Sensory impairments and the risk of cognitive decline and dementia across sex, age, and regions: Longitudinal insights from Europe.

BACKGROUND: In aging populations, understanding predictors of cognitive decline is essential. We aimed to investigate the risk of cognitive decline and dementia by sensory impairments across sex, age, and European regions, and examined the mediating role of activities of daily living (ADL), physical activity, and depressive symptoms. METHODS: A cohort study of 72,287 Europeans aged 50+ participating in at least two waves of the Survey of Health, Ageing and Retirement in Europe. We employed mixed-effects and time-to-event models, incorporating sex interactions, and adjusting for socio-demographic factors and medical history. RESULTS: Compared to individuals with good vision and hearing, lower cognitive function was found for people with vision impairment (VI) (males: coef. -0.70, 95 % CI -0.95; -0.46; females: coef. -1.12, 95 % CI -1.33; -0.92), hearing impairment (HI) (males: coef. -0.64, 95 % CI -0.93; -0.35; females: coef. -0.96, 95 % CI -1.27; -0.65) and dual sensory impairment (DSI, i.e. VI and HI) (males: coef. -1.81, 95 % CI -2.16; -1.46; females: coef. -2.71, 95 % CI -3.05; -2.38), particularly among females. Moreover, higher dementia risk was observed among participants with VI (hazard ratio (HR) 1.29, 95 % CI 1.17; 1.43), HI (HR 1.18, 95 % CI 1.05; 1.34), and DSI (HR 1.62, 95 % CI 1.45; 1.81) with no sex-interactions. Findings were overall consistent across age and European regions. CONCLUSION: The results suggest the necessity of preventing sensory impairments to maintain good cognitive function. Mitigating depressive symptoms, ADL limitations, and physical inactivity could potentially reduce a significant portion of the total effect of sensory impairments on cognitive decline.

Predictors and long-term patterns of medication adherence to glaucoma treatment in Denmark-an observational registry study of 30 100 Danish patients with glaucoma.

BACKGROUND: Self-treatment with glaucoma medication (eye drops) has been associated with adherence challenges. Poor adherence results in worse outcomes in terms of visual field loss. OBJECTIVE: To investigate patterns in medication adherence among Danish patients with glaucoma in relation to selected predictors of adherence, long-term adherence patterns, and long-term societal economic consequences of poor adherence. METHODS AND ANALYSIS: This register-based study included 30 100 glaucoma patients followed for 10 years between 2000 and 2018. Glaucoma was identified from the Danish national registers by diagnosis of Open Angle Glaucoma and/or by redeemed prescriptions of glaucoma medication. Logistic regression models were applied to estimate patient characteristics related to medical adherence. Diagnosis-related group fees were applied to estimate healthcare costs. RESULTS: High adherence in the first year(s) of treatment was less likely among men (ORfirst year: 0.78, 95% CI: 0.75 to 0.82), younger individuals and among those with a positive Charlson Comorbidity Index (CCI) score (ORfirst year/CCI≥3: 0.71, 95% CI: 0.63 to 0.80). Adherence in the first year and in the first two years was associated with adherence in the fifth (ORfirst year: 4.55, 95% CI: 4.30 to 4.82/ORfirst two years: 6.47, 95% CI: 6.10 to 6.86) as with adherence in the 10th year with slightly lower estimates. Being medical adherent was related to higher costs related to glaucoma medication after 5 and 10 years comparing with poor adherence, whereas poor adherence was associated with a marked increase in long-term costs for hospital contacts. CONCLUSION: Increasing age, female sex and low comorbidity score are correlated with better adherence to glaucoma treatment. Adherence in the first years of treatment may be a good predictor for future adherence. In the long term, patients with poor adherence are overall more expensive to society in terms of hospital contacts.

First documented movement of a humpback whale between the Cape Verde Islands and West Greenland.

The endangered population of humpback whales (Megaptera novaeangliae) breeding and calving off the Cape Verde Islands (CVI) are known to migrate to feeding areas located along the eastern margin of the North Atlantic Ocean (Iceland, and Norway). Here, we report for the first time a confirmed migration of an individual humpback whale from CVI breeding ground to a western North Atlantic feeding ground of West Greenland. This individual humpback, which was photographed and identified off the coast of West Greenland in 2021, was previously documented in CVI 22 years before (1999). An annual subsistence hunt for humpbacks occurs in West Greenland and the resighting at this location with a humpback whale from CVI has strong implications for the conservation efforts of the small CVI population.

