risk of bias to some concerns of bias. Thirty-eight studies reported rates of depressive symptoms after stoma surgery as a proportion of the respective study populations, and from these, the median rate across all timepoints was 42.9% 42.9% (IQR: 24.2-58.9%). Pooled scores for respective validated depression measures (Hospital Anxiety and Depression Score (HADS), Beck Depression Inventory (BDI), and Patient Health Questionnaire-9 (PHQ-9)) across studies reporting those scores were below clinical thresholds for major depressive disorder according to severity criteria of the respective scores. In the three studies that used the HADS to compare non-stoma versus stoma surgical populations, depressive symptoms were 58% less frequent in non-stoma populations. Region (Asia-Pacific; Europe; Middle East/Africa; North America) was significantly associated with postoperative depressive symptoms (p = 0.002), whereas age (p = 0.592) and sex (p = 0.069) were not., Conclusions: Depressive symptoms occur in almost half of stoma surgery patients, which is higher than the general population, and many inflammatory bowel disease and colorectal cancer populations outlined in the literature. However, validated measures suggest this is mostly at a level of clinical severity below major depressive disorder. Stoma patient outcomes and postoperative psychosocial adjustment may be enhanced by increased psychological evaluation and care in the perioperative period., (© 2023. The Author(s).)

Clinical and animal studies have shown that gut microbiome disturbances can affect neural function and behaviors via the microbiota-gut-brain axis, and may be implicated in the pathogenesis of several brain diseases. However, exactly how the gut microbiome modulates nervous system activity remains obscure. Here, using a single-cell nucleus sequencing approach, we sought to characterize the cell type-specific transcriptomic changes in the prefrontal cortex and hippocampus derived from germ-free (GF), specific pathogen free, and colonized-GF mice. We found that the absence of gut microbiota resulted in cell-specific transcriptomic changes. Furthermore, microglia transcriptomes were preferentially influenced, which could be effectively reversed by microbial colonization. Significantly, the gut microbiome modulated the mutual transformation of microglial subpopulations in the two regions. Cross-species analysis showed that the transcriptome changes of these microglial subpopulations were mainly associated with Alzheimer's disease (AD) and major depressive disorder (MDD), which were further supported by animal behavioral tests. Our findings demonstrate that gut microbiota mainly modulate the mutual transformation of microglial subtypes, which may lead to new insights into the pathogenesis of AD and MDD., (© 2023. The Author(s).)

Objective: This study aimed to explore the gender specificity of gut microbiome in patients with unipolar and bipolar depression disorder by analyzing the data of gut microbiome in this two mental disorders and healthy people., Methods: A case-control study using 16S ribosomal RNA gene sequencing from fecal samples of MDD (male set, n = 43; female set, n = 77) and BD (male set, n = 82; female set, n = 83) compared with HCs (male set, n = 71; female set, n = 100) was conducted. Linear discriminant analysis was used to identify microbial characteristics. Through cooccurrence analysis, the potential correlations of the differential gut microbiota in different genders was explored. Finally, the gender-specific distinguishing microorganisms were identified as biomaker, and the diagnostic performance was verified by five-fold cross validation., Results: A specific cluster was found enriched only in female MDD set, including 4 Bacteroideae OTUs. Similarly, 3 Lachnospiraceae OTUs was found significantly increased in female BD compared with other groups. In addition, the consistent enrichment of Pseudomonadacea in male and female may be the characteristic disease-related gut microbiota of BD. Besides, the diagnostic potential of gender specific biomarker panel in male (male validation AUC: 0.758-0.874, accurancy: 0.693-0.792; female validation AUC: 0.727-0.883, accurancy: 0.678-0.781) and female (male validation AUC: 0.787-0.883, accurancy: 0.719-0.784; female validation AUC: 0.795-0.898, accurancy: 0.689-0.838) has also been identified and confirmed., Conclusions: The microbiological changes in both MDD and BD are sex specific, and gender specific biomarker panel has better diagnostic performance, which provide a certain reference in sex difference for future clinical differentiation and microbial intervention., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Suicide rates in the United States (US) reached a peak in 2018 and declined in 2019 and 2020, with substantial and often growing disparities by age, sex, race/ethnicity, geography, veteran status, sexual minority status, socioeconomic status, and method employed (means disparity). In this narrative review and commentary, we highlight these many disparities in US suicide deaths, then examine the possible causes and potential solutions, with the overarching goal of reducing suicide death disparities to achieve health equity.The data implicate untreated, undertreated, or unidentified depression or other mental illness, and access to firearms, as two modifiable risk factors for suicide across all groups. The data also reveal firearm suicides increasing sharply and linearly with increasing county rurality, while suicide rates by falls (e.g., from tall structures) decrease linearly by increasing rurality, and suicide rates by other means remain fairly constant regardless of relative county urbanization. In addition, for all geographies, gun suicides are significantly higher in males than females, and highest in ages 51-85 + years old for both sexes. Of all US suicides from 1999-2019, 55% of male suicides and 29% of female suicides were by gun in metropolitan (metro) areas, versus 65% (Male) and 42% (Female) suicides by gun in non-metro areas. Guns accounted for 89% of suicides in non-metro males aged 71-85 + years old. Guns (i.e., employment of more lethal means) are also thought to be a major reason why males have, on average, 2-4 times higher suicide rates than women, despite having only 1/4-1/2 as many suicide attempts as women. Overall the literature and data strongly implicate firearm access as a risk factor for suicide across all populations, and even more so for male, rural, and older populations.To achieve the most significant results in suicide prevention across all groups, we need 1) more emphasis on policies and universal programs to reduce suicidal behaviors, and 2) enhanced population-based strategies for ameliorating the two most prominent modifiable targets for suicide prevention: depression and firearms., (© 2022. The Author(s).)

