Human TLR-7-, -8-, and -9-mediated induction of IFN-alpha/beta and -lambda Is IRAK-4 dependent and redundant for protective immunity to viruses

Five TLRs are thought to play an important role in antiviral immunity, sensing viral products and inducing IFN-alpha/beta and -lambda. Surprisingly, patients with a defect of IRAK-4, a critical kinase downstream from TLRs, are resistant to common viruses. We show here that IFN-alpha/beta and -lambda induction via TLR-7, TLR-8, and TLR-9 was abolished in IRAK-4-deficient blood cells. In contrast, IFN-alpha/beta and -lambda were induced normally by TLR-3 and TLR-4 agonists. Moreover, IFN-beta and -lambda were normally induced by TLR-3 agonists and viruses in IRAK-4-deficient fibroblasts. We further show that IFN-alpha/beta and -lambda production in response to 9 of 11 viruses tested was normal or weakly affected in IRAK-4-deficient blood cells. Thus, IRAK-4-deficient patients may control viral infections by TLR-3- and TLR-4-dependent and/or TLR-independent production of IFNs. The TLR-7-, TLR-8-, and TLR-9-dependent induction of IFN-alpha/beta and -lambda is strictly IRAK-4 dependent and paradoxically redundant for protective immunity to most viruses in humans.     

A genetic and clinical study of individuals with nonsyndromic retinopathy consequent upon sequence variants in HGSNAT,the gene associated with Sanfilippo C mucopolysaccharidosis

Pathogenic variants in the gene HGSNAT (heparan‐α‐glucosaminide N‐acetyltransferase) have been reported to underlie two distinct recessive conditions, depending on the specific genotype, mucopolysaccharidosis type IIIC (MPSIIIC)—a severe childhood‐onset lysosomal storage disorder, and adult‐onset nonsyndromic retinitis pigmentosa (RP). Here we describe the largest cohort to‐date of HGSNAT‐associated nonsyndromic RP patients, and describe their retinal phenotype, leukocyte enzymatic activity, and likely pathogenic genotypes. We identified biallelic HGSNAT variants in 17 individuals (15 families) as the likely cause of their RP. None showed any other symptoms of MPSIIIC. All had a mild but significant reduction of HGSNAT enzyme activity in leukocytes. The retinal condition was generally of late‐onset, showing progressive degeneration of a concentric area of paramacular retina, with preservation but reduced electroretinogram responses. Symptoms, electrophysiology, and imaging suggest the rod photoreceptor to be the cell initially compromised. HGSNAT enzymatic testing was useful in resolving diagnostic dilemmas in compatible patients. We identified seven novel sequence variants [p.(Arg239Cys); p.(Ser296Leu); p.(Phe428Cys); p.(Gly248Ala); p.(Gly418Arg), c.1543‐2A>C; c.1708delA], three of which were considered to be retina‐disease‐specific alleles. The most prevalent retina‐disease‐specific allele p.(Ala615Thr) was observed heterozygously or homozygously in 8 and 5 individuals respectively (7 and 4 families). Two siblings in one family, while identical for the HGSNAT locus, but discordant for retinal disease, suggest the influence of trans‐acting genetic or environmental modifying factors.     

Orosensory Perception of Fat/Sweet Stimuli and Appetite-Regulating Peptides before and after Sleeve Gastrectomy or Gastric Bypass in Adult Women with Obesity

The aim of this study was to explore the impact of bariatric surgery on fat and sweet taste perceptions and to determine the possible correlations with gut appetite-regulating peptides and subjective food sensations. Women suffering from severe obesity (BMI > 35 kg/m²) were studied 2 weeks before and 6 months after a vertical sleeve gastrectomy (VSG, n = 32) or a Roux-en-Y gastric bypass (RYGB, n = 12). Linoleic acid (LA) and sucrose perception thresholds were determined using the three-alternative forced-choice procedure, gut hormones were assayed before and after a test meal and subjective changes in oral food sensations were self-reported using a standardized questionnaire. Despite a global positive effect of both surgeries on the reported gustatory sensations, a change in the taste sensitivity was only found after RYGB for LA. However, the fat and sweet taste perceptions were not homogenous between patients who underwent the same surgery procedure, suggesting the existence of two subgroups: patients with and without taste improvement. These gustatory changes were not correlated to the surgery-mediated modifications of the main gut appetite-regulating hormones. Collectively these data highlight the complexity of relationships between bariatric surgery and taste sensitivity and suggest that VSG and RYGB might impact the fatty taste perception differently.     

