Purpose of the Review

Herein, we report on the proceedings of the workshop entitled “Post-Genome analysis for musculoskeletal biology” that was held in July of 2022 in Safed, Galilee, Israel. Supported by the Israel Science Foundation, the goal of this workshop was to bring together established investigators and their trainees who were interested in understanding the etiology of musculoskeletal disease, from Israel and from around the world.

Recent Findings

Presentations at this workshop spanned the spectrum from basic science to clinical studies. A major emphasis of the discussion centered on genetic studies in humans, and the limitations and advantages of such studies. The power of coupling studies using human data with functional follow-up studies in pre-clinical models such as mice, rats, and zebrafish was discussed in depth. The advantages and limitations of mice and zebrafish for faithfully modelling aspects of human disease were debated, specifically in the context of age-related diseases such as osteoporosis, osteoarthritis, adult-onset auto-immune disease, and osteosarcopenia.

Summary

There remain significant gaps in our understanding of the nature and etiology of human musculoskeletal disease. While therapies and medications exist, much work is still needed to find safe and effective interventions for all patients suffering from diseases associated with age-related deterioration of musculoskeletal tissues. The potential of forward and reverse genetic studies has not been exhausted for diseases of muscles, joints, and bones.

Does our mood change as time passes? This question is central to behavioural and affective science, yet it remains largely unexamined. To investigate, we intermixed subjective momentary mood ratings into repetitive psychology paradigms. Here we demonstrate that task and rest periods lowered participants’ mood, an effect we call ‘Mood Drift Over Time’. This finding was replicated in 19 cohorts totalling 28,482 adult and adolescent participants. The drift was relatively large (−13.8% after 7.3 min of rest, Cohen’s d = 0.574) and was consistent across cohorts. Behaviour was also impacted: participants were less likely to gamble in a task that followed a rest period. Importantly, the drift slope was inversely related to reward sensitivity. We show that accounting for time using a linear term significantly improves the fit of a computational model of mood. Our work provides conceptual and methodological reasons for researchers to account for time’s effects when studying mood and behaviour.

Background: The treatment of latent tuberculosis infection (LTBI) among high-risk populations is an essential component of Tuberculosis (TB) elimination. However, non-compliance with LTBI treatment remains a major obstacle hindering TB elimination efforts. We have previously reported high treatment compliance with nurse-managed, twice-weekly, directly observed Isoniazid treatment (DOT) for LTBI among hard-to-reach Ethiopian immigrants (EI’s). Objectives: to compare rate of completion of treatment, cost, and major adverse drug events with daily self-administered Isoniazid treatment (SAT) to nurse-managed Isoniazid DOT among hard-to-reach EIs. Materials and Methods: We conducted a retrospective study and compared self-administered LTBI treatment outcomes among EIs housed in reception centers during 2008–2012 to EIs treated with DOT. Results: Overall, 455 EIs were included (231 DOT, 224 SAT) in the study. We found no significant difference in treatment completion rates between the two groups (93.0% DOT vs. 87.9% SAT, p = 0.08). However, cases of grade III, drug-induced hepatitis were significantly fewer and treatment costs were significantly lower with the nurse–managed DOT compared with SAT (0% vs. 2.2%, p = 0.028, 363 vs. 521 United States Dollars, p < 0.001, respectively). Conclusions: Nurse-managed, twice-weekly DOT among hard-to-reach EIs housed in reception centers had less severe drug-related adverse events and reduced treatment cost compared with daily isoniazid SAT, yet we found no significant difference in treatment completion between the two strategies in this population.

