Cisplatin Toxicity Is Mediated by Direct Binding to Toll-Like Receptor 4 through a Mechanism That Is Distinct from Metal Allergens.

Cisplatin is an effective chemotherapeutic agent, yet its use is limited by several adverse drug reactions, known as cisplatin-induced toxicities (CITs). We recently demonstrated that cisplatin could elicit proinflammatory responses associated with CITs through Toll-like receptor 4 (TLR4). TLR4 is best recognized for binding bacterial lipopolysaccharide (LPS) via its coreceptor, MD-2. TLR4 is also proposed to directly bind transition metals, such as nickel. Little is known about the nature of the cisplatin-TLR4 interaction. Here, we show that soluble TLR4 was capable of blocking cisplatin-induced, but not LPS-induced, TLR4 activation. Cisplatin and nickel, but not LPS, were able to directly bind soluble TLR4 in a microscale thermophoresis binding assay. Interestingly, TLR4 histidine variants that abolish nickel binding reduced, but did not eliminate, cisplatin-induced TLR4 activation. This was corroborated by binding data that showed cisplatin, but not nickel, could directly bind mouse TLR4 that lacks these histidine residues. Altogether, our findings suggest that TLR4 can directly bind cisplatin in a manner that is enhanced by, but not dependent on, histidine residues that facilitate binding to transition metals. SIGNIFICANCE STATEMENT: This work describes how the xenobiotic cisplatin interacts with Toll-like receptor 4 (TLR4) to initiate proinflammatory signaling that underlies cisplatin toxicities, which are severe adverse outcomes in cisplatin treatment. Here, this study provides a mechanistic bridge between cisplatin extracellular interactions with TLR4 and previous observations that genetic and chemical inhibition of TLR4 mitigates cisplatin-induced toxicity.

Toll-like receptor 4 is activated by platinum and contributes to cisplatin-induced ototoxicity.

Toll-like receptor 4 (TLR4) recognizes bacterial lipopolysaccharide (LPS) and can also be activated by some Group 9/10 transition metals, which is believed to mediate immune hypersensitivity reactions. In this work, we test whether TLR4 can be activated by the Group 10 metal platinum and the platinum-based chemotherapeutic cisplatin. Cisplatin is invaluable in childhood cancer treatment but its use is limited due to a permanent hearing loss (cisplatin-induced ototoxicity, CIO) adverse effect. We demonstrate that platinum and cisplatin activate pathways downstream of TLR4 to a similar extent as the known TLR4 agonists LPS and nickel. We further show that TLR4 is required for cisplatin-induced inflammatory, oxidative, and cell death responses in hair cells in vitro and for hair cell damage in vivo. Finally, we identify a TLR4 small molecule inhibitor able to curtail cisplatin toxicity in vitro. Thus, our findings indicate that TLR4 is a promising therapeutic target to mitigate CIO.

Recombinant Adjuvanted Zoster Vaccine and Reduced Risk of Coronavirus Disease 2019 Diagnosis and Hospitalization in Older Adults.

BACKGROUND: Some vaccines elicit nonspecific immune responses that may protect against heterologous infections. We evaluated the association between recombinant adjuvanted zoster vaccine (RZV) and coronavirus disease 2019 (COVID-19) outcomes at Kaiser Permanente Southern California. METHODS: In a cohort design, adults aged ≥50 years who received ≥1 RZV dose before 1 March 2020 were matched 1:2 to unvaccinated individuals and followed until 31 December 2020. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for COVID-19 outcomes were estimated using Cox proportional hazards regression. In a test-negative design, cases had a positive severe acute respiratory syndrome coronavirus 2 test and controls had only negative tests, during 1 March-31 December 2020. Adjusted odds ratios (aORs) and 95% CIs for RZV receipt were estimated using logistic regression. RESULTS: In the cohort design, 149 244 RZV recipients were matched to 298 488 unvaccinated individuals. The aHRs for COVID-19 diagnosis and hospitalization were 0.84 (95% CI, .81-.87) and 0.68 (95% CI, .64-.74), respectively. In the test-negative design, 8.4% of 75 726 test-positive cases and 13.1% of 340 898 test-negative controls had received ≥1 RZV dose (aOR, 0.84 [95% CI, .81-.86]). CONCLUSIONS: RZV vaccination was associated with a 16% lower risk of COVID-19 diagnosis and 32% lower risk of hospitalization. Further study of vaccine-induced nonspecific immunity for potential attenuation of future pandemics is warranted.

