Whole-genome sequencing of non-typeable Haemophilus influenzae isolated from a tertiary care hospital in Surabaya, Indonesia.

BACKGROUND: Haemophilus influenzae causes life-threatening invasive diseases such as septicaemia and meningitis. Reports on circulating H. influenzae causing invasive disease in lower-middle income settings, including Indonesia, are lacking. This study describes the serotype distributions and whole-genome sequence (WGS) data of H. influenzae isolated from hospitalized patients at Soetomo Hospital, Surabaya, Indonesia. METHODS: H. influenzae isolates were isolated from blood and pleural fluid specimens and identified using culture-based and molecular methods, followed by serotyping and WGS using RT‒PCR and Illumina MiSeq, respectively. Sequencing reads were assembled, and further analyses were undertaken to determine the genomic content and reconstruct the phylogeny. A second dataset consisting of publicly available H. influenzae genomes was curated to conduct phylogenetic analyses of isolates in this study in the context of globally circulating isolates. RESULTS: Ten H. influenzae isolates from hospitalized patients were collected, and septicaemia was the most common diagnosis (n=8). RT‒PCR and WGS were performed to determine whether all the isolates were nontypeable H. influenzae (NTHi). There were four newly identified STs distributed across the two main clusters. A total of 91 out of 126 virulence factor (VF)-related genes in Haemophilus sp. were detected in at least one isolate. Further evaluation incorporating a global collection of H. influenzae genomes confirmed the diverse population structure of NTHi in this study. CONCLUSION: This study showed that all H. influenzae recovered from invasive disease patients were nonvaccine-preventable NTHi isolates. The inclusion of WGS revealed four novel STs and the possession of key VF-associated genes.

Rebound of pediatric invasive pneumococcal disease in Portugal after the COVID-19 pandemic was not associated with significant serotype changes.

OBJECTIVES: The COVID-19 pandemic led to the institution of public health measures in many countries which reduced respiratory infections. We aimed to identify and characterize changes in pediatric (<18 years) invasive pneumococcal disease (pIPD) in Portugal in 2018-2023. METHODS: pIPD cases were identified by culture and molecular methods and stratified by age and serotype. When available the susceptibility of the isolates to antimicrobials was evaluated. RESULTS: pIPD cases were markedly reduced in the last trimester of 2019-2020 and the entire 2020-2021 season. While 2021-2022 was in line with pre-pandemic seasons, in 2022-2023, the number of pIPD cases exceeded those found pre-pandemic. Molecular tests were responsible for identifying and serotyping 30% of cases, highlighting their importance in evaluating pIPD. Among the 316 pIPD cases, 37 different serotypes were detected, of which serotypes 3 (n = 85, 26.9%), 8 (n = 25, 7.9%), 10A (n = 21, 6.6%) and 24F (n = 20, 6.3%) were the most frequent. The post-pandemic serotype distribution reflected mostly pre-pandemic trends and the rebound was not driven by particular serotypes. We identified many vaccine failures, most (n = 37) representing serotype 3 infections. Penicillin non-susceptibility increased from 14% pre-pandemic to 29%, with serotype 24F becoming particularly significant. CONCLUSIONS: The higher number of cases of pIPD post-COVID-19 in Portugal raises the possibility of a higher burden of pneumococcal disease in Europe post-pandemic. The relatively stable serotype distribution and the current availability of the higher valency conjugate vaccines PCV15 and PCV20, potentially preventing a large proportion of pIPD (43% and 67%, respectively), offer an opportunity to control this increase.

A rapid molecular detection tool for toxigenic M1UK Streptococcus pyogenes.

BACKGROUND: The gradual replacement of the Streptococcus pyogenes M1global genotype by a newly emergent M1UK variant is a global public health threat warranting increased surveillance. M1UK differs from progenitor M1global genotype by 27 single nucleotide polymorphisms (SNPs) and is characterised by increased speA superantigen expression in vitro. METHODS: An allele-specific real-time PCR assay was developed for the rapid detection of M1UK strains. The assay was used in combination with whole-genome sequencing to determine emm (sub)type distribution for 51 invasive (n = 9) and non-invasive (n = 42) S. pyogenes clinical isolates. RESULTS: Emm1 was the most prevalent S. pyogenes emm serotype (n = 11) in this set of clinical isolates, with M1UK being the dominant emm1 genotype (4/5 invasive, 3/6 non-invasive isolates). The assay accurately detected M1UK strains. Whole genome sequencing revealed continued presence of Australian M1UK sub-lineages associated with epidemic scarlet fever-causing S. pyogenes in Asia. CONCLUSIONS: Our study establishes a suitable target for detection of the toxigenic M1UK, and confirms the maintenance of M1UK strains in Queensland, Australia. This assay can be deployed in laboratories and provides a valuable, cost-effective tool to enhance surveillance of the expanding M1UK clone.

Prediction of post-PCV13 pneumococcal evolution using invasive disease data enhanced by inverse-invasiveness weighting.

