Women with type 2 diabetes are disproportionally affected by macrovascular complications; we here investigated whether this is also the case for microvascular complications and retinal microvascular ...measures.
In a population-based cohort study of individuals aged 40-75 years (n = 3410; 49% women, 29% type 2 diabetes (oversampled by design)), we estimated sex-specific associations, and differences therein, of (pre)diabetes (reference: normal glucose metabolism), and of continuous measures of glycemia with microvascular complications and retinal measures (nephropathy, sensory neuropathy, and retinal arteriolar and venular diameters and dilatation). Sex differences were analyzed using regression models with interaction terms (i.e. sex-by- (pre)diabetes and sex-by-glycemia) and were adjusted for potential confounders.
Men with type 2 diabetes (but not those with prediabetes) compared to men with normal glucose metabolism, (and men with higher levels of glycemia), had significantly higher prevalences of nephropathy (odds ratio: 1.58 95% CI (1.01;2.46)) and sensory neuropathy (odds ratio: 2.46 (1.67;3.63)), larger retinal arteriolar diameters (difference: 4.29 µm (1.22;7.36)) and less retinal arteriolar dilatation (difference: - 0.74% (- 1.22; - 0.25)). In women, these associations were numerically in the same direction, but generally not statistically significant (odds ratios: 1.71 (0.90;3.25) and 1.22 (0.75;1.98); differences: 0.29 µm (- 3.50;4.07) and: - 0.52% (- 1.11;0.08), respectively). Interaction analyses revealed no consistent pattern of sex differences in the associations of either prediabetes or type 2 diabetes or glycemia with microvascular complications or retinal measures. The prevalence of advanced-stage complications was too low for evaluation.
Our findings show that women with type 2 diabetes are not disproportionately affected by early microvascular complications.
Abstract
A new variant of
Streptococcus pyogenes
serotype M1 (designated ‘M1
UK
’) has been reported in the United Kingdom, linked with seasonal scarlet fever surges, marked increase in invasive ...infections, and exhibiting enhanced expression of the superantigen SpeA. The progenitor
S. pyogenes
‘M1
global
’ and M1
UK
clones can be differentiated by 27 SNPs and 4 indels, yet the mechanism for
speA
upregulation is unknown. Here we investigate the previously unappreciated expansion of M1
UK
in Australia, now isolated from the majority of serious infections caused by serotype M1
S. pyogenes
. M1
UK
sub-lineages circulating in Australia also contain a novel toxin repertoire associated with epidemic scarlet fever causing
S. pyogenes
in Asia. A single SNP in the 5’ transcriptional leader sequence of the transfer-messenger RNA gene
ssrA
drives enhanced SpeA superantigen expression as a result of
ssrA
terminator read-through in the M1
UK
lineage. This represents a previously unappreciated mechanism of toxin expression and urges enhanced international surveillance.
A comprehensive understanding of anticancer immune responses is paramount for the optimal application and development of cancer immunotherapies. We unravelled local and systemic immune profiles in ...patients with colorectal cancer (CRC) by high-dimensional analysis to provide an unbiased characterisation of the immune contexture of CRC.
Thirty-six immune cell markers were simultaneously assessed at the single-cell level by mass cytometry in 35 CRC tissues, 26 tumour-associated lymph nodes, 17 colorectal healthy mucosa and 19 peripheral blood samples from 31 patients with CRC. Additionally, functional, transcriptional and spatial analyses of tumour-infiltrating lymphocytes were performed by flow cytometry, single-cell RNA-sequencing and multispectral immunofluorescence.
We discovered that a previously unappreciated innate lymphocyte population (Lin
CD7
CD127
CD56
CD45RO
) was enriched in CRC tissues and displayed cytotoxic activity. This subset demonstrated a tissue-resident (CD103
CD69
) phenotype and was most abundant in immunogenic mismatch repair (MMR)-deficient CRCs. Their presence in tumours was correlated with the infiltration of tumour-resident cytotoxic, helper and γδ T cells with highly similar activated (HLA-DR
CD38
PD-1
) phenotypes. Remarkably, activated γδ T cells were almost exclusively found in MMR-deficient cancers. Non-activated counterparts of tumour-resident cytotoxic and γδ T cells were present in CRC and healthy mucosa tissues, but not in lymph nodes, with the exception of tumour-positive lymph nodes.
This work provides a blueprint for the understanding of the heterogeneous and intricate immune landscape of CRC, including the identification of previously unappreciated immune cell subsets. The concomitant presence of tumour-resident innate and adaptive immune cell populations suggests a multitargeted exploitation of their antitumour properties in a therapeutic setting.
