Causation in neuroscience: keeping mechanism meaningful.

A fundamental goal of research in neuroscience is to uncover the causal structure of the brain. This focus on causation makes sense, because causal information can provide explanations of brain function and identify reliable targets with which to understand cognitive function and prevent or change neurological conditions and psychiatric disorders. In this research, one of the most frequently used causal concepts is 'mechanism' - this is seen in the literature and language of the field, in grant and funding inquiries that specify what research is supported, and in journal guidelines on which contributions are considered for publication. In these contexts, mechanisms are commonly tied to expressions of the main aims of the field and cited as the 'fundamental', 'foundational' and/or 'basic' unit for understanding the brain. Despite its common usage and perceived importance, mechanism is used in different ways that are rarely distinguished. Given that this concept is defined in different ways throughout the field - and that there is often no clarification of which definition is intended - there remains a marked ambiguity about the fundamental goals, orientation and principles of the field. Here we provide an overview of causation and mechanism from the perspectives of neuroscience and philosophy of science, in order to address these challenges.

Polygene risk scores and randomized experiments.

We explore Madole & Harden's (2022) suggestion that single-nucleotide polymorphism (SNP)/trait correlations are analogous to randomized experiments and thus can be given a causal interpretation.

Relationships Between Early Maternal Warmth and Social Connection: A Randomized Clinical Trial With Naltrexone.

OBJECTIVE: Early experiences of having received maternal warmth predict responses to opportunities to connect with others later in life. However, the understanding of neurochemical mechanisms by which such relationships emerge remains incomplete. Endogenous opioids, involved in social connection in both animals and humans, may contribute to this link. Therefore, the current study examined a) relationships between early maternal warmth and brain and self-report responses to novel social targets (i.e., outcomes that may promote social connection) and b) the effect of the opioid antagonist, naltrexone, on such relationships. METHODS: Eighty-two adult participants completed a retrospective report of early maternal warmth. On a second visit, participants were randomized to 50 mg of oral naltrexone (n = 42) or placebo (n = 40), followed by a magnetic resonance imaging scan where functional brain activity in response to images of novel social targets (strangers) was assessed. Approximately 24 hours later, participants reported on their feelings of social connection since leaving the scanner. RESULTS: In the placebo condition, greater early maternal warmth was associated with less dorsal anterior cingulate cortex, anterior insula, ventral striatum, and amygdala activity in response to images of novel social targets (r values ≥ -0.360, p values ≤ .031), and greater feelings of social connection (r = 0.524, p < .001) outside of the laboratory. The same relationships, however, were not present in the naltrexone condition. CONCLUSIONS: Results highlight relationships between early maternal warmth and responses to the social world at large and suggest that opioids might contribute to social connection by supporting the buffering effects of warm early life experiences on social connection later in life.Trial Registration: Clinical Trials NCT02818036.

Burden of diagnostic investigations at the end of life for people with chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is an incurable, chronic condition that leads to significant morbidity and mortality, with most patients dying in hospital. While diagnostic tests are important for actively managing patients during hospital admissions, the balance between benefit and harm should always be considered. This is particularly important when patients reach the end of life, when the focus is to reduce burdensome interventions. AIMS: To examine the use of diagnostic testing in a cohort of people with COPD who died in hospital. METHODS: Retrospective medical record audits were completed at two Australian hospitals (Royal Melbourne Hospital and Northeast Health Wangaratta), with all patients who died from COPD over 12 years between 1 January 2004 and 31 December 2015 included. RESULTS: Three hundred and forty-three patients were included, with a median of 11 diagnostic testing episodes per patient. Undergoing higher numbers of diagnostic tests was associated with younger age, intensive care unit admission and non-invasive ventilation use. Reduced testing was associated with recent hospital admission for COPD, domiciliary oxygen use and a prior admission with documentation limiting medical treatment. Most patients underwent diagnostic tests in the last 2 days of life, and 12% of patients had ongoing diagnostic tests performed after a documented decision was made to change the goal of care to provide comfort care only. CONCLUSION: There were missed opportunities to reduce the burden of diagnostic tests and focus on comfort at the end of life. Increased physician education regarding communication and end-of-life care, including recognising active dying may address these issues.