Pro-Inflammatory Signalling PRRopels Cisplatin-Induced Toxicity.

Cisplatin is a platinum-based chemotherapeutic that has long since been effective against a variety of solid-cancers, substantially improving the five-year survival rates for cancer patients. Its use has also historically been limited by its adverse drug reactions, or cisplatin-induced toxicities (CITs). Of these reactions, cisplatin-induced nephrotoxicity (CIN), cisplatin-induced peripheral neuropathy (CIPN), and cisplatin-induced ototoxicity (CIO) are the three most common of several CITs recognised thus far. While the anti-cancer activity of cisplatin is well understood, the mechanisms driving its toxicities have only begun to be defined. Most of the literature pertains to damage caused by oxidative stress that occurs downstream of cisplatin treatment, but recent evidence suggests that the instigator of CIT development is inflammation. Cisplatin has been shown to induce pro-inflammatory signalling in CIN, CIPN, and CIO, all of which are associated with persisting markers of inflammation, particularly from the innate immune system. This review covered the hallmarks of inflammation common and distinct between different CITs, the role of innate immune components in development of CITs, as well as current treatments targeting pro-inflammatory signalling pathways to conserve the use of cisplatin in chemotherapy and improve long-term health outcomes of cancer patients.

Pertussis in infants in Nordic countries.

AIM: A life-course immunisation approach is required to prevent and control pertussis. We aimed at reviewing pertussis incidence among infants in Denmark, Finland, Norway and Sweden, and at putting these data in the context of national surveillance systems and vaccination schedules. METHODS: We collected 2014-2018 data on pertussis incidence, on pertussis vaccination schedules and on coverage of the third dose of the diphtheria toxoid, tetanus toxoid and acellular pertussis vaccine from publicly available sources. We gathered opinions on national surveillance systems from public health and paediatrics experts of the relevant countries. RESULTS: The pertussis vaccination schedules and coverage in infancy were similar across countries. All countries except Denmark recommended an additional booster vaccine dose for adolescents. None of the countries had maternal immunisation recommendation. Mean pertussis incidence in Denmark, Sweden and Finland was 168, 76 and 35 per 100,000 infant-years, respectively. Data were insufficient to derive a mean incidence in Norway. There were no systematic differences in the national surveillance systems across the countries. CONCLUSION: The higher mean pertussis incidence in Denmark may be explained by the lack of recommendations for adolescent pertussis booster vaccination. Further investigations are warranted.

Burden of Pertussis in COPD: A Retrospective Database Study in England.

Chronic obstructive pulmonary disease (COPD) may increase the risk and severity of pertussis infection. Health care resource utilization (HCRU) and direct medical costs (DMC) of treating pertussis among patients with COPD are unknown. Reported incidence of pertussis among individuals aged ≥ 50 years with COPD was assessed in Clinical Practice Research Datalink and Hospital Episode Statistics databases during 2009-2018 using a retrospective cohort design. HCRU and DMC from the National Health Service perspective were compared between patients with COPD and pertussis and propensity score-matched patients with COPD without pertussis. Seventy-eight new pertussis events were identified among 387 086 patients with COPD aged ≥ 50 years (incidence rate: 4.73; 95% confidence interval 3.74-5.91 per 100 000 person-years). HCRU and DMC were assessed among 67 patients with COPD and pertussis and 267 matched controls. During the month before the pertussis diagnosis, the rates of general practitioner (GP)/nurse visits (4289 vs. 1774 per 100 patient-years) and accident and emergency visits (182 vs. 18 per 100 patient-years) were higher in the pertussis cohort; GP/nurse visits (2935 vs. 1705 per 100 patient-years) were also higher during the following 2 months (all p < 0.001). During the month before the pertussis diagnosis, annualized per-patient total DMC were £2012 higher in the pertussis cohort (£3729 vs. £1717; p < 0.001); during the following 2 months, they were £2407 higher (£5498 vs. £3091; p < 0.001). In conclusion, a pertussis episode among individuals with COPD resulted in significant increases in HCRU and DMC around the pertussis event.