After introducing pneumococcal conjugate vaccines (PCVs), serotype replacement occurred in Streptococcus pneumoniae. Predicting which pneumococcal strains will become common in carriage after vaccination can enhance vaccine design, public health interventions, and understanding of pneumococcal evolution. Invasive pneumococcal isolates were collected during 1998-2018 by the Active Bacterial Core surveillance (ABCs). Carriage data from Massachusetts (MA) and Southwest United States were used to calculate weights. Using pre-vaccine data, serotype-specific inverse-invasiveness weights were defined as the ratio of the proportion of the serotype in carriage to the proportion in invasive data. Genomic data were processed under bioinformatic pipelines to define genetically similar sequence clusters (i.e., strains), and accessory genes (COGs) present in 5-95% of isolates. Weights were applied to adjust observed strain proportions and COG frequencies. The negative frequency-dependent selection (NFDS) model predicted strain proportions by calculating the post-vaccine strain composition in the weighted invasive disease population that would best match pre-vaccine COG frequencies. Inverse-invasiveness weighting increased the correlation of COG frequencies between invasive and carriage data in linear or logit scale for pre-vaccine, post-PCV7, and post-PCV13; and between different epochs in the invasive data. Weighting the invasive data significantly improved the NFDS model's accuracy in predicting strain proportions in the carriage population in the post-PCV13 epoch, with the adjusted R2 increasing from 0.254 before weighting to 0.545 after weighting. The weighting system adjusted invasive disease data to better represent the pneumococcal carriage population, allowing the NFDS mechanism to predict strain proportions in carriage in the post-PCV13 epoch. Our methods enrich the value of genomic sequences from invasive disease surveillance.IMPORTANCEStreptococcus pneumoniae, a common colonizer in the human nasopharynx, can cause invasive diseases including pneumonia, bacteremia, and meningitis mostly in children under 5 years or older adults. The PCV7 was introduced in 2000 in the United States within the pediatric population to prevent disease and reduce deaths, followed by PCV13 in 2010, PCV15 in 2022, and PCV20 in 2023. After the removal of vaccine serotypes, the prevalence of carriage remained stable as the vacated pediatric ecological niche was filled with certain non-vaccine serotypes. Predicting which pneumococcal clones, and which serotypes, will be most successful in colonization after vaccination can enhance vaccine design and public health interventions, while also improving our understanding of pneumococcal evolution. While carriage data, which are collected from the pneumococcal population that is competing to colonize and transmit, are most directly relevant to evolutionary studies, invasive disease data are often more plentiful. Previously, evolutionary models based on negative frequency-dependent selection (NFDS) on the accessory genome were shown to predict which non-vaccine strains and serotypes were most successful in colonization following the introduction of PCV7. Here, we show that an inverse-invasiveness weighting system applied to invasive disease surveillance data allows the NFDS model to predict strain proportions in the projected carriage population in the post-PCV13/pre-PCV15 and pre-PCV20 epoch. The significance of our research lies in using a sample of invasive disease surveillance data to extend the use of NFDS as an evolutionary mechanism to predict post-PCV13 population dynamics. This has shown that we can correct for biased sampling that arises from differences in virulence and can enrich the value of genomic data from disease surveillance and advance our understanding of how NFDS impacts carriage population dynamics after both PCV7 and PCV13 vaccination.

Genetic markers associated with host status and clonal expansion of Group B Streptococcus in the Netherlands.

Objectives: Certain Group B Streptococcus (GBS) genotypes are associated with invasive disease in neonates. We conducted a comparative genomic analysis of GBS isolates from neonatal disease and maternal carriage in the Netherlands to determine distribution of genetic markers between the two host groups. Methods: Whole genome sequencing was used to characterise 685 neonatal invasive isolates (2006-2021) and 733 maternal carriage isolates (2017-2021) collected in the Netherlands. Results: Clonal complex (CC) 17 and serotype III were significantly more common in disease while carriage isolates were associated with serotypes II, IV, V as well as CC1. Previously reported CC17-A1 sub-lineage was dominant among disease isolates and significantly less common in carriage. The phiStag1 phage, previously associated with expansion of invasive CC17 isolates in the Netherlands, was more common among disease isolates compared to carriage isolates overall, however it was equally distributed between CC17 isolates from carriage and disease. Prevalence of antimicrobial resistance genes was overall lower in disease compared to carriage isolates, but increased significantly over time, mediated by rise in prevalence of a multidrug resistance element ICESag37 among disease isolates. Conclusion: There is a stable association between certain GBS genotypes and invasive disease, which suggests opportunities for developing more precise disease prevention strategies based on GBS targeted screening. In contrast, GBS mobile genetic elements appear less likely to be correlated with carriage or disease, and instead are associated with clonal expansion events across the GBS population.

Presence of Group A streptococcus frequently assayed virulence genes in invasive disease: a systematic review and meta-analysis.