Progressive Improvement in Midfacial Volume 18 to 24 Months After Simultaneous Fat Grafting and Facelift: An Insight to Fat Graft Remodeling.

BACKGROUND: Although many facelift techniques incorporate fat grafting with tissue repositioning and removal, the intermediate and long-term changes in facial volume after these techniques is unknown. Whereas fillers for facial volume have predictable life spans, we know little about the facial volume changes following fat grafting with facelift surgery. OBJECTIVES: The authors sought to track the short-term and long-term effects on midfacial volume change. METHODS: We evaluated a subset of patients who were followed by 3-dimensional (3D) photometric imaging 18 to 24 months after facelift with fat grafting to the deep midfacial fat compartments and buccal fat pads. Volume changes were measured preoperatively and postoperatively every 1, 3, 6, 12, 18, and 24 months using the 3D photometry. RESULTS: At the 1- to 2-month follow-up period, average facial volume was 49.60% of the initial fat injected. At the 18- to 24-month follow-up period, average facial volume was 73.64% of the initial fat injected, indicating an increase in midfacial volume. Upon graphing available photometric data, dynamic changes in facial volume were observed. In 5 midfacial zones, facial volume appeared to initially decline (average decline, 49.0% of original fat injection), troughing at 10 months (range, 2-15 months), but later inclined (average increase in volume, 95.9% of original fat injection), peaking around 16 months (range, 4-24 months). CONCLUSIONS: Progressive improvement in midfacial volume in part may be explained by the graft replacement theory of Suga and Yoshimura, which suggests that grafted adipose tissue immediately dies after transplantation and is replaced by adipose-derived stem or progenitor cells.

Antimicrobial prescription in patients dying from chronic obstructive pulmonary disease.

BACKGROUND: Despite rising antimicrobial resistance, treatment guidelines for chronic obstructive pulmonary disease (COPD) exacerbations are frequently ignored. Patients with terminal conditions are often prescribed antimicrobials despite the goal of care to reduce burdensome treatments. The appropriate use of antimicrobials in patients who die from an exacerbation of COPD is unknown. AIM: To review antimicrobial prescription during the final admission in patients who died from an acute exacerbation of COPD. METHODS: A retrospective medical record audit was performed for 475 patients who died over 12 years (2004-2015). Patients were analysed within three groups: Group 1 - pneumonia on chest radiograph, Group 2 - infective exacerbation of COPD +/- raised inflammatory markers (white cell count, C-reactive protein) and Group 3 - non-infective exacerbation of COPD. RESULTS: A total of 221 patients died from COPD. The median age was 80 years, and 136 (60%) were male. Median respiratory function: forced expiratory volume in 1 s 0.8 L (41.0%), forced vital capacity 2.0 L (74.0%) and diffusing capacity for carbon monoxide 8 (40.5%). A total of 109 (49.3%) patients used home oxygen and 156 (70.6%) were ex-smokers. Of the cohort, 90.5% received antimicrobials. In Groups 1, 2 and 3, 68 (94.4%), 108 (92.3%) and 24 (75.0%) patients received antimicrobials respectively. Guideline-concordant therapy was administered to 31.7% of patients (Group 1: 79.2%, Group 2: 4.3%, Group 3: 25.0%), 60.2% of patients received ceftriaxone and 44.8% received azithromycin. The median duration of therapy was 4 days and 27.1% received antimicrobials at the time of death. CONCLUSION: Antimicrobials are overprescribed, and non-guideline antimicrobials are overused in patients who die from COPD. Further education of medical staff, regular medication reviews and the use of disease severity scores or clinical pathways may improve antimicrobial stewardship.

Neural Correlates of Giving Social Support: Differences Between Giving Targeted Versus Untargeted Support.