Sustained effects on immune cell subsets and autoreactivity in multiple sclerosis patients treated with oral cladribine.

Introduction: Cladribine tablet therapy is an efficacious treatment for multiple sclerosis (MS). Recently, we showed that one year after the initiation of cladribine treatment, T and B cell crosstalk was impaired, reducing potentially pathogenic effector functions along with a specific reduction of autoreactivity to RAS guanyl releasing protein 2 (RASGRP2). In the present study we conducted a longitudinal analysis of the effect of cladribine treatment in patients with RRMS, focusing on the extent to which the effects observed on T and B cell subsets and autoreactivity after one year of treatment are maintained, modulated, or amplified during the second year of treatment. Methods: In this case-control exploratory study, frequencies and absolute counts of peripheral T and B cell subsets and B cell cytokine production from untreated patients with relapsing-remitting MS (RRMS) and patients treated with cladribine for 52 (W52), 60 (W60), 72 (W72) and 96 (W96) weeks, were measured using flow cytometry. Autoreactivity was assessed using a FluoroSpot assay. Results: We found a substantial reduction in circulating memory B cells and proinflammatory B cell responses. Furthermore, we observed reduced T cell responses to autoantigens possibly presented by B cells (RASGRP2 and a-B crystallin (CRYAB)) at W52 and W96 and a further reduction in responses to the myelin antigens myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG) after 96 weeks. Conclusion: We conclude that the effects of cladribine observed after year one are maintained and, for some effects, even increased two years after the initiation of a full course of treatment with cladribine tablets.

CD11c+ B cells in relapsing-remitting multiple sclerosis and effects of anti-CD20 therapy.

OBJECTIVES: B cells are important in the pathogenesis of multiple sclerosis. It is yet unknown which subsets may be involved, but atypical B cells have been proposed as mediators of autoimmunity. In this study, we investigated differences in B-cell subsets between controls and patients with untreated and anti-CD20-treated multiple sclerosis. METHODS: We recruited 155 participants for an exploratory cohort comprising peripheral blood and cerebrospinal fluid, and a validation cohort comprising peripheral blood. Flow cytometry was used to characterize B-cell phenotypes and effector functions of CD11c+ atypical B cells. RESULTS: There were no differences in circulating B cells between controls and untreated multiple sclerosis. As expected, anti-CD20-treated patients had a markedly lower B-cell count. Of B cells remaining after treatment, we observed higher proportions of CD11c+ B cells and plasmablasts. CD11c+ B cells were expanded in cerebrospinal fluid compared to peripheral blood in controls and untreated multiple sclerosis. Surprisingly, the proportion of CD11c+ cerebrospinal fluid B cells was higher in controls and after anti-CD20 therapy than in untreated multiple sclerosis. Apart from the presence of plasmablasts, the cerebrospinal fluid B-cell composition after anti-CD20 therapy resembled that of controls. CD11c+ B cells demonstrated a high potential for both proinflammatory and regulatory cytokine production. INTERPRETATION: The study demonstrates that CD11c+ B cells and plasmablasts are less efficiently depleted by anti-CD20 therapy, and that CD11c+ B cells comprise a phenotypically and functionally distinct, albeit heterogenous, B-cell subset with the capacity of exerting both proinflammatory and regulatory functions.

Urologic surveillance of persons with spinal cord injuries - a scoping review.

STUDY DESIGN: Scoping review - standardized according to the Equator-network and the Prisma-Statement guidelines with PRISMA-ScR. OBJECTIVES: Review the literature concerning surveillance of the urinary- and renal systems in persons with spinal cord injuries (SCI). Specifically, to assess: #1 the usability of non-invasive and non-ultrasound methods, #2 the usage of systematic ultrasound surveillance #3 patient characteristics which predispose to urinary tract abnormalities (UTA) or renal function deterioration. METHODS: The literature assessed was collected from PubMed by creating a search string comprised of three main phrases: #1 persons with SCI, #2 kidney function and #3 surveillance program. The final search resulted in 685 studies. Eligibility criteria were defined prior to the search to assess the studies systematically. RESULTS: Four studies found serum cystatin C (s-cysC) to be accurate in estimating the glomerular filtration rate in persons with SCI. One study found no difference in UTA between surveillance adherent and surveillance non-adherent persons up to 30 years post injury. UTA and especially renal function deterioration seems rare the first 15 years post-injury. Non-traumatic SCI, time since injury, high detrusor pressure, upper urinary tract dilation, vesicourethral reflux, trabeculated bladder, history of calculi removal are significant risk factors for developing UTA or renal function deterioration. CONCLUSION: Measurements of S-cysC should be considered to replace serum creatinine in most cases. Surveillance non-adherent persons are not at higher risk of developing UTA. A selective surveillance based on a baseline risk profile may be beneficial for patients and caretakers.