Machine learning may assist in medical student evaluation. This study involved scoring short answer questions administered at three centres. Bidirectional encoder representations from transformers were particularly effective for professionalism question scoring (accuracy ranging from 41.6% to 92.5%). In the scoring of 3-mark professionalism questions, as compared with clinical questions, machine learning had a lower classification accuracy (P < 0.05). The role of machine learning in medical professionalism evaluation warrants further investigation., (© 2022 Royal Australasian College of Physicians.)

Major depressive disorder (MDD) is a debilitating mental disease, but its underlying molecular mechanisms remain obscure. Our previously established model of naturally occurring depression-like (DL) behaviors in Macaca fascicularis, which is characterized by microbiota-gut-brain (MGB) axis disturbances, can be used to interrogate how a disturbed gut ecosystem may impact the molecular pathology of MDD. Here, gut metagenomics were used to characterize how gut virus and bacterial species, and associated metabolites, change in depression-like monkey model. We identified a panel of 33 gut virus and 14 bacterial species that could discriminate the depression-like from control macaques. In addition, using lipidomic analyses of central and peripheral samples obtained from these animals, we found that the DL macaque were characterized by alterations in the relative abundance, carbon-chain length, and unsaturation degree of 1,2-diacylglyceride (DG) in the prefrontal cortex (PFC), in a brain region-specific manner. In addition, lipid-reaction analysis identified more active and inactive lipid pathways in PFC than in amygdala or hippocampus, with DG being a key nodal player in these lipid pathways. Significantly, co-occurrence network analysis showed that the DG levels may be relevant to the onset of negative emotions behaviors in PFC. Together our findings suggest that altered DG levels and structure in the PFC are hallmarks of the DL macaque, thus providing a new framework for understanding the gut microbiome's role in depression., (© 2022. The Author(s).)

To utilise effectively tools that employ machine learning (ML) in clinical practice medical students and doctors will require a degree of understanding of ML models. To evaluate current levels of understanding, a formative examination and survey was conducted across three centres in Australia, New Zealand and the United States. Of the 245 individuals who participated in the study (response rate = 45.4%), the majority had difficulty with identifying weaknesses in model performance analysis. Further studies examining educational interventions addressing such ML topics are warranted., (© 2021 Royal Australasian College of Physicians.)