OBJECTIVE: Giving support contributes to the link between social ties and health; however, the neural mechanisms are not known. Giving support in humans may rely on neural regions implicated in parental care in animals. The current studies, therefore, assess the contribution of parental care-related neural regions to giving support in humans and, as a further theoretical test, examine whether the benefits of giving targeted support to single, identifiable individuals in need extend to giving untargeted support to larger societal causes. METHODS: For study 1 (n = 45, M (SD) age = 21.98 (3.29), 69% females), participants completed a giving support task, followed by an emotional faces task in the functional magnetic resonance imaging scanner. For study 2 (n = 382, M (SD) age = 43.03 (7.28), 52% females), participants self-reported on their giving support behavior and completed an emotional faces task in the functional magnetic resonance imaging scanner. RESULTS: In study 1, giving targeted (versus untargeted) support resulted in greater feelings of social connection and support effectiveness. Furthermore, greater septal area activity, a region centrally involved in parental care in animals, to giving targeted support was associated with less right amygdala activity to an emotional faces task (r = -.297, 95% confidence interval = -.547 to -.043). Study 2 replicated and extended this association to show that self-reports of giving targeted support were associated with less amygdala activity to a different emotional faces task, even when adjusting for other social factors (r = -.105, 95% confidence interval = -.200 to -.011). Giving untargeted support was not related to amygdala activity in either study. CONCLUSIONS: Results highlight the unique benefits of giving targeted support and elucidate neural pathways by which giving support may lead to health.

A Palliative Approach is Adopted for Many Patients Dying in Hospital with Chronic Obstructive Pulmonary Disease.

Severe chronic breathlessness in advanced chronic obstructive pulmonary disease (COPD) is undertreated and few patients access specialist palliative care in the years before death. This study aimed to determine if symptom palliation or a palliative approach were delivered during the final hospital admission in which death occurred. Retrospective medical record audits were completed at two Australian hospitals, with all patients who died from COPD over 12 years between 1 January 2004 and 31 December 2015 included. Of 343 patients included, 217 (63%) were male with median age 79 years (IQR 71.4-85.0). Median respiratory function: FEV1 0.80L (42% predicted), FVC 2.02L (73% predicted) and DLco 9 (42% predicted). 164 (48%) used domiciliary oxygen. Sixty (18%) patients accessed specialist palliative care and 17 (5%) wrote an advance directive prior to the final admission. In the final admission, 252 (74%) patients had their goal of care changed to aim for comfort (palliation) and 99 (29%) were referred to specialist palliative care. Two hundred and eighty-six (83%) patients received opioids and 226 (66%) received benzodiazepines, within 1 or 2 days respectively after admission to palliate symptoms. Median starting and final opioid doses were 10 mg (IQR = 5-20) and 20 mg (IQR = 7-45) oral morphine equivalent/24 h. Hospital site and year of admission were significantly associated with palliative care provision. Respiratory and general physicians provided a palliative approach to the majority of COPD patients during their terminal admission, however, few patients were referred to specialist palliative care. Similarly, there were missed opportunities to offer symptom palliation and a palliative approach in the years before death.

Regenerative Cells For Facial Surgery: Biofilling and Biocontouring.