Pharmacokinetics and pharmacodynamics of cannabis-based medicine in a patient population included in a randomized, placebo-controlled, clinical trial.

Information on the pharmacokinetics (PK) and pharmacodynamics (PD) of orally administered cannabis-based medicine (CBM) in capsule formulation in patient populations is sparse. In this exploratory study, we aimed to evaluate the PK and PD in a probable steady state of CBM in neuropathic pain and spasticity in a population of patients with multiple sclerosis (MS). Of 134 patients participating in a randomized, double-blinded, placebo-controlled, trial, 23 patients with MS (17 female) mean age 52 years (range 21-67) were enrolled in this substudy. They received oral capsules containing Δ9 -tetrahydrocannabinol (THC, n = 4), cannabidiol (CBD, n = 6), a combination (THC&CBD, n = 4), or placebo (n = 9). Maximum doses were 22.5 mg (THC) and 45 mg (CBD) a day divided into three administrations. PD parameters were evaluated for pain and spasticity. Blood samples were analyzed using an ultra-high-performance liquid chromatography-tandem mass spectrometer after protein precipitation and phospholipid removal. PK parameters were estimated using computerized modeling. The variation in daily dose and PK between individuals was considerable in a steady state, yet comparable with previous reports from healthy controls. Based on a simulation of the best model, the estimated PK parameters (mean) for THC (5 mg) were Cmax 1.21 ng/mL, Tmax 2.68 h, and half-life 2.75 h, and for CBD (10 mg) were Cmax 2.67 ng/mL, Tmax 0.10 h, and half-life 4.95 h, respectively. No effect was found on the PD parameters, but the placebo response was considerable. More immediate adverse events were registered in the active treatment groups compared with the placebo group.

Sex differences in vision and hearing impairments across age and European regions : Findings from SHARE.

AIM: Although sensory impairments are common conditions among older people, research often fails to consider the role of sex. We examined sex differences in vision impairment and hearing impairment across age and European regions. METHODS: We conducted a cross-sectional study based on a pooled sample of 65,656 females and 54,881 males aged 50 years and older participating in the Survey of Health, Ageing and Retirement in Europe (SHARE) from 2004-2020. Logistic regression models with robust standard errors providing odds ratios (OR) and 95% confidence intervals (CI) were used to examine associations. RESULTS: European females had generally higher odds of vision impairment (OR 1.16, 95% CI 1.12-1.21) but lower odds of hearing impairment than European males (OR 0.70, 95% CI 0.67-0.73). The female disadvantage in vision increased with advancing age, whereas the female advantage in hearing decreased. No overall sex difference in vision was found in northern Europe, but females had more vision impairments than males in southern (OR 1.23, 95% CI 1.14-1.32), western (OR 1.14, 95% CI 1.08-1.21) and eastern (OR 1.10, 95% CI 1.02-1.20) Europe. Females were healthier than males in terms of hearing in all regions, with the largest female advantage in northern Europe (OR 0.58, 95% CI 0.53-0.64). CONCLUSION: Our findings demonstrate an overall consistent pattern of sex differences in sensory impairments across Europe showing an increasing female disadvantage in vision and a decreasing female advantage in hearing with advancing age.

Counselling customers at risk of the triple whammy effect at community pharmacies - A feasibility study.