Introduction: It is currently unclear what the role of Group A streptococcus (GAS) virulence factors (VFs) is in contributing to the invasive potential of GAS. This work investigated the evidence for the association of GAS VFs with invasive disease. Methods: We employed a broad search strategy for studies reporting the presence of GAS VFs in invasive and non-invasive GAS disease. Data were independently extracted by two reviewers, quality assessed, and meta-analyzed using Stata®. Results: A total of 32 studies reported on 45 putative virulence factors [invasive (n = 3,236); non-invasive (n = 5,218)], characterized by polymerase chain reaction (PCR) (n = 30) and whole-genome sequencing (WGS) (n = 2). The risk of bias was rated as low and moderate, in 23 and 9 studies, respectively. Meta-,analyses of high-quality studies (n = 23) revealed a significant association of speM [OR, 1.64 (95%CI, 1.06; 2.52)] with invasive infection. Meta-analysis of WGS studies demonstrated a significant association of hasA [OR, 1.91 (95%CI, 1.36; 2.67)] and speG [OR, 2.83 (95%CI, 1.63; 4.92)] with invasive GAS (iGAS). Meta-analysis of PCR studies indicated a significant association of speA [OR, 1.59 (95%CI, 1.10; 2.30)] and speK [OR, 2.95 (95%CI, 1.81; 4.80)] with invasive infection. A significant inverse association was observed between prtf1 [OR, 0.42 (95%CI, 0.20; 0.87)] and invasive infection. Conclusion: This systematic review and genomic meta-analysis provides evidence of a statistically significant association with invasive infection for the hasA gene, while smeZ, ssa, pnga3, sda1, sic, and NaDase show statistically significantly inverse associations with invasive infection. SpeA, speK, and speG are associated with GAS virulence; however, it is unclear if they are markers of invasive infection. This work could possibly aid in developing preventative strategies.

OptimICE-RD: sacituzumab govitecan + pembrolizumab vs pembrolizumab (± capecitabine) for residual triple-negative breast cancer.

Patients with early-stage triple-negative breast cancer (TNBC) with residual invasive disease after neoadjuvant therapy have a high risk of recurrence even with neoadjuvant and adjuvant treatment with pembrolizumab. Sacituzumab govitecan, a Trop-2-directed antibody-drug conjugate with a topoisomerase I inhibitor payload, improved progression-free survival (PFS) and overall survival (OS) versus chemotherapy in patients with pre-treated metastatic TNBC. Moreover, preclinical data suggest that topoisomerase I inhibitors may enhance the effects of immune checkpoint inhibitors through activation of the cGAS-STING pathway. Here we describe the international randomized phase III AFT-65/ASCENT-05/OptimICE-RD trial, which evaluates the efficacy and safety of sacituzumab govitecan plus pembrolizumab versus treatment of physician's choice (pembrolizumab ± capecitabine) among patients with early-stage TNBC with residual invasive disease after neoadjuvant therapy.Clinical Trial Registration: NCT05633654 (ClinicalTrials.gov)Other Study ID Number(s): Gilead Study ID: GS-US-595-6184Registration date: 1 December 2022Study start date: 12 December 2022Recruitment status: Recruiting.

AFT-65/ASCENT-05/OptimICE-RD is an ongoing clinical trial that is testing a new treatment combination for patients with stage II or III triple-negative breast cancer (TNBC). Stage II­III means the cancer is confined to the breast and/or nearby lymph nodes and can be surgically removed. However, there remains a risk that the cancer could recur after surgery. To reduce this risk, patients with stage II­III TNBC receive anti-cancer medication before and after surgery. For some patients, receipt of anti-cancer medication before surgery produces a pathologic complete response (pCR), meaning there is no observable cancer left behind at surgery. Patients with a pCR have a lower risk of recurrence than patients with residual disease.The AFT-65/ASCENT-05/OptimICE-RD trial includes people with stage II-III TNBC who have residual cancer after completing their course of pre-surgery anti-cancer medication. All participants have any remaining cancer in their breast and/or lymph nodes removed surgically, after which they are randomly assigned to receive one of two treatments. The experimental therapy consists of pembrolizumab along with a medication called sacituzumab govitecan, which kills cancer cells directly and may strengthen the anti-cancer immune response. Pembrolizumab strengthens the anti-cancer immune response, so the hypothesis of this trial is that the two medications will be more effective together. The control therapy consists of pembrolizumab, alone or in combination with a chemotherapy medication called capecitabine, which is the current standard of care. To study the effectiveness of each treatment, the researchers are following up with all participants to learn if and when their breast cancer returns.

Increase in invasive Haemophilus influenzae serotype A infections during the COVID-19 pandemic in New South Wales, Australia.

Haemophilus influenzae, a causative agent of severe invasive infections such as meningitis, sepsis and pneumonia, is classified into encapsulated or typeable (represented by serotypes A to F) and non-typeable varieties (NTHi) by the presence or absence of the polysaccharide capsule. Invasive disease caused by H. influenzae type B (HIB) can be prevented through vaccination which remains the main disease control intervention in many countries. This study examined the genomic diversity of circulating H. influenzae strains associated with invasive disease in New South Wales, Australia, before and during the COVID-19 pandemic. Ninety-six isolates representing 95 cases of invasive H. influenzae infections (iHi) diagnosed between January 2017 and September 2022 were typed and characterised using whole genome sequencing. These cases were caused by serotypes A (n=24), B (n=35), E (n=3), F (n=2) and NTHi (n=32). There was an apparent decline in the number of iHi infections during the COVID-19 pandemic, with a corresponding increase in the proportion of iHi cases caused by serotype A (HIA), which returned to pre-pandemic levels in 2022. Fifteen isolates associated with HIB or non-typeable iHi were resistant to ß-lactams due to a PBP3 mutation or carriage of blaTEM-1. Further, capsular gene duplication was observed in HIB isolates but was not found in HIA. These findings provide important baseline genomic data for ongoing iHi surveillance and control.