Zuk et al in 2001 identified stem and regenerative cells within the stromal vascular fraction of fat. In preclinical studies, these cells appeared to stimulate angiogenesis and reduce inflammation, and soon thereafter, clinical use of stromal vascular fraction (SVF) evolved as researchers such as Rigotti, Coleman, Mojallal, our group, and others demonstrated that fat can be used for both therapeutic and aesthetic indications. The regenerative effects of fat and its contents on facial aesthetics have been shown at the histologic and cellular level. Regeneration of elastin and collagen fibers as well as improvement in capillary density and reduction of inflammation have been reported. We review our current approach to the use of regenerative cells and different types of fat grafts in facial surgery. The fat graft is classified, both from a regenerative point of view as well as a tissue product that can be modified into different tissue characteristics, depending on the area and condition treated. Clinical use of SVF enriched fat, millifat, microfat, and nanofat grafts as well as composite fat grafts are reviewed. Based on clinical experience and evidence to date, it appears that the regenerative effects seen with the use of SVF in aesthetic surgery are modest, but there appear to be definite histologic findings of regeneration. These improvements may not be clinically apparent to a patient when cell enriched fat grafts are compared to fat grafts alone. However, the subtle changes seen in histology may be cumulative over time. Three types of fat grafts are defined: millifat (parcel size 2.4<), microfat (1.2<), and nanofat (400-600 µm). Each are characterized by their injectability ratings and emulsification parcel size as well as amount of sSVF cells. Newer concepts of periosteal fat grafting, buccal fat pad grafting, pyriform aperture fat grafting, intraorbital fat grafting, and nanofat grafting are discussed. Composite fat grafts are presented as a new concept as is biofilling and biocontouring. The use of regenerative cells in facial surgery is evolving rapidly. Our understanding of the anatomic changes that occur with aging has become more precise and our ability to target histologic changes seen with aging has become more effective. Deep fat compartment grafting, superficial fat grafting, nanofat, and SVF are becoming important components of contemporary facial rejuvenation. The use of regenerative approaches in facial rejuvenation is a logical step in changing the paradigm from surgical treatment of aging to a more proactive prevention and maintenance approach that keeps up with changes in the tissues as they age.

Fertility preservation in the female cancer patient.

Hundreds of thousands of young women are diagnosed with cancer each year, but due to advances in screening, diagnosis, and treatment, survival rates have improved dramatically. With improved survival, long-term effects of cancer treatment including infertility need to be addressed and should be discussed as soon as possible. Oncologists should be familiar with their patients' risks of infertility and available options for fertility preservation and future reproduction.

Double plating is a suitable option for periprosthetic distal femur fracture compared to single plate fixation and distal femoral arthroplasty.

Aims: The purpose of this study was to compare reoperation and revision rates of double plating (DP), single plating using a lateral locking plate (SP), or distal femoral arthroplasty (DFA) for the treatment of periprosthetic distal femur fractures (PDFFs). Methods: All patients with PDFF primarily treated with DP, SP, or DFA between 2008 and 2022 at a university teaching hospital were included in this retrospective cohort study. The primary outcome was revision surgery for failure following DP, SP, or DFA. Secondary outcome measures included any reoperation, length of hospital stay, and mortality. All basic demographic and relevant implant and injury details were collected. Radiological analysis included fracture classification and evaluation of metaphyseal and medial comminution. Results: A total of 111 PDFFs (111 patients, median age 82 years (interquartile range (IQR) 75 to 88), 86% female) with 32 (29%) Su classification 1, 37 (34%) Su 2, and 40 (37%) Su 3 fractures were included. The median follow-up was 2.5 years (IQR 1.2 to 5.0). DP, SP, and DFA were used in 15, 66, and 30 patients, respectively. Compared to SP, patients treated with DP were more likely to have metaphyseal comminution (47% vs 14%; p = 0.009), to be low fractures (47% vs 11%; p = 0.009), and to be anatomically reduced (100% vs 71%; p = 0.030). Patients selected for DFA displayed comparable amounts of medial/metaphyseal comminution as those who underwent DP. At a minimum follow-up of two years, revision surgery for failure was performed in 11 (9.9%) cases at a median of five months (IQR 2 to 9): 0 DP patients (0%), 9 SP (14%), and 2 DFA (6.7%) (p = 0.249). Conclusion: Using a strategy of DP fixation in fractures, where the fracture was low but there was enough distal bone to accommodate locking screws, and where there is metaphyseal comminution, resulted in equivalent survival free from revision or reoperation compared to DFA and SP fixation.