Emerging research demonstrates that microbiota-gut-brain (MGB) axis changes are associated with depression onset, but the mechanisms underlying this observation remain largely unknown. The gut microbiome of nonhuman primates is highly similar to that of humans, and some subordinate monkeys naturally display depressive-like behaviors, making them an ideal model for studying these phenomena. Here, we characterized microbial composition and function, and gut-brain metabolic signatures, in female cynomolgus macaque (Macaca fascicularis) displaying naturally occurring depressive-like behaviors. We found that both microbial and metabolic signatures of depressive-like macaques were significantly different from those of controls. The depressive-like monkeys had characteristic disturbances of the phylum Firmicutes. In addition, the depressive-like macaques were characterized by changes in three microbial and four metabolic weighted gene correlation network analysis (WGCNA) clusters of the MGB axis, which were consistently enriched in fatty acyl, sphingolipid, and glycerophospholipid metabolism. These microbial and metabolic modules were significantly correlated with various depressive-like behaviors, thus reinforcing MGB axis perturbations as potential mediators of depression onset. These differential brain metabolites were mainly mapped into the hippocampal glycerophospholipid metabolism in a region-specific manner. Together, these findings provide new microbial and metabolic frameworks for understanding the MGB axis' role in depression, and suggesting that the gut microbiome may participate in the onset of depressive-like behaviors by modulating peripheral and central glycerophospholipid metabolism., (© 2020. The Author(s), under exclusive licence to Springer Nature Limited.)

Cochlear implants (CIs) recover hearing in severely to profoundly hearing-impaired people by electrically stimulating the cochlea. While they are extremely effective, spatial hearing is typically severely limited. Recent studies have shown that haptic stimulation can supplement the electrical CI signal (electro-haptic stimulation) and substantially improve sound localization. In haptic sound-localization studies, the signal is extracted from the audio received by behind-the-ear devices and delivered to each wrist. Localization is achieved using tactile intensity differences (TIDs) across the wrists, which match sound intensity differences across the ears (a key sound localization cue). The current study established sensitivity to across-limb TIDs at three candidate locations for a wearable haptic device, namely: the lower tricep and the palmar and dorsal wrist. At all locations, TID sensitivity was similar to the sensitivity to across-ear intensity differences for normal-hearing listeners. This suggests that greater haptic sound-localization accuracy than previously shown can be achieved. The dynamic range was also measured and far exceeded that available through electrical CI stimulation for all of the locations, suggesting that haptic stimulation could provide additional sound-intensity information. These results indicate that an effective haptic aid could be deployed for any of the candidate locations, and could offer a low-cost, non-invasive means of improving outcomes for hearing-impaired listeners.

Hearing aid and cochlear implant (CI) users often struggle to locate and segregate sounds. The dominant sound-localisation cues are time and intensity differences across the ears. A recent study showed that CI users locate sounds substantially better when these cues are provided through haptic stimulation on each wrist. However, the sensitivity of the wrists to these cues and the robustness of this sensitivity to aging is unknown. The current study showed that time difference sensitivity is much poorer across the wrists than across the ears and declines with age. In contrast, high sensitivity to across-wrist intensity differences was found that was robust to aging. This high sensitivity was observed across a range of stimulation intensities for both amplitude modulated and unmodulated sinusoids and matched across-ear intensity difference sensitivity for normal-hearing individuals. Furthermore, the usable dynamic range for haptic stimulation on the wrists was found to be around four times larger than for CIs. These findings suggest that high-precision haptic sound-localisation can be achieved, which could aid many hearing-impaired listeners. Furthermore, the finding that high-fidelity across-wrist intensity information can be transferred could be exploited in human-machine interfaces to enhance virtual reality and improve remote control of military, medical, or research robots.

Gut microbiome disturbances have been implicated in major depressive disorder (MDD). However, little is known about how the gut virome, microbiome, and fecal metabolome change, and how they interact in MDD. Here, using whole-genome shotgun metagenomic and untargeted metabolomic methods, we identified 3 bacteriophages, 47 bacterial species, and 50 fecal metabolites showing notable differences in abundance between MDD patients and healthy controls (HCs). Patients with MDD were mainly characterized by increased abundance of the genus Bacteroides and decreased abundance of the genera Blautia and Eubacterium These multilevel omics alterations generated a characteristic MDD coexpression network. Disturbed microbial genes and fecal metabolites were consistently mapped to amino acid (γ-aminobutyrate, phenylalanine, and tryptophan) metabolism. Furthermore, we identified a combinatorial marker panel that robustly discriminated MDD from HC individuals in both the discovery and validation sets. Our findings provide a deep insight into understanding of the roles of disturbed gut ecosystem in MDD., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Variations in anxiety-related behavior are associated with individual allostatic set-points in chronically stressed rats. Actively offensive rats with the externalizing indicators of sniffling and climbing the stimulus and material tearing during 10 days of predator scent stress had reduced plasma corticosterone, increased striatal glutamate metabolites, and increased adrenal 11-dehydrocorticosterone content compared to passively defensive rats with the internalizing indicators of freezing and grooming, as well as to controls without any behavioral changes. These findings suggest that rats that display active offensive activity in response to stress develop anxiety associated with decreased allostatic set-points and increased resistance to stress.