The efficacy of checkpoint blockade immunotherapies in colorectal cancer is currently restricted to a minority of patients diagnosed with mismatch repair-deficient tumors having high mutation burden. ...However, this observation does not exclude the existence of neoantigen-specific T cells in colorectal cancers with low mutation burden and the exploitation of their anti-cancer potential for immunotherapy. Therefore, we investigated whether autologous neoantigen-specific T cell responses could also be observed in patients diagnosed with mismatch repair-proficient colorectal cancers.
Whole-exome and transcriptome sequencing were performed on cancer and normal tissues from seven colorectal cancer patients diagnosed with mismatch repair-proficient tumors to detect putative neoantigens. Corresponding neo-epitopes were synthesized and tested for recognition by in vitro expanded T cells that were isolated from tumor tissues (tumor-infiltrating lymphocytes) and from peripheral mononuclear blood cells stimulated with tumor material.
Neoantigen-specific T cell reactivity was detected to several neo-epitopes in the tumor-infiltrating lymphocytes of three patients while their respective cancers expressed 15, 21, and 30 non-synonymous variants. Cell sorting of tumor-infiltrating lymphocytes based on the co-expression of CD39 and CD103 pinpointed the presence of neoantigen-specific T cells in the CD39
CD103
T cell subset. Strikingly, the tumors containing neoantigen-reactive TIL were classified as consensus molecular subtype 4 (CMS4), which is associated with TGF-β pathway activation and worse clinical outcome.
We have detected neoantigen-targeted reactivity by autologous T cells in mismatch repair-proficient colorectal cancers of the CMS4 subtype. These findings warrant the development of specific immunotherapeutic strategies that selectively boost the activity of neoantigen-specific T cells and target the TGF-β pathway to reinforce T cell reactivity in this patient group.
Background: Severe neurological involvement in systemic lupus erythematosus (NPSLE) is one of the most dreadful complications of the disease. Objective: To identify the best drug, dose, and ...treatment. Patients and methods: The study was a controlled clinical trial at two tertiary care centres of patients with SLE according to the ACR criteria, with incident (no more than 15 days) onset of severe NP manifestations such as seizures, optic neuritis, peripheral or cranial neuropathy, coma, brainstem disease, or transverse myelitis. Induction treatment with 3 g of IV methylprednisolone (MP) followed by either IV monthly cyclophosphamide (Cy) versus IV MP bimonthly every 4 months for 1 year and then IV Cy or IV MP every 3 months for another year. The primary end point was response to treatment: at least 20% improvement from basal conditions on clinical, laboratory, or specific neurological testing variables. Results: Overall, a response rate of 75% was observed. Of the 32 patients studied, 18/19 receiving Cy and 7/13 receiving MP responded to treatment (p<0.03). Conclusions: Cy seems to be more effective than MP in the treatment of acute, severe NPSLE.
Improvements in magnetic resonance imaging (MRI), total mesorectal excision (TME) surgery, and the use of (chemo)radiotherapy (CRT) have improved local control of rectal cancer; however, we have been ...unable to eradicate local recurrence (LR). Even in the face of TME and negative resection margins (R0), a significant proportion of patients with enlarged lateral lymph nodes (LLNs) suffer from lateral LR (LLR). Japanese studies suggest that the addition of an LLN dissection (LLND) could reduce LLR. This multicenter pooled analysis aims to ascertain whether LLNs actually pose a problem and whether LLND results in fewer LLRs.
Data from 1,216 consecutive patients with cT3/T4 rectal cancers up to 8 cm from the anal verge who underwent surgery in a 5-year period were collected. LLND was performed in 142 patients (12%). MRIs were re-evaluated with a standardized protocol to assess LLN features.
On pretreatment MRI, 703 patients (58%) had visible LLN, and 192 (16%) had a short axis of at least 7 mm. One hundred eight patients developed LR (5-year LR rate, 10.0%), of which 59 (54%) were LLRs (5-year LLR rate, 5.5%). After multivariable analyses, LLNs with a short axis of at least 7 mm resulted in a significantly higher risk of LLR (hazard ratio, 2.060; P = .045) compared with LLNs of less than 7 mm. In patients with LLNs at least 7 mm, (C)RT plus TME plus LLND resulted in a 5-year LLR of 5.7%, which was significantly lower than that in patients who underwent (C)RT plus TME (5-year LLR, 19.5%; P = .042).
LLR is still a significant problem after (C)RT plus TME in LLNs with a short axis at least 7 mm on pretreatment MRI. The addition of LLND results in a significantly lower LLR rate.