Exome Sequencing and the Management of Neurometabolic Disorders.

BACKGROUND: Whole-exome sequencing has transformed gene discovery and diagnosis in rare diseases. Translation into disease-modifying treatments is challenging, particularly for intellectual developmental disorder. However, the exception is inborn errors of metabolism, since many of these disorders are responsive to therapy that targets pathophysiological features at the molecular or cellular level. METHODS: To uncover the genetic basis of potentially treatable inborn errors of metabolism, we combined deep clinical phenotyping (the comprehensive characterization of the discrete components of a patient's clinical and biochemical phenotype) with whole-exome sequencing analysis through a semiautomated bioinformatics pipeline in consecutively enrolled patients with intellectual developmental disorder and unexplained metabolic phenotypes. RESULTS: We performed whole-exome sequencing on samples obtained from 47 probands. Of these patients, 6 were excluded, including 1 who withdrew from the study. The remaining 41 probands had been born to predominantly nonconsanguineous parents of European descent. In 37 probands, we identified variants in 2 genes newly implicated in disease, 9 candidate genes, 22 known genes with newly identified phenotypes, and 9 genes with expected phenotypes; in most of the genes, the variants were classified as either pathogenic or probably pathogenic. Complex phenotypes of patients in five families were explained by coexisting monogenic conditions. We obtained a diagnosis in 28 of 41 probands (68%) who were evaluated. A test of a targeted intervention was performed in 18 patients (44%). CONCLUSIONS: Deep phenotyping and whole-exome sequencing in 41 probands with intellectual developmental disorder and unexplained metabolic abnormalities led to a diagnosis in 68%, the identification of 11 candidate genes newly implicated in neurometabolic disease, and a change in treatment beyond genetic counseling in 44%. (Funded by BC Children's Hospital Foundation and others.).

Estimated dengue force of infection and burden of primary infections among Indian children.

BACKGROUND: Comprehensive, age-stratified dengue surveillance data are unavailable from India and many more dengue cases occur than are reported. Additional information on dengue transmission dynamics can inform understanding of disease endemicity and infection risk. METHODS: Using age-stratified dengue IgG seroprevalence data from 2556 Indian children aged 5-10 years, we estimated annual force of infection (FOI) at each of 6 sites using a binomial regression model. We estimated the ages by which 50 and 70% of children were first infected; and predicted seroprevalence in children aged 1-10 years assuming constant force-of-infection. Applying these infection rates to national census data, we then calculated the number of primary dengue infections occurring, annually, in Indian children. RESULTS: Annual force-of-infection at all sites combined was 11.9% (95% CI 8.8-16.2), varying across sites from 3.5% (95% CI 2.8-4.4) to 21.2% (95% CI 18.4-24.5). Overall, 50 and 70% of children were infected by 5.8 (95% CI 4.3-7.9) and 10.1 (95% CI 7.4-13.7) years respectively. In all sites except Kalyani, > 70% of children had been infected before their 11th birthday, and goodness-of-fit statistics indicated a relatively constant force-of-infection over time except at two sites (Wardha and Hyderabad). Nationwide, we estimated 17,013,527 children (95% CI: 14,518,438- 19,218,733), equivalent to 6.5% of children aged < 11 years, experience their first infection annually. CONCLUSIONS: Dengue force-of-infection in India is comparable to other highly endemic countries. Significant variation across sites exists, likely reflecting local epidemiological variation. The number of annual primary infections is indicative of a significant, under-reported burden of secondary infections and symptomatic episodes. TRIAL REGISTRATION: Registered retrospectively with clinicaltrials.gov ( NCT01477671 ; 18/11/2011) and clinical trials registry of India (ctri.nic.in; CTRI/2011/12/002243 ; 15/12/2011). Date of enrollment of 1st subject: 22/9/2011.