Hundreds of thousands of profoundly hearing-impaired people perceive sounds through electrical stimulation of the auditory nerve using a cochlear implant (CI). However, CI users are often poor at understanding speech in noisy environments and separating sounds that come from different locations. We provided missing speech and spatial hearing cues through haptic stimulation to augment the electrical CI signal. After just 30 min of training, we found this "electro-haptic" stimulation substantially improved speech recognition in multi-talker noise when the speech and noise came from different locations. Our haptic stimulus was delivered to the wrists at an intensity that can be produced by a compact, low-cost, wearable device. These findings represent a significant step towards the production of a non-invasive neuroprosthetic that can improve CI users' ability to understand speech in realistic noisy environments.

The cochlear implant (CI) is the most widely used neuroprosthesis, recovering hearing for more than half a million severely-to-profoundly hearing-impaired people. However, CIs still have significant limitations, with users having severely impaired pitch perception. Pitch is critical to speech understanding (particularly in noise), to separating different sounds in complex acoustic environments, and to music enjoyment. In recent decades, researchers have attempted to overcome shortcomings in CIs by improving implant technology and surgical techniques, but with limited success. In the current study, we take a new approach of providing missing pitch information through haptic stimulation on the forearm, using our new mosaicOne&#95;B device. The mosaicOne&#95;B extracts pitch information in real-time and presents it via 12 motors that are arranged in ascending pitch along the forearm, with each motor representing a different pitch. In normal-hearing subjects listening to CI simulated audio, we showed that participants were able to discriminate pitch differences at a similar performance level to that achieved by normal-hearing listeners. Furthermore, the device was shown to be highly robust to background noise. This enhanced pitch discrimination has the potential to significantly improve music perception, speech recognition, and speech prosody perception in CI users.

[This corrects the article DOI: 10.1002/advs.201901441.]., (© 2020 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Depression and obesity are significant global health concerns that commonly occur together. An integrated group cognitive behavioural therapy program was therefore developed to simultaneously address comorbid depression and obesity., Methods: Twenty-four participants (63% women, mean age 46 years) who screened positively for depression with a body mass index ≥25 were recruited from a self-referred general population sample. The group therapy program (10 two-hour weekly sessions) was examined in a single-arm, before-after pilot trial, conducted in a behavioural health clinic in Adelaide, Australia. Primary outcomes included survey and assessment-based analyses of depression, anxiety, body image, self-esteem, and weight (kg), assessed at four time-points: baseline, post-intervention, three-months and 12-months post program. Eighteen participants (75%) completed the program and all assessments., Results: Significant improvements in depression, anxiety, self-esteem and body shape concern scores, several quality of life domains, eating behaviours and total physical activity (among others) - but not weight - were observed over the course of the trial., Conclusions: Results from this pilot trial suggest that combining interventions for depression and obesity may be useful. Further development of the program, particularly regarding the potential for physical health benefits, and a randomised controlled trial, are warranted., Trial Registration: Trial registration: ANZCTR, ACTRN12617001079336, 13 July 2017. Retrospectively registered after date of the first consent (6 July 2017), but before the date of the first intervention session (20 July 2017).