Optical coherence tomography (OCT) of the retina and around the optic nerve head and corneal confocal microscopy (CCM) are non-invasive and repeatable techniques that can quantify ocular ...neurodegenerative changes in individuals with diabetes. We systematically reviewed studies of ocular neurodegenerative changes in adults with type 1 or type 2 diabetes and noted changes in the retina, the optic nerve head, and the cornea. Of the 30 studies that met our inclusion criteria, 14 used OCT and 16 used CCM to assess ocular neurodegenerative changes. Even in the absence of diabetic retinopathy, several layers in the retina and the mean retinal nerve fibre layer around the optic nerve head were significantly thinner (-5·36 μm 95% CI -7·13 to -3·58) in individuals with type 2 diabetes compared with individuals without diabetes. In individuals with type 1 diabetes without retinopathy none of the intraretinal layer thicknesses were significantly reduced compared with individuals without diabetes. In the absence of diabetic polyneuropathy, individuals with type 2 diabetes had a lower nerve density (nerve branch density: -1·10/mm(2) 95% CI -4·22 to 2·02), nerve fibre density: -5·80/mm(2) -8·06 to -3·54, and nerve fibre length: -4·00 mm/mm(2) -5·93 to -2·07) in the subbasal nerve plexus of the cornea than individuals without diabetes. Individuals with type 1 diabetes without polyneuropathy also had a lower nerve density (nerve branch density: -7·74/mm(2) 95% CI -14·13 to -1·34, nerve fibre density: -2·68/mm(2) -5·56 to 0·20), and nerve fibre length: -2·58 mm/mm(2) -3·94 to -1·21). Ocular neurodegenerative changes are more evident when diabetic retinopathy or polyneuropathy is present. OCT and CCM are potentially useful, in addition to conventional clinical methods, to assess diabetic neurodegenerative changes. Additional research is needed to determine their incremental benefit and to standardise procedures before the application of OCT and CCM in daily practice.
OBJECTIVES: To investigate whether higher circulating levels of C‐reactive protein (CRP), interleukin‐6 (IL‐6), and α1‐antichymotrypsin (ACT) are associated with worse cognitive function and decline ...in old age.
DESIGN: Two independent population‐based cohort studies.
SETTING: The Rotterdam Study (mean follow‐up 4.6 years) and the Leiden 85‐plus Study (maximal follow‐up 5 years).
PARTICIPANTS: Three thousand eight hundred seventy‐four individuals, mean age 72, from the Rotterdam Study, and 491 individuals, all aged 85, from the Leiden 85‐plus Study.
MEASUREMENTS: Both studies assessed global cognition, executive function, and memory. Linear regression analyses were used in the current study to investigate the associations between inflammatory markers and cognitive function and decline.
RESULTS: In the Rotterdam Study, higher levels of CRP and IL‐6 were cross‐sectionally associated with worse global cognition and executive function (P<.05). ACT was not associated with cognitive function. In the Leiden 85‐plus Study, estimates were similar for CRP, although not statistically significant. Higher IL‐6 levels were related to a steeper annual decline in memory function in the longitudinal analysis in the Leiden 85‐plus Study (P<.05). The effect of higher IL‐6 levels on global and memory function decline was stronger in apolipoprotein E (APOE) ɛ4 carriers (P‐interaction=.01) than in those who were not (P‐interaction=.05). In the Rotterdam Study, higher IL‐6 levels were related to a steeper annual decline in global cognition in APOE ɛ4 carriers only.
CONCLUSION: Systemic markers of inflammation are only moderately associated with cognitive function and decline and tend to be stronger in carriers of the APOE ɛ4 allele. Systemic markers of inflammation are not suitable for risk stratification.
Safe and effective coronavirus disease-19 (COVID-19) vaccines are urgently needed to control the ongoing pandemic. While single-dose vaccine regimens would provide multiple advantages, two doses may ...improve the magnitude and durability of immunity and protective efficacy. We assessed one- and two-dose regimens of the Ad26.COV2.S vaccine candidate in adult and aged nonhuman primates (NHPs). A two-dose Ad26.COV2.S regimen induced higher peak binding and neutralizing antibody responses compared with a single dose. In one-dose regimens, neutralizing antibody responses were stable for at least 14 wk, providing an early indication of durability. Ad26.COV2.S induced humoral immunity and T helper cell (Th cell) 1-skewed cellular responses in aged NHPs that were comparable to those in adult animals. Aged Ad26.COV2.S-vaccinated animals challenged 3 mo after dose 1 with a SARS-CoV-2 spike G614 variant showed near complete lower and substantial upper respiratory tract protection for both regimens. Neutralization of variants of concern by NHP sera was reduced for B.1.351 lineages while maintained for the B.1.1.7 lineage independent of Ad26.COV2.S vaccine regimen.
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