An initial health economic evaluation of pharmacogenomic testing in patients treated for childhood cancer with anthracyclines.

BACKGROUND: Anthracyclines are a class of highly effective chemotherapeutic drugs commonly used to treat cancer patients. Anthracyclines, however, are associated with the development of serious adverse reactions, including anthracycline-induced cardiotoxicity (ACT). It is not possible, within current practice, to accurately individualize treatment to minimize risk. PROCEDURE: Recently, genetic variants have been associated with the risk of ACT in children. Building on these findings and the related genetic test, a predictive model was developed which classifies pediatric patients by their risk of developing ACT. We assessed the value of this ACT-predictive risk classification in addressing ACT. RESULTS: With current care, the estimated average lifetime cost of ACT is $8,667 per anthracycline-treated patient and approximately 7% of patients are expected to die from ACT. The projected impact of the information from the new predictive model is a 17% reduction in the risk of mortality from ACT and savings of about 6%: lives saved and lower costs. CONCLUSION: The newly identified genetic variants associated with the risk of ACT provide information that allows a more reliable prediction of the risk of ACT for a given patient and can be obtained at a very moderate cost, which is expected to lead to meaningful progress in reducing harm and costs associated with ACT.

Mitochondrial carbonic anhydrase VA deficiency resulting from CA5A alterations presents with hyperammonemia in early childhood.

Four children in three unrelated families (one consanguineous) presented with lethargy, hyperlactatemia, and hyperammonemia of unexplained origin during the neonatal period and early childhood. We identified and validated three different CA5A alterations, including a homozygous missense mutation (c.697T>C) in two siblings, a homozygous splice site mutation (c.555G>A) leading to skipping of exon 4, and a homozygous 4 kb deletion of exon 6. The deleterious nature of the homozygous mutation c.697T>C (p.Ser233Pro) was demonstrated by reduced enzymatic activity and increased temperature sensitivity. Carbonic anhydrase VA (CA-VA) was absent in liver in the child with the homozygous exon 6 deletion. The metabolite profiles in the affected individuals fit CA-VA deficiency, showing evidence of impaired provision of bicarbonate to the four enzymes that participate in key pathways in intermediary metabolism: carbamoylphosphate synthetase 1 (urea cycle), pyruvate carboxylase (anaplerosis, gluconeogenesis), propionyl-CoA carboxylase, and 3-methylcrotonyl-CoA carboxylase (branched chain amino acids catabolism). In the three children who were administered carglumic acid, hyperammonemia resolved. CA-VA deficiency should therefore be added to urea cycle defects, organic acidurias, and pyruvate carboxylase deficiency as a treatable condition in the differential diagnosis of hyperammonemia in the neonate and young child.

Recommendations for genetic testing to reduce the incidence of anthracycline-induced cardiotoxicity.

AIMS: Anthracycline-induced cardiotoxicity (ACT) occurs in 57% of treated patients and remains an important limitation of anthracycline-based chemotherapy. In various genetic association studies, potential genetic risk markers for ACT have been identified. Therefore, we developed evidence-based clinical practice recommendations for pharmacogenomic testing to further individualize therapy based on ACT risk. METHODS: We followed a standard guideline development process, including a systematic literature search, evidence synthesis and critical appraisal, and the development of clinical practice recommendations with an international expert group. RESULTS: RARG rs2229774, SLC28A3 rs7853758 and UGT1A6 rs17863783 variants currently have the strongest and the most consistent evidence for association with ACT. Genetic variants in ABCC1, ABCC2, ABCC5, ABCB1, ABCB4, CBR3, RAC2, NCF4, CYBA, GSTP1, CAT, SULT2B1, POR, HAS3, SLC22A7, SCL22A17, HFE and NOS3 have also been associated with ACT, but require additional validation. We recommend pharmacogenomic testing for the RARG rs2229774 (S427L), SLC28A3 rs7853758 (L461L) and UGT1A6*4 rs17863783 (V209V) variants in childhood cancer patients with an indication for doxorubicin or daunorubicin therapy (Level B - moderate). Based on an overall risk stratification, taking into account genetic and clinical risk factors, we recommend a number of management options including increased frequency of echocardiogram monitoring, follow-up, as well as therapeutic options within the current standard of clinical practice. CONCLUSIONS: Existing evidence demonstrates that genetic factors have the potential to improve the discrimination between individuals at higher and lower risk of ACT. Genetic testing may therefore support both patient care decisions and evidence development for an improved prevention of ACT.