Discriminating depressive episodes of bipolar disorder (BD) from major depressive disorder (MDD) is a major clinical challenge. Recently, gut microbiome alterations are implicated in these two mood disorders; however, little is known about the shared and distinct microbial characteristics in MDD versus BD. Here, using 16S ribosomal RNA (rRNA) gene sequencing, the microbial compositions of 165 subjects with MDD are compared with 217 BD, and 217 healthy controls (HCs). It is found that the microbial compositions are different between the three groups. Compared to HCs, MDD is characterized by altered covarying operational taxonomic units (OTUs) assigned to the Bacteroidaceae family, and BD shows disturbed covarying OTUs belonging to Lachnospiraceae, Prevotellaceae, and Ruminococcaceae families. Furthermore, a signature of 26 OTUs is identified that can distinguish patients with MDD from those with BD or HCs, with area under the curve (AUC) values ranging from 0.961 to 0.986 in discovery sets, and 0.702 to 0.741 in validation sets. Moreover, 4 of 26 microbial markers correlate with disease severity in MDD or BD. Together, distinct gut microbial compositions are identified in MDD compared to BD and HCs, and a novel marker panel is provided for distinguishing MDD from BD based on gut microbiome signatures., Competing Interests: The authors declare no conflict of interest., (© 2020 The Authors. Published by WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim.)

Competing Interests: The authors declare that they have no conflict of interest.

Myasthenia gravis (MG) is a devastating acquired autoimmune disease. Emerging evidence indicates that the gut microbiome plays a key role in maintaining immune system homeostasis. This work reports that MG is characterized by decreased α-phylogenetic diversity, and significantly disturbed gut microbiome and fecal metabolome. The altered gut microbial composition is associated with fecal metabolome changes, with 38.75% of altered bacterial operational taxonomic units showing significant correlations with a range of metabolite biomarkers. Some microbes are particularly linked with MG severity. Moreover, a combination of microbial makers and their correlated metabolites enable discriminating MG from healthy controls (HCs) with 100% accuracy. To investigate whether disturbed gut mcirobiome might contribute to the onset of MG, germ-free (GF) mice are initially colonized with MG microbiota (MMb) or healthy microbiota (HMb), and then immunized in a classic mouse model of MG. The MMb mice demonstrate substantially impaired locomotion ability compared with the HMb mice. This effect could be reversed by cocolonizing GF mice with both MMb and HMb. The MMb mice also exhibit similar disturbances of fecal metabolic pathways as found in MG. Together these data demonstrate disturbances in microbiome composition and activity that are likely to be relevant to the pathogenesis of MG., Competing Interests: The authors declare no conflict of interest.

Objectives: With the high and rising total cost of medical school, medical student debt is an increasing concern for medical students and graduates, with significant potential to impact the well-being of physicians and their patients. We hypothesised that medical student debt levels would be negatively correlated with mental health and academic performance, and would influence career direction (ie, medical specialty choice)., Design: We performed a systematic literature review to identify articles that assessed associations between medical student mental health, academic performance, specialty choice and debt. The databases PubMed, Medline, Embase, Scopus and PsycINFO were searched on 12 April 2017, for combinations of the medical subject headings Medical Student and Debt as search terms. Updates were incorporated on 24 April 2019., Results: 678 articles were identified, of which 52 met the inclusion criteria after being reviewed in full text. The majority of studies were conducted in the USA with some from Canada, New Zealand, Scotland and Australia. The most heavily researched aspect was the association between medical student debt and specialty choice, with the majority of studies finding that medical student debt was associated with pursuit of higher paying specialties. In addition, reported levels of financial stress were high among medical students, and correlated with debt. Finally, debt was also shown to be associated with poorer academic performance., Conclusions: Medical student debt levels are negatively associated with mental well-being and academic outcomes, and high debt is likely to drive students towards choosing higher paying specialties. Additional prospective studies may be warranted, to better understand how educational debt loads are affecting the well-being, career preparation and career choices of physicians-in-training, which may in turn impact the quality of care provided to their current and future patients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The concepts of allostatic load and overload, i. e., a dramatic increase in the allostatic load that predisposes to disease, have been extensively described in the literature. Here, we show that rats engaging in active offensive response (AOR) behavioral strategies to chronic predator scent stress (PSS) display less anxiety behavior and lower plasma cortisol levels vs. rats engaging in passive defensive response (PDR) behavioral strategies to chronic PSS. In the same chronic PSS paradigm, AOR rats also have higher lactate and lower glutamate levels in amygdala but not in control-region hippocampus vs. PDR rats. The implications of these findings for regulation of allostatic and stress responses, and post-traumatic stress disorder (PTSD) are discussed.

