Improved Cardiorespiratory Fitness Is Associated with Increased Cortical Thickness in Mild Cognitive Impairment

Cortical atrophy is a biomarker of Alzheimer’s disease (AD) that correlates with clinical symptoms. This study examined changes in cortical thickness from before to after an exercise intervention in mild cognitive impairment (MCI) and healthy elders. Thirty physically inactive older adults (14 MCI, 16 healthy controls) underwent MRI before and after participating in a 12-week moderate intensity walking intervention. Participants were between the ages of 61 and 88. Change in cardiorespiratory fitness was assessed using residualized scores of the peak rate of oxygen consumption (V̇O2peak) from pre- to post-intervention. Structural magnetic resonance images were processed using FreeSurfer v5.1.0. V̇O2peak increased an average of 8.49%, which was comparable between MCI and healthy elders. Overall, cortical thickness was stable except for a significant decrease in the right fusiform gyrus in both groups. However, improvement in cardiorespiratory fitness due to the intervention (V̇O2peak) was positively correlated with cortical thickness change in the bilateral insula, precentral gyri, precuneus, posterior cingulate, and inferior and superior frontal cortices. Moreover, MCI participants exhibited stronger positive correlations compared to healthy elders in the left insula and superior temporal gyrus. A 12-week moderate intensity walking intervention led to significantly improved fitness in both MCI and healthy elders. Improved V̇O2peak was associated with widespread increased cortical thickness, which was similar between MCI and healthy elders. Thus, regular exercise may be an especially beneficial intervention to counteract cortical atrophy in all risk groups, and may provide protection against future cognitive decline in both healthy elders and MCI

Exercise Training and Functional Connectivity Changes in Mild Cognitive Empairment and Healthy Elders

Background: Effective interventions are needed to improve brain function in mild cognitive impairment (MCI), an early stage of Alzheimer’s disease (AD). The posterior cingulate cortex (PCC)/precuneus is a hub of the default mode network (DMN) and is preferentially vulnerable to disruption of functional connectivity in MCI and AD. Objective: We investigated whether 12 weeks of aerobic exercise could enhance functional connectivity of the PCC/precuneus in MCI and healthy elders. Methods: Sixteen MCI and 16 healthy elders (age range = 60–88) engaged in a supervised 12-week walking exercise intervention. Functional MRI was acquired at rest; the PCC/precuneus was used as a seed for correlated brain activity maps. Results: A linear mixed effects model revealed a significant interaction in the right parietal lobe: the MCI group showed increased connectivity while the healthy elders showed decreased connectivity. In addition, both groups showed increased connectivity with the left postcentral gyrus. Comparing pre to post intervention changes within each group, the MCI group showed increased connectivity in 10 regions spanning frontal, parietal, temporal and insular lobes, and the cerebellum. Healthy elders did not demonstrate any significant connectivity changes. Conclusion: The observed results show increased functional connectivity of the PCC/precuneus in individuals with MCI after 12 weeks of moderate intensity walking exercise training. The protective effects of exercise training on cognition may be realized through the enhancement of neural recruitment mechanisms, which may possibly increase cognitive reserve. Whether these effects of exercise training may delay further cognitive decline in patients diagnosed with MCI remains to be demonstrated

Outdoor music festivals: Cacophonous consumption or melodious moderation?

Large outdoor music festivals have emerged as part of a general expansion of licensed recreational activities, but in research terms they have been largely impenetrable due to commercial sensitivities. These sensitivities notwithstanding, the number and scale of such events necessitate a greater understanding of alcohol and drug use and the potential to promote normative protective behaviours in this context. This study examines self-reported alcohol and drug behaviours of 1589 attendees at a music festival in Scotland during the summer of 2008. Similarities between the outdoor rock music festivals and the dance club scene are considered alongside the challenges associated with risk reduction in these settings. Results show that alcohol was consumed by the majority of samples; however, negative consequences were reported by a minority of respondents, suggesting evidence of controlled hedonism within a situation traditionally associated with unrestrained excess. Similarly, the majority of samples did not use drugs. The majority also report a number of self-regulating protective behaviours suggesting that alcohol and drug use is contained within a developing social culture of ‘controlled intoxication’. Results further suggest that although music festivals are transitory events, there is a degree of consistency amongst attendees. Music festivals may therefore be atypical but potentially effective environments to increase protective behaviours using normative messaging and modern communications media. This study was resourced exclusively by local alcohol and drug partnerships

Family-centred approaches to the prevention of mother to child transmission of HIV