The combination of diuretics, angiotensin-converting enzyme inhibitors (ACE-i)/angiotensin II receptor blockers (ARBs) and non-steroidal anti-inflammatory drugs (NSAID) involves a risk of acute renal failure known as the triple whammy effect (TWE). NSAID can be provided by prescription or over the counter (OTC) and community pharmacies counsel on this medication every day to contribute to medication safety. The objective of this study is to test the feasibility of an intervention where community pharmacies identify and counsel customers at risk of the TWE. Participating pharmacies were recruited across Denmark and the Faroe Islands. In April to May 2021, all staff at 13 community pharmacies chose 10 workdays to collect data in an electronic tool on their risk assessment, the customers' medication, and counselling about the TWE for customers asking for NSAID. Pharmacy staff were instructed in correct data collection and received learning material and a patient information leaflet on the TWE. These data were analysed descriptively. Staff evaluated the learning material and patient information leaflet in a questionnaire. The quantitative answers from the questionnaire were analysed descriptively and the qualitative answers were analysed using content analysis. According to the pharmacies' risk assessment, 12.1% (n = 215) of customers asking for NSAID were at risk of the TWE. The data on customers' medication showed that only 8.0% (n = 142) were actually at risk of TWE. Of those, 43.0% (n = 61) asked for NSAID on prescription and 57.0% (n = 81) for OTC. In the evaluation of materials pharmacy staff reported overall satisfaction with the learning material, which they reported increased their knowledge of TWE and helped them in their counselling. They also reported satisfaction with the patient information leaflet. Despite pharmacy staff reporting satisfaction with the learning material, it still did not educate staff well enough in assessing the risk of TWE for customers asking for NSAID. More research is needed on TWE interventions in community pharmacies because this study shows that there is a potential for community pharmacies to identify and counsel persons at risk of the TWE.

Danish community pharmacies supporting self-care for patients.

In Denmark, self-care has been a part of the health care professional and health political discourse since the middle of the 1970s particularly in relation to prevention. However, the concept has become more visible in connection with the Danish government's public health programme "Healthy throughout life" from 2002 to 2010, where patients' self-care was highlighted as an important element in preventing disease progression and complications. Self-care in Denmark is seen as a partnership between the patient and the health care professional. Some self-care activities in Danish community pharmacies are mentioned in national and municipal guidelines for better prevention and self-care regarding obesity, sexual health, smoking cessation, teaching patients/relatives and vaccination. This paper describes self-care activities and services delivered by Danish community pharmacies gathered from survey results at 33 community pharmacies, oral communication with the Association of Danish Pharmacies and published papers on Danish community pharmacy services. Self-care activities in Danish community pharmacies include counselling (about health, self-care, prescription medication, and OTC medication), health campaigns, collaborations with other health care professionals and patient associations and community pharmacy services, all with the purpose to support correct medication use, medication safety and to contribute to health promotion and prevention. These cover activities on prevention, detection, minor ailments, and chronic disease. Six of ten future community pharmacy contributions to medication safety and prevention in future health care, described by the Association of Danish Pharmacies, are related to community pharmacies' support of patients towards better self-care. In the future, Danish community pharmacies should consider offering self-care activities by expanding existing counselling, community pharmacy services and collaborations. Remuneration also needs to be aligned for the activities to succeed and become an integrated part of prevention packages and national initiatives that support patient self-care.

An evolutionarily distinct ringed seal in the Ilulissat Icefjord.

The Earth's polar regions are low rates of inter- and intraspecific diversification. An extreme mammalian example is the Arctic ringed seal (Pusa hispida hispida), which is assumed to be panmictic across its circumpolar Arctic range. Yet, local Inuit communities in Greenland and Canada recognize several regional variants; a finding supported by scientific studies of body size variation. It is however unclear whether this phenotypic variation reflects plasticity, morphs or distinct ecotypes. Here, we combine genomic, biologging and survey data, to document the existence of a unique ringed seal ecotype in the Ilulissat Icefjord (locally 'Kangia'), Greenland; a UNESCO World Heritage site, which is home to the most productive marine-terminating glacier in the Arctic. Genomic analyses reveal a divergence of Kangia ringed seals from other Arctic ringed seals about 240 kya, followed by secondary contact since the Last Glacial Maximum. Despite ongoing gene flow, multiple genomic regions appear under strong selection in Kangia ringed seals, including candidate genes associated with pelage coloration, growth and osmoregulation, potentially explaining the Kangia seal's phenotypic and behavioural uniqueness. The description of 'hidden' diversity and adaptations in yet another Arctic species merits a reassessment of the evolutionary processes that have shaped Arctic diversity and the traditional view of this region as an evolutionary freezer. Our study highlights the value of indigenous knowledge in guiding science and calls for efforts to identify distinct populations or ecotypes to understand how these might respond differently to environmental change.

Immune reconstitution following alemtuzumab therapy is characterized by exhausted T cells, increased regulatory control of proinflammatory T cells and reduced B cell control.