Background Exposure to natural environments has beneficial effects on health and mental well-being. Less is known about the effects of exposure to green walls (GW) and the effects on state positive body image (SPBI). Our aim was to examine the effect of short visit to GW compared to gray walls on SPBI and to examine possible mediation pathways through feelings. Methods We recruited 200 healthy adult participants and conducted a quasi-experimental study using a within-subjects design. Mixed-effects linear regression models were used to examine the effect of exposure to GW (a vertical vegetated environment) compared to gray walls, and small garden (a horizontal vegetation) on the outcome (SPBI), and mediators (positive and negative feelings). We conducted a mediation analysis and calculated the proportion of the effect that could be explained by the mediators. Results Exposure to GW compared to gray walls significantly increased the mean of SPBI by 0.17 (95% CI: 0.09, 0.25) and no significant differences were observed between exposure to GW and exposure to small garden (0.07, 95% CI: -0.02, 0.15). Exposure to GW compared to gray walls significantly increased positive feelings by 2.21 (95%CI: 1.35, 3.07) but not negative feelings (-0.47, 95%CI: -0.99, 0.06). Mediation analysis revealed that the effect of positive feelings explained 45% (95% CI: 24%, 90%) of the effect of exposure to the GW on SPBI. The mediation by negative feelings was not significant. Conclusions This study is an important step in understanding the effect of exposure to nature on SPBI and the health benefits from GW. The mediation effect that we found by positive feelings was not investigated previously and further studies should examine other pathways. Understanding these connections is the first step in developing an environmental intervention program in public health and the mental well-being field.

Breakthrough bleeding is a side effect of progesterone-only pills (POPs) in 40% of women, and is reduced to 10% with combined hormonal contraceptives (CHCs). In addition, breakthrough bleeding is reduced if POP is supplemented with norethisterone. As breakthrough bleeding is responsible for a quarter of women stopping the pill, it is vital to realize that CHC is an alternative to POP—even during lactation. CHCs are considered safe during lactation, do not reduce milk production, nor impede infant development. Nevertheless, CHCs are often not prescribed for lactating mothers due to this misconception that they reduce milk production. Among Orthodox Jews, breakthrough bleeding frequently results in stopping POP, as Jewish religious law prohibits any physical contact of the mother with her partner during active bleeding, and for 7 days after bleeding. When such bleeding occurs, not choosing a CHC alternative, results in couples risking discontinuation of POP, and in conceiving within a year of the previous birth, with its increased risk of preterm labor and birth defects. To measure how physicians respond to the presumed dilemma of balancing the risk of breakthrough bleeding versus the concern of reduction of milk production, we conducted a preliminary online survey. Physicians were asked if they would prescribe CHC instead of POP to breastfeeding mothers, 3 months postpartum with breakthrough bleeding. Half of the physicians responded they would prescribe CHC, whereas close to half of the physicians responded that they would not. The main reasons given by the respondents for avoiding CHC was a concern regarding possible milk reduction. These results confirm a significant degree of a lack of updated pharmacological information regarding the options of oral contraceptive use for lactating mothers, particularly for those where breakthrough bleeding has major behavioral and religious consequences. Thus, we contend that the risk of breakthrough bleeding justifies the more routine use of CHC in lieu of POP in lactating mothers.

Lactobacillaceae are Gram-positive, and lactic acid-positive (LAB) bacteria frequently serve as probiotics. We first systematically compared five LAB strains for the effects of different carbohydrates on their free-living and biofilm lifestyles. We found that fermentable sugars triggered an altered carrying capacity with strain specificity during planktonic growth, calling for adding a buffering system during the formulation of probiotics. In addition, heterogeneous response to fermentable sugars was manifested in microbial aggregation (measured by image-stream flow cytometry), colony development, and attachment to mucin. Of all probiotic strains, L. rhamnosus GG (LGG), a prevalent probiotic specie, manifested an enhanced survival of self-imposed acid stress, consistent with enhanced cell wall modulation observed by transmitting electron microscopy and proteomic analysis. A comprehensive proteomic and metabolomic study revealed that the formation of biofilms and aggregation capacity is a specific response to glucose and independent of self-imposed acid stress. In contrast, the increased competitiveness and aggression of LGG and other LAB strains towards enteric pathogens were a synergistic outcome of a change in organic acid production, glucose-dependent bacteriocin production, and fermentation-specific volatile production. Our improved resolution into the cellular circuits (metabolome, proteome, and volatilome) of probiotic strains and their interactions can lead to developing novel therapeutic approaches to combat GI tract infections.