Clinical Practice Recommendations for the Management and Prevention of Cisplatin-Induced Hearing Loss Using Pharmacogenetic Markers.

Currently no pharmacogenomics-based criteria exist to guide clinicians in identifying individuals who are at risk of hearing loss from cisplatin-based chemotherapy. This review summarizes findings from pharmacogenomic studies that report genetic polymorphisms associated with cisplatin-induced hearing loss and aims to (1) provide up-to-date information on new developments in the field, (2) provide recommendations for the use of pharmacogenetic testing in the prevention, assessment, and management of cisplatin-induced hearing loss in children and adults, and (3) identify knowledge gaps to direct and prioritize future research. These practice recommendations for pharmacogenetic testing in the context of cisplatin-induced hearing loss reflect a review and evaluation of recent literature, and are designed to assist clinicians in providing optimal clinical care for patients receiving cisplatin-based chemotherapy.

Common Questions About the Evaluation of Acute Pelvic Pain.

Acute pelvic pain is defined as lower abdominal or pelvic pain of less than three months' duration. It is a common presentation in primary care. Evaluation can be challenging because of a broad differential diagnosis and because many associated signs and symptoms are nonspecific. The most common diagnoses in reproductive-aged women with acute pelvic pain are idiopathic pelvic pain, pelvic inflammatory disease, acute appendicitis, ovarian cysts, ectopic pregnancy, and endometriosis. Among postmenopausal women, cancer must be considered. Findings from the history and physical examination can point to likely diagnoses, and laboratory testing and imaging can help confirm. Women of reproductive age should take a pregnancy test. In early pregnancy, transvaginal ultrasonography and beta human chorionic gonadotropin levels can help identify ectopic pregnancy and spontaneous abortion. For nonpregnant women, ultrasonography or computed tomography is indicated, depending on the possible diagnosis (e.g., ultrasonography is preferred when ovarian pathology is suspected). If ultrasonography results are nondiagnostic, magnetic resonance imaging can be helpful in pregnant women when acute appendicitis is suspected. If magnetic resonance imaging is unavailable, computed tomography may be indicated.

The Salmonella type III effector SspH2 specifically exploits the NLR co-chaperone activity of SGT1 to subvert immunity.

To further its pathogenesis, S. Typhimurium delivers effector proteins into host cells, including the novel E3 ubiquitin ligase (NEL) effector SspH2. Using model systems in a cross-kingdom approach we gained further insight into the molecular function of this effector. Here, we show that SspH2 modulates innate immunity in both mammalian and plant cells. In mammalian cell culture, SspH2 significantly enhanced Nod1-mediated IL-8 secretion when transiently expressed or bacterially delivered. In addition, SspH2 also enhanced an Rx-dependent hypersensitive response in planta. In both of these nucleotide-binding leucine rich repeat receptor (NLR) model systems, SspH2-mediated phenotypes required its catalytic E3 ubiquitin ligase activity and interaction with the conserved host protein SGT1. SGT1 has an essential cell cycle function and an additional function as an NLR co-chaperone in animal and plant cells. Interaction between SspH2 and SGT1 was restricted to SGT1 proteins that have NLR co-chaperone function and accordingly, SspH2 did not affect SGT1 cell cycle functions. Mechanistic studies revealed that SspH2 interacted with, and ubiquitinated Nod1 and could induce Nod1 activity in an agonist-independent manner if catalytically active. Interestingly, SspH2 in vitro ubiquitination activity and protein stability were enhanced by SGT1. Overall, this work adds to our understanding of the sophisticated mechanisms used by bacterial effectors to co-opt host pathways by demonstrating that SspH2 can subvert immune responses by selectively exploiting the functions of a conserved host co-chaperone.

Global impact of Salmonella pathogenicity island 2-secreted effectors on the host phosphoproteome.