Alemtuzumab is a monoclonal antibody targeting CD52 on the surface of immune cells, approved for the treatment of active relapsing-remitting multiple sclerosis (RRMS). The purpose of this study was to analyze the repopulation of peripheral lymphocytes following alemtuzumab-induced lymphocyte depletion and investigate associations with disease activity and development of secondary autoimmunity. For this, blood samples were collected two years after initiation of alemtuzumab treatment and lymphocytes were subjected to a comprehensive flow cytometry analysis. Included in the study were 40 patients treated with alemtuzumab and 40 treatment-naïve patients with RRMS. Disease activity and development of secondary autoimmune disease was evaluated after three years of treatment. Our study confirms that alemtuzumab treatment profoundly alters the circulating lymphocyte phenotype and describes a reconstituted immune system characterized by T cell activation/exhaustion, an increased regulatory control of IL-17 producing effector T cells and CD20+ T cells, and a reduced control of B cells. There were no obvious associations between immune cell subsets and disease activity or development of secondary autoimmune disease during treatment with alemtuzumab. Our results indicate that the reconstituted immune response is skewed towards a more effective regulatory control of MS-associated proinflammatory T cell responses. Also, the enlarged pool of naïve B cells together with the apparent decrease in control of B cell activity may explain why alemtuzumab-treated patients retain the ability to mount a humoral immune response towards new antigens.

Dose-Response of Myofibrillar Protein Synthesis To Ingested Whey Protein During Energy Restriction in Overweight Postmenopausal Women: A Randomized, Controlled Trial.

BACKGROUND: Diet-induced weight loss is associated with a decline in lean body mass, as mediated by an impaired response of muscle protein synthesis (MPS). The dose-response of MPS to ingested protein, with or without resistance exercise, is well characterized during energy balance but limited data exist under conditions of energy restriction in clinical populations. OBJECTIVE: To determine the dose-response of MPS to ingested whey protein following short-term diet-induced energy restriction in overweight, postmenopausal, women at rest and postexercise. DESIGN: Forty middle-aged (58.6±0.4 y), overweight (BMI: 28.6±0.4), postmenopausal women were randomly assigned to 1 of 4 groups: Three groups underwent 5 d of energy restriction (∼800 kcal/d). On day 6, participants performed a unilateral leg resistance exercise bout before ingesting either a bolus of 15g (ERW15, n = 10), 35g (ERW35, n = 10) or 60g (ERW60, n = 10) of whey protein. The fourth group (n = 10) ingested a 35g whey protein bolus after 5 d of an energy balanced diet (EBW35, n = 10). Myofibrillar fractional synthetic rate (FSR) was calculated under basal, fed (FED) and postexercise (FED-EX) conditions by combining an L-[ring-13C6] phenylalanine tracer infusion with the collection of bilateral muscle biopsies. RESULTS: Myofibrillar FSR was greater in ERW35 (0.043±0.003%/h, P = 0.013) and ERW60 (0.042±0.003%/h, P = 0.026) than ERW15 (0.032 ± 0.003%/h), with no differences between ERW35 and ERW60 (P = 1.000). Myofibrillar FSR was greater in FED (0.044 ± 0.003%/h, P < 0.001) and FED-EX (0.048 ± 0.003%/h, P < 0.001) than BASAL (0.027 ± 0.003%/h), but no differences were detected between FED and FED-EX (P = 0.732) conditions. No differences in myofibrillar FSR were observed between EBW35 (0.042 ± 0.003%/h) and ERW35 (0.043 ± 0.003%/h, P = 0.744). CONCLUSION: A 35 g dose of whey protein, ingested with or without resistance exercise, is sufficient to stimulate a maximal acute response of MPS following short-term energy restriction in overweight, postmenopausal women, and thus may provide a per serving protein recommendation to mitigate muscle loss during a weight loss program. TRIAL REGISTRY: clinicaltrials.gov (ID: NCT03326284).

Cannabis-Based Medicine for Neuropathic Pain and Spasticity-A Multicenter, Randomized, Double-Blinded, Placebo-Controlled Trial.