Underrecognition and Suboptimal Quality of Care for Nonalcoholic Fatty Liver Disease Cirrhosis in Primary Care Patients with Diabetes Mellitus.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a leading cause of cirrhosis but is underrecognized in primary care. Cirrhosis management requires complex monitoring, and the quality of care (QoC) for NAFLD cirrhosis patients in primary care may be inadequate. METHODS: In this retrospective-prospective cohort study of primary care patients with diabetes mellitus, we identified patients with NAFLD cirrhosis by 1) evidence of cirrhosis from abdominal imaging identified by natural language processing, or 2) existence of International Classification of Diseases code for cirrhosis. A finding of either was followed by manual chart review for confirmation of both cirrhosis and NAFLD. We then determined if cirrhosis care measures were up-to-date, including hepatitis A and B vaccination, Model for End-Stage Liver Disease score components, esophagogastroduodenoscopy, and hepatocellular carcinoma screening. We created a composite score quantifying overall QoC (scale 0-8), with high QoC defined as ≥6 points. RESULTS: Among 3,028 primary care patients with diabetes mellitus, we identified 51 (1.7%) with NAFLD cirrhosis. Although 78% had ≥3 average primary care visits/year, only 24% completed hepatocellular carcinoma screening at least annually in at least 75% of years since diagnosis. The average QoC composite score was 4.9 (SD 2.4), and less than one-third had high QoC. CONCLUSIONS: NAFLD cirrhosis is prevalent but underdiagnosed in primary care, and receipt of comprehensive QoC was suboptimal. Given the rising incidence of NAFLD cirrhosis, primary care providers need improved awareness and mechanisms to ensure high QoC for this population.

New quality outcome indicators for bone metastases: expert consensus analysis of patients, their families and specialist healthcare professionals.

OBJECTIVES: As workload increases, surgical care for patients with bone metastases is increasingly decentralised, with a shift in management away from primary bone tumour units to local centres. We must ensure that patients have similar outcomes regardless of where they receive their treatment. The aim was to develop and validate a set of quality outcome indicators (QOIs) to evaluate treatment success for patients undergoing surgery for bone metastases. METHODS: Outcome recommendations were adapted from the literature and field tested in a retrospective patient cohort to determine feasibility. The provisional outcome indicators were assessed during a modified RAND/Delphi consensus process by a group of patients, relatives and healthcare professionals with validated targets added. RESULTS: 1534 articles were reviewed. 38 quality objectives were extracted and assessed for feasibility using clinical records for 117 patients. 28 provisional outcome indicators proceeded to expert consensus and were reviewed by a group of 22 panellists including 10 patients and 4 relatives/carers. After two rounds, 15 QOIs were generated, with validated targets based on expert consensus. These included specific statements such as 'surgery improves pain and reduces the need for morphine, target: at follow-up, pain is documented in 80% of individuals and 50% of these have reduced need for morphine'. CONCLUSIONS: The published evidence and guidelines were adapted into a set of outcome indicators validated by patients, their family/carers and healthcare professionals. These can be used to compare care between centres and identify units of excellence in maximising good outcome after surgery for bone metastases.

Geomorphological controls on estuary hydrodynamics with implications for diatom blooms in deglaciated coastal areas.

Understanding local hydraulic conditions is imperative to coastal harmful algal bloom (HAB) monitoring. The research summarized herein describes how the locations and tidal phases selected for coastal hazard sampling can influence measurement results used to guide management decisions for HABs. Our study was conducted in Frenchman Bay, Maine, known for its complex deglaciated coastline, strong tidal influence, and shellfishing activities that are susceptible to problematic HABs such as those produced by some species (spp.) of the diatom genus Pseudo-nitzschia. In-situ measurements of current velocity, density, and turbulence collected over a semidiurnal tidal cycle and a companion numerical model simulation of the study area provide concurrent evidence of two adjacent counter-rotating sub-mesoscale eddies (2-4 km diameter) that persist in the depth-averaged residual circulation. The eddies are generated in the wake of several islands in an area with abrupt bathymetric gradients, both legacy conditions partly derived from deglaciation ∼15 kya. Increased concentrations of Pseudo-nitzschia spp. measured during the semidiurnal survey follow a trend of elevated turbulent dissipation rates near the water surface, indicating that surface sampling alone might not adequately indicate species abundance. Additional measurements of Pseudo-nitzschia spp. from two years of weekly sampling in the region show that algal cell abundance is highest where residual eddies form. These findings provide incentive to examine current practices of HAB monitoring and management by linking coastal geomorphology to hydraulic conditions influencing HAB sampling outcomes, coastal morphometric features to material accumulation hotspots, and millennial time scales to modern hydraulic conditions.