Abemaciclib as adjuvant treatment for high-risk early breast cancer / Abemaciclib en adyuvancia para el tratamiento del cáncer de mama precoz de alto riesgo

Objective: To adapt the GHEMA report of abemaciclib, an inhibitor of cyclin-dependent kinases 4 and 6. European Medicines Agency authorization (April 2022) includes, in combination with endocrine therapy, the adjuvant treatment of adult patients with hormone receptor positive, human epidermal growth factor receptor 2 negative, node-positive, early breast cancer at high risk of recurrence. Method: The efficacy and safety of abemaciclib were evaluated in a randomized, open-label, and multicenter phase III study. A total of 5637 patients diagnosed with early breast cancer with hormone receptor positive, human epidermal growth factor receptor 2 negative, node positive, and high risk of recurrence were included. High risk was defined as patients with 4 or more positive axillary lymph nodes, or 1–3 positive axillary lymph nodes and at least one of the following: tumor size ≥5 cm, histologic grade 3, or Ki-67≥20%. Patients were randomized (1:1) to receive adjuvant abemaciclib+endocrine therapy (n = 2808) or endocrine therapy alone (n = 2829) for 2 years, with endocrine therapy prescribed for at least 5 years. Results: With a median follow-up of 15.5 months, abemaciclib+endocrine therapy demonstrated a statistically significant improvement in invasive disease-free survival versus endocrine therapy alone [HR = 0.747 (95% CI 0.598–0.932), P = 0.0096]; achieving an absolute improvement of 3.5% invasive disease-free survival rate at 2-years. These results were maintained, with a median follow-up of 27.7 months: absolute improvement of 2.7% and 5.4% in invasive disease-free survival rate at 2 and 3 years, respectively. All-causality grade 3 or 4 adverse events were 45.9% for abemaciclib and 12.9% for endocrine therapy, and included neutropenia (19.6% vs. 0.8%), leukopenia (11.4% vs. 0.4%), and diarrhea (7.8% vs. 0.2%). Conclusions: The results of the pivotal trial are sufficient to consider abemaciclib as adjuvant treatment for...(AU)

Objetivo: Adaptar el informe GHEMA de abemaciclib, un inhibidor de quinasas dependientes de ciclinas 4 y 6, con autorización de la Agencia Europea del Medicamento en abril de 2022 para el tratamiento adyuvante de pacientes adultos con cáncer de mama precoz, receptor hormonal positivo, receptor del factor de crecimiento epidérmico negativo, con afectación ganglionar y riesgo elevado de recaída; en combinación con hormonoterapia. Método: La eficacia y seguridad de abemaciclib se evaluó en un estudio fase III multicéntrico, aleatorizado y abierto. Se incluyeron 5.637 pacientes diagnosticados de cáncer de mama precoz con ganglios positivos, receptor hormonal positivo, receptor del factor de crecimiento epidérmico negativo y alto riesgo de recaída. El criterio de alto riesgo se definió como la presencia de ≥ 4 ganglios positivos, o de 1–3 ganglios y al menos una de las siguientes características: tamaño del tumor ≥5 cm, grado histológico 3 o Ki-67 ≥ 20%. Los pacientes fueron aleatorizados (1:1) a recibir durante 2 años abemaciclib + hormonoterapia (n = 2.808) u hormonoterapia sola (n = 2.829). En ambos brazos el tratamiento con hormonoterapia se mantuvo mínimo 5 años. Resultados: Con una mediana de seguimiento de 15,5 meses, abemaciclib + hormonoterapia mostró beneficio significativo frente a la hormonoterapia sola [HR = 0,747 (IC95% 0,598-0,932), p = 0,0096], con una mejora absoluta del 3,5% en la tasa de supervivencia libre de enfermedad invasiva a 2 los años. Este beneficio se mantuvo con una mediana de seguimiento de 27,7 meses, logrando una mejora en la tasa de supervivencia libre de enfermedad invasiva del 2,7% y del 5,4% a los 2 y 3 años, respectivamente. La incidencia de efectos adversos grado 3–4 fue superior en el brazo de abemaciclib (45,9% vs. 12,9%); e incluía neutropenia (19,6% vs. 0,8%), leucopenia (11,4% vs. 0,4%) y diarrea (7,8% vs. 0,2%). Conclusiones: Los resultados del ensayo pivotal son suficientes para considerar abemaciclib como...(AU)

Abemaciclib en adyuvancia para el tratamiento del cáncer de mama precoz de alto riesgo / Abemaciclib as adjuvant treatment for high-risk early breast cancer

Objective: To adapt the GHEMA report of abemaciclib, an inhibitor of cyclin-dependent kinases 4 and 6. European Medicines Agency authorization (April 2022) includes, in combination with endocrine therapy, the adjuvant treatment of adult patients with hormone receptor positive, human epidermal growth factor receptor 2 negative, node-positive, early breast cancer at high risk of recurrence. Method: The efficacy and safety of abemaciclib were evaluated in a randomized, open-label, and multicenter phase III study. A total of 5637 patients diagnosed with early breast cancer with hormone receptor positive, human epidermal growth factor receptor 2 negative, node positive, and high risk of recurrence were included. High risk was defined as patients with 4 or more positive axillary lymph nodes, or 1–3 positive axillary lymph nodes and at least one of the following: tumor size ≥5 cm, histologic grade 3, or Ki-67≥20%. Patients were randomized (1:1) to receive adjuvant abemaciclib+endocrine therapy (n = 2808) or endocrine therapy alone (n = 2829) for 2 years, with endocrine therapy prescribed for at least 5 years. Results: With a median follow-up of 15.5 months, abemaciclib+endocrine therapy demonstrated a statistically significant improvement in invasive disease-free survival versus endocrine therapy alone [HR = 0.747 (95% CI 0.598–0.932), P = 0.0096]; achieving an absolute improvement of 3.5% invasive disease-free survival rate at 2-years. These results were maintained, with a median follow-up of 27.7 months: absolute improvement of 2.7% and 5.4% in invasive disease-free survival rate at 2 and 3 years, respectively. All-causality grade 3 or 4 adverse events were 45.9% for abemaciclib and 12.9% for endocrine therapy, and included neutropenia (19.6% vs. 0.8%), leukopenia (11.4% vs. 0.4%), and diarrhea (7.8% vs. 0.2%). Conclusions: The results of the pivotal trial are sufficient to consider abemaciclib as adjuvant treatment for...(AU)