Background: Prevention of mother to child transmission (PMTCT) programmes have traditionally been narrow in scope, targeting biomedical interventions during the perinatal period, rather than considering HIV as a family disease. This limited focus restricts programmes' effectiveness, and the opportunity to broaden prevention measures has largely been overlooked. Although prevention of vertical transmission is crucial, consideration of the family environment can enhance PMTCT. Family-centred approaches to HIV prevention and care present an important direction for preventing paediatric infections while improving overall family health. This paper reviews available literature on PMTCT programmatic models that have taken a broader or family-centred approach. We describe findings and barriers to the delivery of family-centred PMTCT and identify a number of promising new directions that may achieve more holistic services for children and families. Methods: Literature on the effectiveness of family-centred PMTCT interventions available via PubMed, EMBASE and PsycINFO were searched from 1990 to the present. Four hundred and three abstracts were generated. These were narrowed to those describing or evaluating PMTCT models that target broader aspects of the family system before, during and/or after delivery of an infant at risk of acquiring HIV infection (N = 14). Results: The most common aspects of family-centred care incorporated by PMTCT studies and programme models included counselling, testing, and provision of antiretroviral treatment for infected pregnant women and their partners. Antiretroviral therapy was also commonly extended to other infected family members. Efforts to involve fathers in family-based PMTCT counselling, infant feeding counselling, and general decision making were less common, though promising. Also promising, but rare, were PMTCT programmes that use interventions to enrich family capacity and functioning; these include risk assessments for intimate partner violence, attention to mental health issues, and the integration of early childhood development services. Conclusions: Despite barriers, numerous opportunities exist to expand PMTCT services to address the health needs of the entire family. Our review of models utilizing these approaches indicates that family-centred prevention measures can be effectively integrated within programmes. However, additional research is needed in order to more thoroughly evaluate their impact on PMTCT, as well as on broader family health outcomes

A Three Monoclonal Antibody Combination Potently Neutralizes Multiple Botulinum Neurotoxin Serotype E Subtypes.

Human botulism is most commonly caused by botulinum neurotoxin (BoNT) serotypes A, B, and E. For this work, we sought to develop a human monoclonal antibody (mAb)-based antitoxin capable of binding and neutralizing multiple subtypes of BoNT/E. Libraries of yeast-displayed single chain Fv (scFv) antibodies were created from the heavy and light chain variable region genes of humans immunized with pentavalent-toxoid- and BoNT/E-binding scFv isolated by Fluorescence-Activated Cell Sorting (FACS). A total of 10 scFv were isolated that bound one or more BoNT/E subtypes with nanomolar-level equilibrium dissociation constants (KD). By diversifying the V-regions of the lead mAbs and selecting for cross-reactivity, we generated three scFv that bound all four BoNT/E subtypes tested at three non-overlapping epitopes. The scFvs were converted to IgG that had KD values for the different BoNT/E subtypes ranging from 9.7 nM to 2.28 pM. An equimolar combination of the three mAbs was able to potently neutralize BoNT/E1, BoNT/E3, and BoNT/E4 in a mouse neutralization assay. The mAbs have potential utility as therapeutics and as diagnostics capable of recognizing multiple BoNT/E subtypes. A derivative of the three-antibody combination (NTM-1633) is in pre-clinical development with an investigational new drug (IND) application filing expected in 2018

Universal and specific quantitative detection of botulinum neurotoxin genes

<p>Abstract</p> <p>Background</p> <p><it>Clostridium botulinum</it>, an obligate anaerobic spore-forming bacterium, produces seven antigenic variants of botulinum toxin that are distinguished serologically and termed "serotypes". Botulinum toxin blocks the release of acetylcholine at neuromuscular junctions resulting in flaccid paralysis. The potential lethality of the disease warrants a fast and accurate means of diagnosing suspected instances of food contamination or human intoxication. Currently, the Food and Drug Administration (FDA)-accepted assay to detect and type botulinum neurotoxins (BoNTs) is the mouse protection bioassay. While specific and sensitive, this assay requires the use of laboratory animals, may take up to four days to achieve a diagnosis, and is unsuitable for high-throughput analysis. We report here a two-step PCR assay that identifies all toxin types, that achieves the specificity of the mouse bioassay while surpassing it in equivalent sensitivity, that has capability for high-throughput analysis, and that provides quantitative results within hours. The first step of our assay consists of a conventional PCR that detects the presence of <it>C. botulinum </it>regardless of the neurotoxin type. The second step uses quantitative PCR (qPCR) technology to determine the specific serotype of the neurotoxin.</p> <p>Results</p> <p>We assayed purified <it>C. botulinum </it>DNA and crude toxin preparations, as well as food and stool from healthy individuals spiked with purified BoNT DNA, and one stool sample from a case of infant botulism for the presence of the NTNH gene, which is part of the BoNT gene cluster, and for the presence of serotype-specific BoNT genes. The PCR surpassed the mouse bioassay both in specificity and sensitivity, detecting positive signals in BoNT preparations containing well below the 1 LD₅₀required for detection via the mouse bioassay. These results were type-specific and we were reliably able to quantify as few as 10 genomic copies.</p> <p>Conclusions</p> <p>While other studies have reported conventional or quantitative PCR-based assays for the detection of <it>C. botulinum </it>genes, our procedure's high-throughput capability and its portability allows most laboratories to quickly assess the possible presence of BoNTs either in food processing samples or in suspected cases of botulism. Thus, this assay provides rapid and specific detection of BoNT and toxin complex genes and would enable the targeting of appropriate therapeutics to infected individuals in a timely manner.</p