Schizophrenia (SCZ) is a devastating mental disorder with poorly defined underlying molecular mechanisms. The gut microbiome can modulate brain function and behaviors through the microbiota-gut-brain axis. Here, we found that unmedicated and medicated patients with SCZ had a decreased microbiome α-diversity index and marked disturbances of gut microbial composition versus healthy controls (HCs). Several unique bacterial taxa (e.g., Veillonellaceae and Lachnospiraceae) were associated with SCZ severity. A specific microbial panel (Aerococcaceae, Bifidobacteriaceae, Brucellaceae, Pasteurellaceae, and Rikenellaceae) enabled discriminating patients with SCZ from HCs with 0.769 area under the curve. Compared to HCs, germ-free mice receiving SCZ microbiome fecal transplants had lower glutamate and higher glutamine and GABA in the hippocampus and displayed SCZ-relevant behaviors similar to other mouse models of SCZ involving glutamatergic hypofunction. Together, our findings suggest that the SCZ microbiome itself can alter neurochemistry and neurologic function in ways that may be relevant to SCZ pathology.

The pathogenesis of post-traumatic stress disorder (PTSD) is incompletely understood. We hypothesize that disruptions in mother-child relations may be a key contributor to development of PTSD. A normal and healthy separation-individuation process requires adaptations of self- and interactive contingency in both the mother and her child, especially in early childhood development. Anxious mothers are prone to overprotection, which may hinder the individuation process in their children. We examined long-term stress hormones and other stress markers in subjects three generations removed from the Holocaust, to assess the long-term consequences of inherited behavioral and physiological responses to prior stress and trauma. Jewish subjects who recalled overprotective parental behavior had higher hairsteroid-concentrations and dampened limbic-hypothalamic-pituitary-adrenal (LHPA) axis reactivity compared to German and Russian-German subjects with overprotective parents. We suggest that altered LHPA axis activity in maternally overprotected Jewish subjects may indicate a transmitted pathomechanism of "frustrated individuation" resulting from cross-generational anti-Semitic experiences. Thus measurements of hairsteroid-concentrations and parenting practices may have clinical value for diagnosis of PTSD. We propose that this apparent inherited adaptivity of LHPA axis activity could promote higher individual stress resistance, albeit with risk of an allostatic overload.

Targeted mutagenesis in mice is a powerful tool for functional analysis of genes. However, genetic variation between embryonic stem cells (ESCs) used for targeting (previously almost exclusively 129-derived) and recipient strains (often C57BL/6J) typically results in congenic mice in which the targeted gene is flanked by ESC-derived passenger DNA potentially containing mutations. Comparative genomic analysis of 129 and C57BL/6J mouse strains revealed indels and single nucleotide polymorphisms resulting in alternative or aberrant amino acid sequences in 1,084 genes in the 129-strain genome. Annotating these passenger mutations to the reported genetically modified congenic mice that were generated using 129-strain ESCs revealed that nearly all these mice possess multiple passenger mutations potentially influencing the phenotypic outcome. We illustrated this phenotypic interference of 129-derived passenger mutations with several case studies and developed a Me-PaMuFind-It web tool to estimate the number and possible effect of passenger mutations in transgenic mice of interest., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: It is not understood why some pulmonary fibroses such as cryptogenic organizing pneumonia (COP) respond well to treatment, while others like usual interstitial pneumonia (UIP) do not. Increased understanding of the structure and function of the matrix in this area is critical to improving our understanding of the biology of these diseases and developing novel therapies. The objectives herein are to provide new insights into the underlying collagen- and matrix-related biological mechanisms driving COP versus UIP., Methods: Two-photon second harmonic generation (SHG) and excitation fluorescence microscopies were used to interrogate and quantify differences between intrinsic fibrillar collagen and elastin matrix signals in healthy, COP, and UIP lung., Results: Collagen microstructure was different in UIP versus healthy lung, but not in COP versus healthy, as indicated by the ratio of forward-to-backward propagating SHG signal (FSHG/BSHG). This collagen microstructure as assessed by FSHG/BSHG was also different in areas with preserved alveolar architecture adjacent to UIP fibroblastic foci or honeycomb areas versus healthy lung. Fibrosis was evidenced by increased col1 and col3 content in COP and UIP versus healthy, with highest col1:col3 ratio in UIP. Evidence of elastin breakdown (i.e. reduced mature elastin fiber content), and increased collagen:mature elastin ratios, were seen in COP and UIP versus healthy., Conclusions: Fibrillar collagen's subresolution structure (i.e. "microstructure") is altered in UIP versus COP and healthy lung, which may provide novel insights into the biological reasons why unlike COP, UIP is resistant to therapies, and demonstrates the ability of SHG microscopy to potentially distinguish treatable versus intractable pulmonary fibroses.