Patients with multiple sclerosis (MS) and spinal cord injury (SCI) commonly sustain central neuropathic pain (NP) and spasticity. Despite a lack of consistent evidence, cannabis-based medicine (CBM) has been suggested as a supplement treatment. We aimed to investigate the effect of CBM on NP and spasticity in patients with MS or SCI. We performed a randomized, double-blinded, placebo-controlled trial in Denmark. Patients aged ≥18 years with NP (intensity >3, ≤9 on a numerical rating scale (NRS0-10) and/or spasticity (>3 on NRS0-10) were randomized to treatment consisting of either delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD), a combination of THC&CBD in maximum doses of 22.5 mg, 45 mg and 22.5/45 mg per day, respectively, or placebo. A baseline registration was performed before randomization. Treatment duration was six weeks followed by a one-week phaseout. Primary endpoints were the intensity of patient-reported NP and/or spasticity. Between February 2019 and December 2021, 134 patients were randomized (MS n = 119, SCI n = 15), where 32 were assigned to THC, 31 to CBD, 31 to THC&CBD, and 40 to placebo. No significant difference was found for: mean pain intensity (THC 0.42 (-0.54-1.38), CBD 0.45 (-0.47-1.38) and THC&CBD 0.16 (-0.75-1.08)), mean spasticity intensity (THC 0.24 (-0.67-1.45), CBD 0.46 (-0.74-1.65), and THC&CBD 0.10 (-1.18-1.39), secondary outcomes (patient global impression of change and quality of life), or any tertiary outcomes. We aimed to include 448 patients in the trial; however, due to COVID-19 and recruitment challenges, fewer were included. Nevertheless, in this four-arm parallel trial, no effect was found between placebo and active treatment with THC or CBD alone or in combination on NP or spasticity in patients with either MS or SCI. The trial was registered with the EU Clinical Trials Register EudraCT (2018-002315-98).

Stuck in a corner: Anthropogenic noise threatens narwhals in their once pristine Arctic habitat.

Niche-conservative species are especially susceptible to changes in their environment, and detecting the negative effects of new stressors in their habitats is vital for safeguarding of these species. In the Arctic, human disturbance including marine traffic and exploration of resources is increasing rapidly due to climate change-induced reduction of sea ice. Here, we show that the narwhal, Monodon monoceros, is extremely sensitive to human-made noise. Narwhals avoided deep diving (> 350 m) with simultaneous reduction of foraging and increased shallow diving activity as a response to either ship sound alone or ship sound with concurrent seismic airgun pulses. Normal behavior decreased by 50 to 75% at distances where received sound levels were below background noise. Narwhals were equally responsive to both disturbance types, hence demonstrating their acute sensitivity to ship sound. This sensitivity coupled with their special behavioral-ecological strategy including a narrow ecological niche and high site fidelity makes them thus especially vulnerable to human impacts in the Arctic.

Intrathecal CD8+CD20+ T Cells in Primary Progressive Multiple Sclerosis.

BACKGROUND AND OBJECTIVE: Despite accumulating evidence of intrathecal inflammation in patients with primary progressive multiple sclerosis (PPMS), immunomodulatory and suppressive treatment strategies have proven unsuccessful. With this study, we investigated the involvement of CD20+ T cells and the effect of dimethyl fumarate on CD20+ T cells in PPMS. METHODS: The main outcomes in this observational, case-control study were flow cytometry assessments of blood and CSF CD20+ T cells and ELISA measurements of myelin basic protein and neurofilament light chain in untreated patients with PPMS and patients treated for 48 weeks with dimethyl fumarate or placebo. MRI measures included new and enlarging T2-weighted lesions over 48 weeks and lesion, normal-appearing white matter, cortical, and thalamic volume. RESULTS: Assessing CD20+ T cells in patients with PPMS and controls showed an increased percentage of CD20+ T cells in the blood of untreated patients and a strong enrichment in the CSF. In addition, a higher frequency of CD8+CD20+ T cells in the CSF correlated with a higher concentration of myelin basic protein and T2-weighted lesion volume and with a lower normal-appearing white matter and thalamus volume. Furthermore, CD8+CD20+ T cells were associated with the development of new T2 lesions. After 48 weeks of treatment with dimethyl fumarate, total T cells in CSF were reduced; however, CD20+ T cells were unaffected. DISCUSSION: This study shows an association between intrathecal CD8+CD20+ T cells, white matter injury, and thalamic atrophy in PPMS, suggesting a role of CD8+CD20+ T cells in the immunopathogenesis of PPMS. The results also suggest that limited efficacy of dimethyl fumarate in PPMS may, at least partly, be a consequence of failure to suppress CD8+CD20+ T cells in CSF.