During the late stages of infection, Salmonella secretes numerous effectors through a type III secretion system that is encoded within Salmonella pathogenicity island 2 (SPI2). Despite the importance of SPI2 as a major virulence factor leading to the systemic spread of the bacteria and diseases, a global view of its effects on host responses is still lacking. Here, we measured global impacts of SPI2 effectors on the host phosphorylation and protein expression levels in RAW264.7 and in HeLa cells, as macrophage and nonphagocytic models of infection. We observe that SPI2 effectors differentially modulate the host phosphoproteome and cellular processes (e.g. protein trafficking, cytoskeletal regulation, and immune signaling) in a host cell-dependent manner. Our unbiased approach reveals the involvement of many previously unrecognized proteins, including E3 ligases (HERC4, RanBP2, and RAD18), kinases (CDK, SIK3, and WNK1), and histones (H2B1F, H4, and H15), in late stages of Salmonella infection. Furthermore, from this phosphoproteome analysis and other quantitative screens, we identified HSP27 as a direct in vitro and in vivo molecular target of the only type III secreted kinase, SteC. Using biochemical and cell biological assays, we demonstrate that SteC phosphorylates multiple sites in HSP27 and induces actin rearrangement through this protein. Together, these results provide a broader landscape of host players contributing to specific processes/pathways mediated by SPI2 effectors than was previously appreciated.

Systematic Literature Review on the Incidence of Herpes Zoster in Populations at Increased Risk of Disease in the EU/EEA, Switzerland, and the UK.

INTRODUCTION: Older adults and patients with underlying conditions such as immunocompromised (IC) populations (e.g., due to medical conditions or immunosuppressive medication) are at increased risk for herpes zoster (HZ). The first HZ recombinant vaccine for IC patients was approved in 2020. Limited evidence exists to inform decision-makers on HZ incidence in high-risk patients in Europe. This systematic literature review (SLR) assessed HZ incidence across 14 high-risk populations in the European Union/European Economic Area, Switzerland, and the United Kingdom. METHODS: An SLR (Embase, Medline, 2002-2022, observational studies) was performed to identify HZ incidence (i.e., primary outcomes: rate or cumulative; secondary: relative incidence) in type 1 and 2 diabetes mellitus (DM); chronic obstructive pulmonary disease and asthma; depression; rheumatic disorders (RD); multiple sclerosis (MS); inflammatory bowel diseases (IBD); psoriasis; lupus; human immunodeficiency virus (HIV); solid organ transplantation (SOT); solid organ malignancy (SOM); hematologic malignancy (HM); and stem cell transplantation (SCT). RESULTS: Of 776 unique records screened, 59 studies were included (24 reported incidence rate per 1000 person-years; two, cumulative incidence per 1000 persons; and 33, relative incidence). The highest incidence rates were reported for SOT (12.1-78.8) and SCT (37.2-56.1); HM (2.9-32.0); RD (0.41-21.5); lupus (11.0-16.5); IC mixed population (11.3-15.5); HIV/AIDS (11.8-13.0); chronic respiratory diseases (4.7-11.4); SOM (8.8-11.0); IBD (7.0-10.8); DM (4.3-9.4); depression (7.2-7.6); MS (5.7-6.3); and psoriasis (5.3-6.1). In many high-risk populations, HZ incidence was higher for older age groups, women, and some treatments. CONCLUSIONS: The HZ incidence rate in Europe increased with age and varied across high-risk populations, with high rates for solid organ and stem cell transplants, cancer, and rheumatoid arthritis. Most studies were retrospective with methodological differences affecting generalizability and comparability. Future studies should stratify data by IC population, age, sex, severity, medication, and study timeframe.

Incidence and Burden of Herpes Zoster in Sweden: A Regional Population-Based Register Study.