Second-harmonic generation (SHG) allows for the analysis of tumor collagen structural changes throughout metastatic progression. SHG directionality, measured through the ratio of the forward-propagating to backward-propagating signal (F/B ratio), is affected by collagen fibril diameter, spacing, and disorder of fibril packing within a fiber. As tumors progress, these parameters evolve, producing concurrent changes in F/B. It has been recently shown that the F/B of highly metastatic invasive ductal carcinoma (IDC) breast tumors is significantly different from less metastatic tumors. This suggests a possible relationship between the microstructure of collagen, as measured by the F/B, and the ability of tumor cells to locomote through that collagen. Utilizing in vitro collagen gels of different F/B ratios, we explored the relationship between collagen microstructure and motility of tumor cells in a “clean” environment, free of the myriad cells, and signals found in in vivo. We found a significant relationship between F/B and the total distance traveled by the tumor cell, as well as both the average and maximum velocities of the cells. Consequently, one possible mechanism underlying the observed relationship between tumor F/B and metastatic output in IDC patient samples is a direct influence of collagen structure on tumor cell motility.

Background: Matrix metalloproteases and collagen are key participants in breast cancer, but their precise roles in cancer etiology and progression remain unclear. MMP13 helps regulate collagen structure and has been ascribed largely harmful roles in cancer, but some studies demonstrate that MMP13 may also protect against tumor pathology. Other studies indicate that collagen's organizational patterns at the breast tumor-host interface influence metastatic potential. Therefore we investigated how MMP13 modulates collagen I, a principal collagen subtype in breast tissue, and affects tumor pathology and metastasis in a mouse model of breast cancer., Methods: Tumors were implanted into murine mammary tissues, and their growth analyzed in Wildtype and MMP13 KO mice. Following extraction, tumors were analyzed for collagen I levels and collagen I macro- and micro-structural properties at the tumor-host boundary using immunocytochemistry and two-photon and second harmonic generation microscopy. Lungs were analyzed for metastases counts, to correlate collagen I changes with a clinically significant functional parameter. Statistical analyses were performed by t-test, analysis of variance, or Wilcoxon-Mann-Whitney tests as appropriate., Results: We found that genetic ablation of host stromal MMP13 led to: 1. Increased mammary tumor collagen I content, 2. Marked changes in collagen I spatial organization, and 3. Altered collagen I microstructure at the tumor-host boundary, as well as 4. Increased metastasis from the primary mammary tumor to lungs., Conclusions: These results implicate host MMP13 as a key regulator of collagen I structure and metastasis in mammary tumors, thus making it an attractive potential therapeutic target by which we might alter metastatic potential, one of the chief determinants of clinical outcome in breast cancer. In addition to identifying stromal MMP13 is an important regulator of the tumor microenvironment and metastasis, these results also suggest that stromal MMP13 may protect against breast cancer pathology under some conditions, a finding with important implications for development of chemotherapies directed against matrix metalloproteases.

Collagen fibers can be imaged with second harmonic generation (SHG) and are associated with efficient tumor cell locomotion. Preferential locomotion along these fibers correlates with a more aggressively metastatic phenotype, and changes in SHG emission properties accompany changes in metastatic outcome. We therefore attempted to elucidate the cellular and molecular machinery that influences SHG in order to understand how the microstructure of tumor collagen fibers is regulated. By quantifying SHG and immunofluorescence (IF) from tumors grown in mice with and without stromal tumor necrosis factor (TNF)-α and in the presence or absence of tumor-associated macrophages (TAMs), we determined that depletion of TAMs alters tumor collagen fibrillar microstructure as quantified by SHG and IF. Furthermore, we determined that abrogation of TNF-α expression by tumor stromal cells also alters fibrillar microstructure and that subsequent depletion of TAMs has no further effect. In each case, metastatic burden correlated with optical readouts of collagen microstructure. Our results implicate TAMs and stromal TNF-α as regulators of breast tumor collagen microstructure and suggest that this regulation plays a role in tumor metastasis. Furthermore, these results indicate that quantification of SHG represents a useful strategy for evaluating the cells and molecular pathways responsible for manipulating fibrillar collagen in breast tumor models.