Objetivo: Adaptar el informe GHEMA de abemaciclib, un inhibidor de quinasas dependientes de ciclinas 4 y 6, con autorización de la Agencia Europea del Medicamento en abril de 2022 para el tratamiento adyuvante de pacientes adultos con cáncer de mama precoz, receptor hormonal positivo, receptor del factor de crecimiento epidérmico negativo, con afectación ganglionar y riesgo elevado de recaída; en combinación con hormonoterapia. Método: La eficacia y seguridad de abemaciclib se evaluó en un estudio fase III multicéntrico, aleatorizado y abierto. Se incluyeron 5.637 pacientes diagnosticados de cáncer de mama precoz con ganglios positivos, receptor hormonal positivo, receptor del factor de crecimiento epidérmico negativo y alto riesgo de recaída. El criterio de alto riesgo se definió como la presencia de ≥ 4 ganglios positivos, o de 1–3 ganglios y al menos una de las siguientes características: tamaño del tumor ≥5 cm, grado histológico 3 o Ki-67 ≥ 20%. Los pacientes fueron aleatorizados (1:1) a recibir durante 2 años abemaciclib + hormonoterapia (n = 2.808) u hormonoterapia sola (n = 2.829). En ambos brazos el tratamiento con hormonoterapia se mantuvo mínimo 5 años. Resultados: Con una mediana de seguimiento de 15,5 meses, abemaciclib + hormonoterapia mostró beneficio significativo frente a la hormonoterapia sola [HR = 0,747 (IC95% 0,598-0,932), p = 0,0096], con una mejora absoluta del 3,5% en la tasa de supervivencia libre de enfermedad invasiva a 2 los años. Este beneficio se mantuvo con una mediana de seguimiento de 27,7 meses, logrando una mejora en la tasa de supervivencia libre de enfermedad invasiva del 2,7% y del 5,4% a los 2 y 3 años, respectivamente. La incidencia de efectos adversos grado 3–4 fue superior en el brazo de abemaciclib (45,9% vs. 12,9%); e incluía neutropenia (19,6% vs. 0,8%), leucopenia (11,4% vs. 0,4%) y diarrea (7,8% vs. 0,2%). Conclusiones: Los resultados del ensayo pivotal son suficientes para considerar abemaciclib como...(AU)

Rehabilitation Outcomes in Multiple Sclerosis Patients on Ocrelizumab Diagnosed With West Nile Virus Encephalitis.

Multiple sclerosis (MS) has a global prevalence exceeding two million people and is a leading cause of non-traumatic physical disability. MS can be treated with ocrelizumab, an anti-CD20 monoclonal antibody. West Nile virus (WNV) is the most common cause of mosquito-borne viral encephalitis in North America. It can lead to neuroinvasive WNV disease (WNND) affecting the brain and peripheral nervous system, especially in immunocompromised patients, such as those being treated with ocrelizumab for MS. WNND is exceedingly rare and reported in less than 1% of cases of WNV. It has been established that inpatient rehabilitation improves functional outcomes in patients with MS and those with WNND. However, the inpatient rehabilitation outcomes in patients diagnosed with both WNND and MS have not been reported. In this study, we aimed to examine the rehabilitation outcomes of MS patients on ocrelizumab diagnosed with WNND. We performed a retrospective chart review of patients with MS treated with ocrelizumab, who were diagnosed with WNND and admitted to a single facility. Rehabilitation outcomes were assessed using functional independence measure (FIM) scores on admission and discharge. Three patients met the inclusion criteria; two in acute rehab, and one in the long-term acute care hospital (LTACH). Both patients admitted to acute inpatient rehabilitation showed an improvement in FIM scores from admission to discharge, one patient from 9 to 16 and the other from 14 to 54. However, the patient admitted to the LTACH had no improvement in FIM score from admission to discharge. Patients admitted to acute rehab were ultimately discharged home, while the patient admitted to the LTACH required discharge to a subacute rehabilitation facility. Based on our findings, intense and prolonged comprehensive inpatient rehabilitation is associated with improved functional outcomes and increased likelihood of discharge to home in this population suffering from both central and peripheral nervous system involvement due to MS and WNND.

Incidence of invasive infections with Group B streptococcus in adults in Norway 1996-2019: a nationwide registry-based case-control study.