INTRODUCTION: Herpes zoster (HZ) is a painful disease that mainly affects individuals whose immune system has been weakened because of increasing age (> 50 years) or certain diseases or treatments. We estimated the complete burden of HZ. METHODS: This population-based register study analysed healthcare data from the VEGA and Digitalis databases of Västra Götaland Region (VGR), Sweden. The VEGA database includes all patients in VGR, covering both hospital and primary care. The Digitalis records prescribed medications. The study population included patients aged ≥ 18 years with at least one registered primary or secondary HZ diagnosis (based on International Classification of Diseases [ICD] codes) between 2005 and 2021. Incidence rates (95% confidence intervals [CI]) were stratified by age, sex and diagnosis/analgesic prescription. RESULTS: Overall HZ incidence increased from 2.5 (95% CI 2.4-2.6) in 2005 to 4.2 (95% CI 4.1-4.3) in 2021. The increase in incidence was rapid from 2005 to 2013, followed by a plateauing trend. From 2014-2019, the lifetime risk of HZ, excluding recurrent cases, was 36.5% (95% CI 35.5-37.4%). Municipal differences ranged from 34.4% (95% CI 32.5-36.4%) to 43.6% (95% CI 39.9-47.4%). Recurrence rates of HZ were 8.7% and 9.1% with follow-up periods of 5.5 and 10.5 years, respectively. Reported postherpetic neuralgia (PHN) cases increased five-fold over the study period. In 2019, 19% of all HZ patients developed HZ-related neuropathic pain; 13.6% had signs of persistent pain (> 90 days; i.e. PHN). An increased occurrence of cerebral and cardiovascular disease was observed in HZ patients. Among high-risk groups the occurrence of HZ peaked among those with inflammatory and autoimmune diseases. CONCLUSION: HZ and PHN risk in Sweden is comparable to that in other European countries prior to implementing HZ national vaccination programs. Municipal differences suggest that the lifetime risk of HZ in Sweden is at least 36.5%. CLINICAL TRIAL REGISTRATION: NCT Number ( www. CLINICALTRIALS: gov ).

What is the context?The varicella-zoster virus (VZV) can reactivate after primary infection and cause herpes zoster or shingles.Shingles is painful and mostly affects people aged > 50 years or those who have weakened immunity due to age, illness or medical treatments.The National Immunization Program (NIP) in Sweden does not currently include vaccination against shingles.We evaluated how often individuals from Västra Götaland Region, Sweden, experienced shingles and its complications.What is new?Overall, the number of shingles and PHN cases increased significantly from 2005 to 2021.We found that 14% of patients with shingles had pain persisting for > 3 months after a shingles episode.Most people developing shingles (about 70%) are healthy individuals without comorbidities, although those with underlying health issues have more risk of getting shingles.Over a follow-up period of 5.5 years, 8.7% of patients with shingles had more than one shingles episode.What is the impact?The occurrence of shingles and postherpetic neuralgia in Sweden is higher than what was reported previously and is comparable to other European countries before the implementation of shingles vaccination programmes.

Randomized, Open-Label Phase 3 Study Evaluating Immunogenicity, Safety, and Reactogenicity of RSVPreF3 OA Coadministered with FLU-QIV-HD in Adults Aged ≥ 65.

INTRODUCTION: Respiratory syncytial virus (RSV) and influenza pose major disease burdens in older adults due to an aging immune system and comorbidities; seasonal overlap exists between these infections. In 2023, the RSV prefusion protein F3 older adult (RSVPreF3 OA) vaccine was first approved in the USA as a single dose for prevention of lower respiratory tract disease due to RSV in adults aged ≥ 60 years. The vaccine has since been approved in the European Union and elsewhere. RSVPreF3 OA and FLU-QIV-HD could be coadministered if immunogenicity, safety, and reactogenicity are not affected. METHODS: This open-label, randomized (1:1), controlled, phase 3 study in 1029 adults aged ≥ 65 years in the USA evaluated the immunogenicity (up to 1 month after last vaccine dose) and safety (up to 6 months after last vaccine dose) of RSVPreF3 OA coadministered with FLU-QIV-HD (co-ad group) versus FLU-QIV-HD alone followed by RSVPreF3 OA at a separate visit 1 month later (control group). Non-inferiority criterion was defined as an upper limit of the two-sided 95% confidence interval of the geometric mean titer (GMT) group ratio (control/co-ad) ≤ 1.5. Secondary endpoints included safety and reactogenicity. RESULTS: Proportions of participants across age categories between groups and proportions of male (50.4%) and female (49.6%) participants were well balanced; most participants were white (68.7%). Group GMT ratios for RSV-A neutralizing titers, hemagglutination inhibition titers for four influenza vaccine strains, and RSV-B neutralizing titers were non-inferior in the co-ad group versus the control group. No clinically meaningful differences in local or systemic solicited and unsolicited adverse events (AEs), serious AEs, and potential immune-mediated diseases were identified. The most common solicited AEs in both groups were injection-site pain and myalgia. CONCLUSION: In adults aged ≥ 65 years, coadministration of RSVPreF3 OA and FLU-QIV-HD was immunogenically non-inferior to the sequential administration of both vaccines 1 month apart, and had clinically acceptable safety and reactogenicity profile. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT05559476.