Cladribine Effects on T and B Cells and T Cell Reactivity in Multiple Sclerosis.

OBJECTIVE: Cladribine tablet therapy is an efficacious treatment for multiple sclerosis (MS), however, its mechanism of action on T and B cell subsets remains unclear. The purpose of this study was to investigate the treatment effects of cladribine on the peripheral pool of T and B cells subsets and reactivity toward central nervous system (CNS) antigens. METHODS: In this cross-sectional exploratory study, frequencies and absolute counts of peripheral T and B cell subsets and B cell cytokine production from untreated patients with relapsing-remitting MS (RRMS) and patients treated with cladribine for 1 year were measured using flow cytometry. Autoreactivity was assessed using a FluoroSpot assay. RESULTS: We found that 1 year after initiation of cladribine treatment, a lower number of CD4+ T cells was persisting whereas CD19+ B cell counts were normalized compared to untreated patients with RRMS. Follicular helper T cells and their effecter subsets producing cytokines exerting distinct B cell helper activity were lower and, additionally, the peripheral B cell pool was skewed toward a naïve and anti-inflammatory phenotype. Finally, reactivity to the recently identified CNS-enriched autoantigen RAS guanyl-releasing protein 2 (RASGRP2), but not to myelin basic protein and myelin oligodendrocyte glycoprotein, was lower in cladribine-treated patients. INTERPRETATION: Together, these investigations on T and B cell subsets suggest that cladribine treatment impairs the B-T cell crosstalk and reduces their ability to mediate pathogenic effector functions. This may result in specific reduction of autoreactivity to RASGRP2 which is expressed in B cells and brain tissue. ANN NEUROL 2023;94:518-530.

The role of preoperative mechanical bowel preparation and oral antibiotics in prevention of anastomotic leakage following restorative resection for primary rectal cancer - a systematic review and meta-analysis.

PURPOSE: Anastomotic leakage after colorectal cancer resection is a feared postoperative complication seen among up till 10-20% of patients, with a higher risk following rectal resection than colon resection. Recent studies suggest that the combined use of preoperative mechanical bowel preparation and oral antibiotics may have a preventive effect on anastomotic leakage. This systematic review aims to explore the association between preoperative mechanical bowel preparation combined with oral antibiotics and the risk of anastomotic leakage following restorative resection for primary rectal cancer. METHODS: Three databases were systematically searched in February 2022. Studies reporting anastomotic leakage rate in patients, who received mechanical bowel preparation and oral antibiotics before elective restorative resection for primary rectal cancer, were included. A meta-analysis was conducted based on the risk ratios of anastomotic leakage. RESULTS: Among 839 studies, 5 studies met the eligibility criteria. The median number of patients were 6111 (80-29,739). The combination of preoperative mechanical bowel preparation and oral antibiotics was associated with a decreased risk of anastomotic leakage (risk ratio = 0.52 (95% confidence interval 0.39-0.69), p-value < 0.001). Limitations included a low number of studies, small sample sizes and the studies being rather heterogenous. CONCLUSION: This systematic review and meta-analysis found that the use of mechanical bowel preparation and oral antibiotics is associated with a decreased risk of anastomotic leakage among patients undergoing restorative resection for primary rectal cancer. The limitations of the review should be taken into consideration when interpreting the results.

Insertion of Chemical Handles into the Backbone of DNA during Solid-Phase Synthesis by Oxidative Coupling of Amines to Phosphites.

Conjugation of molecules or proteins to oligonucleotides can improve their functional and therapeutic capacity. However, such modifications are often limited to the 5' and 3' end of oligonucleotides. Herein, we report the development of an inexpensive and simple method that allows for the insertion of chemical handles into the backbone of oligonucleotides. This method is compatible with standardized automated solid-phase oligonucleotide synthesis, and relies on formation of phosphoramidates. A unique phosphoramidite is incorporated into a growing oligonucleotide, and oxidized to the desired phosphoramidate using iodine and an amine of choice. Azides, alkynes, amines, and alkanes have been linked to oligonucleotides via internally positioned phosphoramidates with oxidative coupling yields above 80 %. We show the design of phosphoramidates from secondary amines that specifically hydrolyze to the phosphate only at decreased pH. Finally, we show the synthesis of an antibody-DNA conjugate, where the oligonucleotide can be selectively released in a pH 5.5 buffer.