PURPOSE: Group B streptococcus (GBS) colonizes the gastrointestinal and vaginal mucosa in healthy adults, but has also become an increasing cause of invasive infection. The aims of this study were to describe the incidence and factors associated with the occurrence of invasive GBS disease in adults in Norway. METHODS: We performed a nationwide retrospective case-control study of invasive GBS infections during 1996-2019, with two control groups; invasive Group A streptococcal disease (GAS) to control for changes in surveillance and diagnostics, and a second representing the general population. RESULTS: A total of 3710 GBS episodes were identified. The age-standardized incidence rate increased steadily from 1.10 (95% CI 0.80-1.50) in 1996 to 6.70 (95% CI 5.90-7.50) per 100,000 person-years in 2019. The incidence rate had an average annual increase of 6.44% (95% CI 5.12-7.78). Incidence rates of GAS varied considerably, and there was no evidence of a consistent change over the study period. GBS incidence was highest among adults > 60 years of age. Cardiovascular disease, cancer, and diabetes were the most common comorbid conditions. There was a shift in the distribution of capsular serotypes from three dominant types to more equal distribution among the six most common serotypes. CONCLUSIONS: The incidence of invasive GBS disease in adults increased significantly from 1996 to 2019. The increasing age of the population with accompanying underlying comorbid conditions might contribute to the increasing burden of invasive GBS disease. Interestingly, type 1 diabetes was also associated with the occurrence of invasive GBS disease.

Clinical Disease and Outcomes of Group B Streptococcus Bloodstream Infections at a Teaching Hospital in Saudi Arabia From 2015 to 2022.

Background Invasive disease due to group B Streptococcus (GBS) infection in adult males and nonpregnant females can cause various diseases, such as primary bacteremia, endocarditis, skin and soft tissue infection (SSTI), and meningitis. Especially in older people, invasive GBS infection has a high case fatality rate. In Saudi Arabia, little is known about the clinical signs and symptoms of GBS bacteremia and the associated risk factors and mortality rate. Methodology We performed a retrospective study at King Abdulaziz University Hospital in Jeddah, Saudi Arabia, a large tertiary hospital, to investigate clinical disease, potential risk factors, susceptibility patterns, and mortality related to GBS in adult males and nonpregnant females diagnosed with GBS bacteremia. All patients ≥14 years of age with GBS-positive blood cultures from January 1, 2015, until December 31, 2022, were included. Patient data such as age, sex, comorbidities, hospital ward, length of hospital stay, monomicrobial versus polymicrobial bloodstream infection, antimicrobials used for treatment, complications, whether an infectious disease specialist had seen them, and outcomes were extracted from the electronic health records. Results A total of 50 patients with GBS bacteremia met the inclusion criteria. The mean age of these patients was 57.0 years (SD = 16.0), and 27 (54%) were female. The 90-day mortality was 11 (22%). In total, 34 (68%) patients had a monomicrobial infection, and among those with polymicrobial infection, methicillin-resistant Staphylococcus aureus was the most common co-infection (56%, n = 9/16). The most common source of infection was SSTI and wound infection in 24 (48%) patients. Most patients had one or more comorbidities; the mean Charlson comorbidity index was 3.8 (SD = 2.4). The most prevalent comorbidity was diabetes mellitus in 35 (70%) patients. Of all variables analyzed, only age was significantly associated with mortality (p = 0.016), and age had a predictive value for mortality (p = 0.035). Conclusions In Saudi Arabia, as in other countries, GBS is an important pathogen, especially in older people, that should be considered when encountering a patient with bacteremia. In addition, in patients over 65 years old, GBS bacteremia carries a high risk for mortality.

Clinical, microbiological, and molecular characterization of pediatric invasive infections by Streptococcus pyogenes in Spain in a context of global outbreak.

In December 2022, an alert was published in the UK and other European countries reporting an unusual increase in the incidence of Streptococcus pyogenes infections. Our aim was to describe the clinical, microbiological, and molecular characteristics of group A Streptococcus invasive infections (iGAS) in children prospectively recruited in Spain (September 2022-March 2023), and compare invasive strains with strains causing mild infections. One hundred thirty isolates of S. pyogenes causing infection (102 iGAS and 28 mild infections) were included in the microbiological study: emm typing, antimicrobial susceptibility testing, and sequencing for core genome multilocus sequence typing (cgMLST), resistome, and virulome analysis. Clinical data were available from 93 cases and 21 controls. Pneumonia was the most frequent clinical syndrome (41/93; 44.1%), followed by deep tissue abscesses (23/93; 24.7%), and osteoarticular infections (11/93; 11.8%). Forty-six of 93 cases (49.5%) required admission to the pediatric intensive care unit. iGAS isolates mainly belonged to emm1 and emm12; emm12 predominated in 2022 but was surpassed by emm1 in 2023. Spread of M1UK sublineage (28/64 M1 isolates) was communicated for the first time in Spain, but it did not replace the still predominant sublineage M1global (36/64). Furthermore, a difference in emm types compared with the mild cases was observed with predominance of emm1, but also important representativeness of emm12 and emm89 isolates. Pneumonia, the most frequent and severe iGAS diagnosed, was associated with the speA gene, while the ssa superantigen was associated with milder cases. iGAS isolates were mainly susceptible to antimicrobials. cgMLST showed five major clusters: ST28-ST1357/emm1, ST36-ST425/emm12, ST242/emm12.37, ST39/emm4, and ST101-ST1295/emm89 isolates. IMPORTANCE: Group A Streptococcus (GAS) is a common bacterial pathogen in the pediatric population. In the last months of 2022, an unusual increase in GAS infections was detected in various countries. Certain strains were overrepresented, although the cause of this raise is not clear. In Spain, a significant increase in mild and severe cases was also observed; this study evaluates the clinical characteristics and the strains involved in both scenarios. Our study showed that the increase in incidence did not correlate with an increase in resistance or with an emm types shift. However, there seemed to be a rise in severity, partly related to a greater rate of pneumonia cases. These findings suggest a general increase in iGAS that highlights the need for surveillance. The introduction of whole genome sequencing in the diagnosis and surveillance of iGAS may improve the understanding of antibiotic resistance, virulence, and clones, facilitating its control and personalized treatment.