The ongoing COVID-19 pandemic caused by SARS-CoV-2 infections has quickly developed into a global public health threat. COVID-19 patients show distinct clinical features, and in some cases, during the severe stage of the condition, the disease severity leads to an acute respiratory disorder. In spite of several pieces of research in this area, the molecular mechanisms behind the development of disease severity are still not clearly understood. Recent studies demonstrated that SARS-CoV-2 alters the host cell splicing and transcriptional response to overcome the host immune response that provides the virus with favorable conditions to replicate efficiently within the host cells. In several disease conditions, aberrant splicing could lead to the development of novel chimeric transcripts that could promote the functional alternations of the cell. As severe SARS-CoV-2 infection was reported to cause abnormal splicing in the infected cells, we could expect the generation and expression of novel chimeric transcripts. However, no study so far has attempted to check whether novel chimeric transcripts are expressed in severe SARS-CoV-2 infections. In this study, we analyzed several publicly available blood transcriptome datasets of severe COVID-19, mild COVID-19, other severe respiratory viral infected patients, and healthy individuals. We identified 424 severe COVID-19 -specific chimeric transcripts, 42 of which were recurrent. Further, we detected 189 chimeric transcripts common to severe COVID-19 and multiple severe respiratory viral infections. Pathway and gene enrichment analysis of the parental genes of these two subsets of chimeric transcripts reveals that these are potentially involved in immune-related processes, interferon signaling, and inflammatory responses, which signify their potential association with immune dysfunction leading to the development of disease severity. Our study provides the first detailed expression landscape of chimeric transcripts in severe COVID-19 and other severe respiratory viral infections.

The gut microbiota refers to an entire population of microorganisms that colonize the gut. This community includes viruses, prokaryotes (bacteria and archaea), and eukaryotes (fungi and parasites). Multiple studies in the last decades described the significant involvement of gut bacteria in gut-brain axis communication; however, the involvement of other members of the gut microbiota has been neglected. Recent studies found that these ‘forgotten’ members of the gut microbiota may also have a role in gut-brain communication, although it is still unclear whether they have a direct effect on the brain or if their effects are mediated by gut bacteria. Here, we provide concrete suggestions for future research to tease out mechanisms of the microbiota-gut-brain axis.

Colonic goblet cells are specialized epithelial cells that secrete mucus to physically separate the host and its microbiota, thus preventing bacterial invasion and inflammation. How goblet cells control the amount of mucus they secrete is unclear. We found that constitutive activation of autophagy in mice via Beclin 1 enables the production of a thicker and less penetrable mucus layer by reducing endoplasmic reticulum (ER) stress. Accordingly, genetically inhibiting Beclin 1-induced autophagy impairs mucus secretion, while pharmacologically alleviating ER stress results in excessive mucus production. This ER-stress-mediated regulation of mucus secretion is microbiota dependent and requires the Crohn's-disease-risk gene Nod2. Overproduction of mucus alters the gut microbiome, specifically expanding mucus-utilizing bacteria, such as Akkermansia muciniphila, and protects against chemical and microbial-driven intestinal inflammation. Thus, ER stress is a cell-intrinsic switch that limits mucus secretion, whereas autophagy maintains intestinal homeostasis by relieving ER stress.

Background

In England routine vaccinations are recorded in either the patients General Practice record or in series of sub-national vaccine registers that are not interoperable. During the COVID-19 pandemic it was established that COVID vaccines would need to be delivered in multiple settings where current vaccine registers do not exist. We describe how a national vaccine register was created to collect data on COVID-19 vaccines.

Methods

The National Immunisation Management System (NIMS) was developed by a range of health and digital government agencies. Vaccinations delivered are entered on an application which is verified by individual National Health Service number in a centralised system. UKHSA receive a feed of this data to use for monitoring vaccine coverage, effectiveness, and safety.

To validate the vaccination data, we compared vaccine records to self-reported vaccination dose, manufacturer, and vaccination date from the enhanced surveillance system from 11 February 2021 to 24 August 2021.

Results

With the Implementation of NIMS, we have been able to successfully record COVID-19 vaccinations delivered in multiple settings.

Of 1,129 individuals, 97.8% were recorded in NIMS as unvaccinated compared to those who self-reported as unvaccinated. One hundred percent and 99.3% of individuals recorded in NIMS as having at least one dose and two doses of the COVID-19 vaccine were also self-reported as having at least one and two doses, respectively. Of the 100% reporting at least one dose, 98.3% self-reported the same vaccination date as NIMS. A total of 98.8% and 99.3% had the same manufacturer information for their first dose and second dose as that which was self-reported, respectively.

Discussion

Daily access to individual-level vaccine data from NIMS has allowed UKHSA to estimate vaccine coverage and provide some of the world’s first vaccine effectiveness estimates rapidly and accurately.