Severe Acute Respiratory Syndrome Coronavirus 2 Seropositivity among Healthcare Personnel in Hospitals and Nursing Homes,Rhode Island,USA, July–August 2020

Healthcare personnel are recognized to be at higher risk for infection with severe acute respiratory syndrome coronavirus 2. We conducted a serologic survey in 15 hospitals and 56 nursing homes across Rhode Island, USA, during July 17–August 28, 2020. Overall seropositivity among 9,863 healthcare personnel was 4.6% (95% CI 4.2%–5.0%) but varied 4-fold between hospital personnel (3.1%, 95% CI 2.7%–3.5%) and nursing home personnel (13.1%, 95% CI 11.5%–14.9%). Within nursing homes, prevalence was highest among personnel working in coronavirus disease units (24.1%; 95% CI 20.6%–27.8%). Adjusted analysis showed that in hospitals, nurses and receptionists/medical assistants had a higher likelihood of seropositivity than physicians. In nursing homes, nursing assistants and social workers/case managers had higher likelihoods of seropositivity than occupational/physical/speech therapists. Nursing home personnel in all occupations had elevated seropositivity compared with hospital counterparts. Additional mitigation strategies are needed to protect nursing home personnel from infection, regardless of occupation.     

Presentation and Outcomes of Antibody-Mediated Rejection Associated With Angiotensin II Receptor 1 Antibodies Among Kidney Transplant Recipients

BackgroundIt remains challenging to manage antibody-mediated rejection (ABMR) associated with angiotensin II type 1 receptor antibodies (AT1R-Abs) in kidney transplant recipients and the outcomes are not well defined. We describe the presentation, clinical course, and outcomes of this condition.MethodsThis retrospective study included kidney transplant recipients with AT1R-Ab levels ≥10 units/mL and biopsy-proven ABMR in the absence of significant HLA-donor-specific antibodies at the time of rejection.ResultsWe identified 13 recipients. Median creatinine (Cr) at rejection was significantly higher (2.05 mg/dL) compared with baseline (1.2 mg/dL), P = .006. After ABMR management, the difference in median Cr was not significant (1.5 mg/dL), P = .152. Median AT1R-Ab level was higher in the pretransplant sample (34.5 units/mL) compared with the level at rejection (19 units/mL) and after rejection treatment (13 units/mL); however, these differences were not significant, P = .129. Eight of the 13 recipients received antibody reduction therapy with plasmapheresis and intravenous immunoglobulin, and 5 of the 13 recipients had other therapies. After rejection management, 6 of the 13 recipients had improvement in Cr to baseline and 7 of the 13 recipients had > 50% reduction in proteinuria.ConclusionsAT1R-Ab–associated ABMR management and outcomes depend on the clinical presentation and may include antibody-reducing therapies among other therapies. Further prospective cohorts will improve recognizing and managing this condition.     

Management of lung transplantation in the COVID-19 era—An international survey

It is unknown if solid organ transplant recipients are at higher risk for severe COVID-19. The management of a lung transplantation (LTx) program and the therapeutic strategies to adapt the immunosuppressive regimen and antiviral measures is a major issue in the COVID-19 era, but little is known about worldwide practice. We sent out to 180 LTx centers worldwide in June 2020 a survey with 63 questions, both regarding the management of a LTx program in the COVID-19 era and the therapeutic strategies to treat COVID-19 LTx recipients. We received a total of 78 responses from 15 countries. Among participants, 81% declared a reduction of the activity and 47% restricted LTx for urgent cases only. Sixteen centers observed deaths on waiting listed patients and eight centers performed LTx for COVID-19 disease. In 62% of the centers, COVID-19 was diagnosed in LTx recipients, most of them not severe cases. The most common immunosuppressive management included a decreased dose or pausing of the cell cycle inhibitors. Remdesivir, hydroxychloroquine, and azithromycin were the most proposed antiviral strategies. Most of the centers have been affected by the COVID-19 pandemic and proposed an active therapeutic strategy to treat LTx recipients with COVID-19.     

Cancer Patterns in the Middle East Special Report from the Middle East Cancer Society

To update its cancer statistics, the newly established Middle East Cancer Society examined the cancer frequency patterns in Egypt and the Gaza Strip. The results revealed differing overall patterns. For men the highest frequencies were found for lymphoma, bladder cancer and cancers of the oral cavity and pharynx in Egypt, and for lung cancer, leukaemia and lymphoma in Gaza. For women, breast cancer had the highest frequency in both areas, followed by cancers of the oral cavity and pharynx in Egypt, and leukaemia and lymphoma in Gaza. The distribution of cancer occurrence by organ system also varied. In the light of the different ethnicities, lifestyles, socioeconomic levels and carcinogenic exposure among the countries of the Middle East, this kind of comparison can provide the background for more sophisticated approaches for discerning risk factors in cancer. We believe that further cooperation among participating countries will overcome the present limitations in data collection, registration and access.