M1UKStreptococcus pyogenes causing community-acquired pneumonia, pleural empyema and streptococcal toxic shock syndrome.

OBJECTIVES: Streptococcus pyogenes causes superficial infections but can also cause deep-seated infections and toxin-mediated diseases. In the present study, phylogenetic and in silico prediction analyses were performed on an antimicrobial resistant M1UKS. pyogenes strain causing severe clinical manifestations during the current surge of invasive group A Streptococcus (iGAS) disease. METHODS: A 40-year-old patient was admitted to the hospital with fever, chest pain and fatigue. Based on the clinical and laboratory findings, a diagnosis of sepsis with disseminated intravascular coagulation, community-acquired pneumonia, pleural empyema and streptococcal toxic shock syndrome was made. Microbial identification was performed by multiplex PCR and conventional culturing. Furthermore, antimicrobial susceptibility testing, whole genome sequencing, phylogenomic analysis and in silico prediction analysis of antimicrobial resistance genes and virulence factors were performed. RESULTS: S. pyogenes isolates were detected in pleural fluid and sputum of the patient. Both isolates belonged to the M1UK lineage of the emm1/ST28 clone, being closely related with an M1UK GAS strain from Australia. They exhibited resistance to erythromycin and clindamycin and susceptibility-increased exposure to levofloxacin and carried genes encoding for protein homologues of antibiotic efflux pumps. Moreover, several virulence factors, and a previously described single-nucleotide polymorphism in the 5' transcriptional leader sequence of the ssrA gene, which enhances expression of SpeA, were detected. CONCLUSIONS: The present antimicrobial-resistant M1UKS. pyogenes strain represents the first report of this emerging lineage associated with such manifestations of iGAS disease.

One small step for stool, one giant leap for IBD surveillance.

Inflammatory bowel diseases (IBDs) are chronic conditions in which the digestive tract undergoes cycles of relapsing and remitting inflammatory episodes that cause patients to experience severe abdominal pain, bleeding, and diarrhea. Developing noninvasive and cost-effective surveillance methods that can detect an ensuing disease bout proffers an avenue to improve the quality of life for patients with IBD. Now, a recent report describes an ingenious, economical approach using a rationally designed Escherichia coli strain that can dynamically monitor inflammation inside the mammalian gastrointestinal tract. The ability of the engineered probiotic to specifically discern between dormant and activated inflammatory states of the digestive system demonstrates that living biosensors can be used to monitor health status, thus providing a powerful proof of concept that heralds the arrival of a new age of clinical diagnostics for people living with inflammatory diseases of the gut.

State transitions across the Strep A disease spectrum: scoping review and evidence gaps.

The spectrum of diseases caused by Streptococcus pyogenes (Strep A) ranges from superficial to serious life-threatening invasive infections. We conducted a scoping review of published articles between 1980 and 2021 to synthesize evidence of state transitions across the Strep A disease spectrum. We identified 175 articles reporting 262 distinct observations of Strep A disease state transitions. Among the included articles, the transition from an invasive or toxin-mediated disease state to another disease state (i.e., to recurrent ARF, RHD or death) was described 115 times (43.9% of all included transition pairs) while the transition to and from locally invasive category was the lowest (n = 7; 0.02%). Transitions from well to any other state was most frequently reported (49%) whereas a relatively higher number of studies (n = 71) reported transition from invasive disease to death. Transitions from any disease state to locally invasive, Strep A pharyngitis to invasive disease, and chronic kidney disease to death were lacking. Transitions related to severe invasive diseases were more frequently reported than superficial ones. Most evidence originated from high-income countries and there is a critical need for new studies in low- and middle-income countries to infer the state transitions across the Strep A disease spectrum in these high-burden settings.

Abemaciclib as adjuvant treatment for high-risk early breast cancer.