Proteasomal and mitochondrial dysfunctions are implicated in chronic neurodegenerative diseases. To investigate the impact of mitochondrial impairment on the proteasome, we treated rat cerebral cortical neurons with oligomycin, antimycin, or rotenone, which inhibit different elements of the electron transport chain. Firstly, we observed a reduction in ubiquitinated proteins and E1 activity. Secondly, we established that 26S proteasomes are disassembled with a decline in activity. Thirdly, we show, to our knowledge for the first time, that calpain activation triggers the selective processing of the 26S proteasome subunit Rpn10. Other proteasome subunits tested were not affected. Calpain also cleaved caspase 3 to an inactive fragment, thus preventing apoptosis that is an energy-dependent cell death pathway. In addition, calpain cleaved the microtubule-associated protein Tau, a major component of neurofibrillary tangles in Alzheimer disease and other tauopathies. Fourthly, we detected a rise in 20S proteasome levels and activity. Finally, we show that both acute (16 h) and long term (up to 7 days) mitochondrial impairment led to down-regulation of ubiquitinated-proteins, 26S proteasome disassembly, and a rise in 20S proteasomes. We postulate that upon mitochondrial dysfunction, ATP depletion and calpain activation contribute to the demise of protein turnover by the ubiquitin/proteasome pathway. The concomitant rise in 20S proteasomes, which seem to degrade proteins in an unregulated and energy-independent manner, in the short term may carry out the turnover of randomly unfolded oxidized proteins. However, if chronic, it could lead to neurodegeneration as regulated protein degradation by the ubiquitin/proteasome pathway is essential for neuronal survival.

Application of two-photon microscopy (TPM) to translational and clinical cancer research has burgeoned over the last several years, as several avenues of pre-clinical research have come to fruition. In this review, we focus on two forms of TPM-two-photon excitation fluorescence microscopy, and second harmonic generation microscopy-as they have been used for investigating cancer pathology in ex vivo and in vivo human tissue. We begin with discussion of two-photon theory and instrumentation particularly as applicable to cancer research, followed by an overview of some of the relevant cancer research literature in areas that include two-photon imaging of human tissue biopsies, human skin in vivo, and the rapidly developing technology of two-photon microendoscopy. We believe these and other evolving two-photon methodologies will continue to help translate cancer research from the bench to the bedside, and ultimately bring minimally invasive methods for cancer diagnosis and treatment to therapeutic reality.

Rheumatoid arthritis (RA) is a chronic autoimmune disease with episodic flares in affected joints; the etiology of RA is largely unknown. Recent studies in mice demonstrated that alterations in lymphatics from affected joints precede flares. Thus, we aimed to develop novel methods for measuring lymph node pressure and lymph viscosity in limbs of mice. Pressure measurements were performed by inserting a glass micropipette connected to a pressure transducer into popliteal lymph nodes (PLN) or axillary lymph nodes (ALN) of mice; subsequently, we determined that the lymphatic pressures of water were 9 and 12 cm, respectively. We are also developing methods for measuring lymph viscosity in lymphatic vessels afferent to PLN, which can be measured by multiphoton fluorescence recovery after photobleaching (MP-FRAP) of fluorescein isothiocyanate-labeled bovine serum albumin (FITC-BSA) injected into the hind footpad. These results demonstrate the potential of lymph node pressure and lymph viscosity measurements, and future studies to test these outcomes as biomarkers of arthritic flare are warranted., (© 2011 New York Academy of Sciences.)

Fluorescent probes for monitoring mitochondrial membrane potential are frequently used for assessing mitochondrial function, particularly in the context of cell fate determination in biological and biomedical research. However, valid interpretation of results obtained with such probes requires careful consideration of numerous controls, as well as possible effects of non-protonic charges on dye behavior. In this context, we provide an overview of some of the important technical considerations, controls, and parallel complementary assays that can be employed to help ensure appropriate interpretation of results, thus providing a practical usage guide for monitoring mitochondrial membrane potentials with cationic probes. In total, this review will help illustrate both the strengths and potential pitfalls of common mitochondrial membrane potential dyes, and highlight best-usage approaches for their efficacious application in life sciences research.