Adults aged 65 years or older are vulnerable to infections caused by influenza and respiratory syncytial viruses, due to an aging immune system and other underlying conditions. Infections with both viruses increase during autumn and winter seasons in temperate climates. In 2023, a vaccine against respiratory syncytial virus, called RSVPreF3 OA, was first approved for use in adults aged 60 years or older in the USA; the vaccine has since also been approved in the European Union and elsewhere. Giving RSVPreF3 OA in the same vaccination visit (coadministration) with a high-dose influenza vaccine, called FLU-QIV-HD, which is given to adults aged 65 years or older, could help protect against both respiratory syncytial virus and influenza. This article reports the results of a phase 3 trial comparing coadministration of the RSVPreF3 OA and FLU-QIV-HD vaccines with sequential administration (FLU-QIV-HD followed by RSVPreF3 OA 1 month later) in 1029 adults aged 65 years or older in the USA. Proportions of participants across age categories between groups, and the proportions of male (50.4%) and female (49.6%) participants were well balanced; most participants were white (68.7%). Immune response to both the vaccines among participants in the coadministration arm was non-inferior to that in the sequential arm. Coadministration was well tolerated, with no meaningful differences in adverse reactions to the vaccines compared with sequential administration. The most common adverse reactions were pain at the injection site and muscle aches. This study supports the coadministration of RSVPreF3 OA and FLU-QIV-HD in adults aged 65 years or older.

Manipulation of host-cell pathways by bacterial pathogens.

Bacterial pathogens operate by attacking crucial intracellular pathways in their hosts. These pathogens usually target more than one intracellular pathway and often interact at several points in each of these pathways to commandeer them fully. Although different bacterial pathogens tend to exploit similar pathway components in the host, the way in which they 'hijack' host cells usually differs. Knowledge of how pathogens target distinct cytoskeletal components and immune-cell signalling pathways is rapidly advancing, together with the understanding of bacterial virulence at a molecular level. Studying how these bacterial pathogens subvert host-cell pathways is central to understanding infectious disease.

Prevention of unintentional childhood injury.

Unintentional injury accounts for 40 percent of childhood deaths annually, most commonly from motor vehicle crashes. The proper use of child restraints is the most effective strategy to prevent injury or death. Motor vehicle restraint guidelines have recently been revised to an age-based system that delays the progression in type of restraint for most children. Strategies to prevent suffocation in children include using appropriate bedding, positioning babies on their backs to sleep, and removing items from the sleep and play environment that could potentially entrap or entangle the child. Fencing that isolates a swimming pool from the yard and surrounding area and "touch" adult supervision (i.e., an adult is in the water and able to reach and grab a child) have been shown to be most effective in preventing drownings. Swimming lessons are recommended for children older than four years. Poison prevention programs have been shown to improve prevention behavior among caregivers, but may not decrease poisoning incidence. Syrup of ipecac is not recommended. Smoke detector maintenance, a home escape plan, and educating children about how to respond during a fire emergency are effective strategies for preventing fire injuries or death. Fall injuries may be reduced by not using walkers for infants and toddlers or bunk beds for children six years and younger. Consistent helmet use while bicycling reduces head and brain injuries. Although direct counseling by physicians appears to improve some parental safety behaviors, its effect on reducing childhood injuries is uncertain. Community-based interventions can be effective in high-risk populations.