OBJECTIVE: To adapt the GHEMA report of abemaciclib, an inhibitor of cyclin-dependent kinases 4 and 6. European Medicines Agency authorization (April 2022) includes, in combination with endocrine therapy, the adjuvant treatment of adult patients with hormone receptor positive, human epidermal growth factor receptor 2 negative, node-positive, early breast cancer at high risk of recurrence. METHOD: The efficacy and safety of abemaciclib were evaluated in a randomized, open-label, and multicenter phase III study. A total of 5637 patients diagnosed with early breast cancer with hormone receptor positive, human epidermal growth factor receptor 2 negative, node positive, and high risk of recurrence were included. High risk was defined as patients with 4 or more positive axillary lymph nodes, or 1-3 positive axillary lymph nodes and at least one of the following: tumor size ≥5 cm, histologic grade 3, or Ki-67≥20%. Patients were randomized (1:1) to receive adjuvant abemaciclib+endocrine therapy (n = 2808) or endocrine therapy alone (n = 2829) for 2 years, with endocrine therapy prescribed for at least 5 years. RESULTS: With a median follow-up of 15.5 months, abemaciclib+endocrine therapy demonstrated a statistically significant improvement in invasive disease-free survival versus endocrine therapy alone [HR = 0.747 (95% CI 0.598-0.932), P = 0.0096]; achieving an absolute improvement of 3.5% invasive disease-free survival rate at 2-years. These results were maintained, with a median follow-up of 27.7 months: absolute improvement of 2.7% and 5.4% in invasive disease-free survival rate at 2 and 3 years, respectively. All-causality grade 3 or 4 adverse events were 45.9% for abemaciclib and 12.9% for endocrine therapy, and included neutropenia (19.6% vs. 0.8%), leukopenia (11.4% vs. 0.4%), and diarrhea (7.8% vs. 0.2%). CONCLUSIONS: The results of the pivotal trial are sufficient to consider abemaciclib as adjuvant treatment for high-risk early breast cancer in highly selected patients. However, in order to the efficacy results present less uncertainty, we must wait for a evaluation later, in which we can have a mature determination at 3 years (with more patients at risk).

Upstaging after Transurethral Resection of the Bladder for Non-Muscle-Invasive Cancer of the Bladder: Who Is at Highest Risk?

INTRODUCTION: Transurethral resection of the bladder (TUR-BT) is the standard initial treatment and diagnosis of bladder cancer (BC). Of note, upstaging into muscle-invasive disease (MIBC) during re-resection occurs in a significant proportion of patients. This study aimed to define risk factors at initial TUR-BT for upstaging. METHODS: TUR-BT between 2009 and 2021 were retrospectively screened (n = 3,237). We included patients with visible tumors that received their primary and re-TUR-BT at our institution. Upstaging was defined as pathological tumor stage progression into MIBC at re-TUR-BT. Clinicopathological variables were analyzed for the impact on upstaging. RESULTS: Two hundred and sixty-six patients/532 TUR-BTs were included in the final analysis. Upstaging occurred in 7.9% (21/266) patients. Patients with upstaging presented with stroma-invasive and papillary non-muscle-invasive BC at primary resection in 85.7% (18/21) and 14.3% (3/21), respectively. Detrusor muscle at primary TUR-BT was significantly less present in patients with upstaging (4.1 vs. 95.9%; p < 0.001). After multivariate analysis, solid tumor configuration (HR: 4.17; 95% CI: 1.23-14.15; p = 0.022) and missing detrusor muscle at initial TUR-BT (HR: 3.58; 95% CI: 1.05-12.24; p = 0.043) were significant risk factors for upstaging into MIBC. CONCLUSIONS: The current study defined two major risk factors for upstaging: missing detrusor muscle and solid tumor configuration. We propose that a second resection should be performed earlier if these risk factors apply.

Abemaciclib as adjuvant treatment for high-risk early breast cancer. / [Artículo traducido] Abemaciclib en adyuvancia para el tratamiento del cáncer de mama precoz de alto riesgo.

OBJECTIVE: To adapt the GHEMA report of abemaciclib, an inhibitor of cyclin-dependent kinases 4 and 6. European Medicines Agency authorisation (April 2022) includes, in combination with endocrine therapy, the adjuvant treatment of adult patients with hormone receptor positive, human epidermal growth factor receptor 2 negative, node-positive, early breast cancer at high risk of recurrence. METHOD: The efficacy and safety of abemaciclib were evaluated in a randomized, open-label and multicenter phase III study. A total of 5,637 patients diagnosed with early breast cancer with hormone receptor positive, human epidermal growth factor receptor 2 negative, node positive and high risk of recurrence were included. High risk was defined as patients with 4 or more positive axillary lymph nodes, or 1-3positive axillary lymph nodes and at least one of the following: tumor size ≥5 cm, histologic grade 3 or Ki-67 ≥ 20%. Patients were randomized (1:1) to receive adjuvant abemaciclib + endocrine therapy (n = 2,808) or endocrine therapy alone (n = 2,829) for 2 years, with endocrine therapy prescribed for at least 5 years. RESULTS: With a median follow-up of 15.5 months, abemaciclib + endocrine therapy demonstrated a statistically significant improvement in invasive disease-free survival versus endocrine therapy alone (HR = 0.747 [95% CI 0.598-0.932], p = 0.0096); achieving an absolute improvement of 3.5% invasive disease-free survival rate at 2-years. These results were maintained, with a median follow-up of 27.7 months: absolute improvement of 2.7% and 5.4% in invasive disease-free survival rate at 2 and 3-years, respectively. All-causality grade 3 or 4 adverse events were 45.9% for abemaciclib and 12.9% for endocrine therapy, and included neutropenia (19.6% vs. 0.8%), leukopenia (11.4% vs. 0.4%) and diarrhea (7.8% vs. 0.2%). CONCLUSIONS: The results of the pivotal trial are sufficient to consider abemaciclib as adjuvant treatment for high-risk early breast cancer in highly selected patients. However, in order to the efficacy results present less uncertainty, we must wait for a evaluation later, in which we can have a mature determination at 3 years (with more patients at risk).