Recalling prior experiences with a close other can fulfill the need for social connection.

Humans need social connection to thrive, but how we fulfill this need is not well understood. Numerous theoretical perspectives propose that continual positive experiences with a close other fulfill the need for social connection. Despite popular acceptance for this notion, little research has investigated the consequences of having multiple experiences with a close other. As a first step toward this goal, the current studies assessed whether recalling prior experiences of social connection with a close other alters feelings of satisfaction toward the same person, the implications of such feelings for social desires outside of the lab (Study 1), and possible brain mechanisms related to fulfilling the need for social connection (Study 2). Consistent with hypotheses, recalling experiences increased feelings of satisfaction toward the close other, but not toward an acquaintance. Further, recalling prior experiences uniquely increased the desire for additional social interaction with the close other, compared with others in general. In Study 2, brain regions related to satiety-the ventral striatum (VS) and ventromedial prefrontal cortex (VMPFC)-showed different patterns to recalling prior experiences with a single close other such that VS activity decreased over recalled experiences, while VMPFC activity remained stable. VMPFC activity, but not VS activity, to recalling experiences with a close other was associated with greater feelings of satisfaction. Together, results are consistent with the proposal that positive experiences, particularly with close others, satisfy the need for social connection. Implications for preventing feelings of social disconnection and maintaining social relatonships over time are discussed. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Examining the impact of schizotypal personality traits on event-related potential (ERP) indexes of sensory gating in a healthy population.

The aim of this study was to better understand the relation of schizotypy traits with sensory gating ability in a sample of community-dwelling individuals with high and low schizotypy traits. Sensory gating was assessed through the paired click paradigm and mid-latency evoked responses (i.e., P50, N100, P200), while schizotypy traits were assessed through the SPQ-BR which was used to classify participants into "high" and "low" schizotypy groups. Based on prior work, we hypothesized that those with the highest schizotypy scores would have reduced sensory gating ability. While this study does not show differences between relatively low and high schizotypy groups on sensory gating ability, it does suggest that our participants may have been experiencing deficits in attention allocation, a downstream cognitive processing measure. Scores on the SPQ-BR suggest that our sample was not close to the high end of the schizotypy traits which may help explain why no differences were found. This research shows the importance of including all levels of schizotypy ratings in clinical research as we can gain a clearer view of the impact of schizotypy on the brain and cognitive functioning in those with "high" levels of schizotypy. Additionally, this work highlights the importance of including measures of important factors such as impulsivity and sensation-seeking to better understand what aspects of schizotypy may be driving these sensory gating alterations reported in the literature.

Metabolic correlates of menopause: an update.

PURPOSE OF REVIEW: Metabolic syndrome (MetS) is a cluster of characteristics that increase the risk of cardiovascular disease and type 2 diabetes mellitus. We will review the most interesting and relevant studies on metabolic correlates of menopause published over the last year. RECENT FINDINGS: In the past year, studies have shifted focus from effects on cardiovascular disease and diabetes to effects of MetS on breast cancer as well as menopausal symptoms. Studies have found and further confirmed its negative effect on both breast cancer and menopausal symptoms. Focus has also been on treatment options including both lifestyle and pharmacologic. Recent studies also further investigate markers/predictors as well as genetic components influencing MetS development. SUMMARY: Over a quarter of the US population is affected by metabolic disease at midlife, and some studies have shown that the incidence of MetS increases with menopause. There are now more Americans who are age 65 and older than at any other time in US history. Thus, it is becoming ever more important to understand metabolic health, as well as the consequences of MetS.