Conceptualization of Surrogate Decision-making Among Spokespersons for Chronically Ill Patients

IMPORTANCE: The value of advance care planning (ACP) has been the subject of recent debate because of mixed findings. This may be, in part, because trials presume that researchers and patient spokespersons share the same understanding of the role of a surrogate decision-maker. We explored how patient surrogates conceptualized and defined surrogate decision-making vs patient advocacy. Understanding how surrogates perceive their role in decision-making is important to avoid misinterpreting the effectiveness of ACP interventions. OBJECTIVE: To understand how patient spokespersons distinguish surrogate decision-making from patient advocacy. DESIGN, SETTING, AND PARTICIPANTS: This qualitative thematic analysis of a subsample of participants from a randomized clinical trial at a tertiary medical center was conducted from September 27, 2012, to June 30, 2021. Participants (n = 36) were the designated spokespersons of adult patients with severe illness who had made a surrogate decision on behalf of the patient since the last follow-up. Analysis was performed from March 21, 2021, to February 7, 2022. MAIN OUTCOMES AND MEASURES: Semistructured interviews examined how patient spokespersons conceptualize differences between surrogate decision-making and advocacy. RESULTS: The study included 36 patient spokespersons (32 women [88.9%]; mean [SD] age, 62.1 [11.8] years) and found substantial variability in how the spokespersons conceptualized what it means to make a surrogate decision for another. A total of 10 spokespersons (27.8%) did not distinguish surrogate decision-making from advocacy. There were 5 definitions for both surrogate decision-making and advocacy. The 3 most common definitions of surrogate decision-making were (1) acting as the final decision-maker (18 [50.0%]), (2) doing what is best for the patient (8 [22.2%]), and (3) making decisions on behalf of patients so that their wishes are respected (6 [16.7%]). The 3 most common definitions of advocacy were (1) doing what is best for the patient (8 [22.2%]), (2) respecting patients\u27 wishes (6 [16.7%]), and (3) providing support to the patient (6 [16.7%]). The most common pairing of definitions by an individual spokesperson involved defining surrogate decision-making as being the final decision-maker, and defining advocacy as acting in the best interest of the patient (6 [16.7%]). CONCLUSIONS AND RELEVANCE: This qualitative study found that many spokespersons perceive their roles as surrogate decision-makers differently than clinicians and researchers likely do, often conflating surrogacy with advocacy. These findings may help explain why researchers have found that ACP does not consistently improve traditional outcomes. If spokespersons do not distinguish surrogate decision-making from advocacy, then what is being reported by spokespersons and measured by clinicians and researchers may not accurately reflect the true association of ACP with outcomes

A Single Tri-Epitopic Antibody Virtually Recapitulates the Potency of a Combination of Three Monoclonal Antibodies in Neutralization of Botulinum Neurotoxin Serotype A.

The standard of treatment for botulism, equine antitoxin, is a foreign protein with associated safety issues and a short serum half-life which excludes its use as a prophylactic antitoxin and makes it a less-than-optimal therapeutic. Due to these limitations, a recombinant monoclonal antibody (mAb) product is preferable. It has been shown that combining three mAbs that bind non-overlapping epitopes leads to highly potent botulinum neurotoxin (BoNT) neutralization. Recently, a triple human antibody combination for BoNT/A has demonstrated potent toxin neutralization in mouse models with no serious adverse events when tested in a Phase I clinical trial. However, a triple antibody therapeutic poses unique development and manufacturing challenges. Thus, potentially to streamline development of BoNT antitoxins, we sought to achieve the potency of multiple mAb combinations in a single IgG-based molecule that has a long serum half-life. The design, production, and testing of a single tri-epitopic IgG1-based mAb (TeAb) containing the binding sites of each of the three parental BoNT/A mAbs yielded an antibody of nearly equal potency to the combination. The approach taken here could be applied to the design and creation of other multivalent antibodies that could be used for a variety of applications, including toxin elimination

Airborne RF Measurement System and Analysis of Representative Flight RF Environment

Environmental radio frequency (RF) data over a broad band of frequencies were needed to evaluate the airspace around several airports. An RF signal measurement system was designed using a spectrum analyzer connected to an aircraft VHF/UHF navigation antenna installed on a small aircraft. This paper presents an overview of the RF measurement system and provides analysis of a sample of RF signal measurement data over a frequency range of 30 MHz to 1000 MHz