Pyelonephritis (Kidney Infection)

The goal of this study is to improve the diagnosis of urinary tract infections (UTI) in older people (≥65 years). The main research questions are: Research questions * What is the optimal cut-off for each individual biomarker NGAL,IL-6,AZU,TIMP2 and CXCL9 and associated, sensitivity, specificity, negative and positive predictive value. * sensitivity, specificity, negative and positive predictive value of a urine leukocyte count cut-off of 200 cells/microL (validation) * What is the optimal combination of biomarkers for UTI diagnosis in older patients * As a secondary objective this study aims to evaluate the association between the levels of individual biomarker levels and 1) duration of symptoms 2) complications, 3) recurrence of UTI within 2 months, and length of hospital stay. Next to this, the performance of the astrego PA100 will be validated in diagnosing bacteriuria. Participants will: * be asked to provide a urine sample once at the beginning of the study * be asked to answer some questions about their symptoms and overall health at the beginning of the study and after 8 weeks * have their vital parameters (temperature and blood pressure) measured once at the beginning of the study

1.0 Hypothesis for the study Antibiotic therapies currently recommended for the treatment of acute pyelonephritis (AP) in children, whether fully by the oral route or initially intravenous (IV, 3 days) followed by the oral route, have a duration of 7 to 14 days (10 days in France). In children with no prior urological malformation, the global clinical and microbiological cure rate after antibiotic treatment completion is around 95%. Recurrence occurs in less than 5% of cases in the 3 months following AP. Renal scarring, when documented, concerns 15% of children 6 months after treatment. Renal scarring can be associated with chronic renal disease. The investigators hypothesize that 3 days of IV treatment is equivalent to extending to 10 days with an oral therapy to prevent long-term renal scarring. The investigators also hypothesize that while achieving equivalent clinical and microbiological success, and prevention of re-infections in the following 3 months, 3 days of IV treatment reduces the risk of acquisition of resistant strains of Enterobacteriaceae and increases the gut microbotia diversity compared to extending to 10 days with an oral therapy. 2.0 Description of knowledge relating to the condition in question Acute pyelonephritis (AP) is the most common proven bacterial infection in pediatric clinical practice. It can lead to sepsis or renal abscess and induce long-term complications such as renal scarring. Renal scarring during childhood can lead to hypertension or chronic renal disease at adult age, although the link between AP and chronic renal disease has not been firmly established. AP is most frequently due to Enterobacteriaceae, mainly Escherichia coli. Extended-spectrum beta-lactamase producing Enterobacteriaceae (ESBL-E) now account for 5% of AP in France and represent a serious threat to public health, owing to limited therapeutic options. The overall clinical success rate in children treated for AP is around 95% and is not significantly different when ESBL-E are implicated. In children with no prior urological malformation, recurrence in the following 3 months occurs in less than 5% of cases. Antibiotic treatment decreases the risk of renal scarring, which remains important, around 15% (95% CI: 11-18) in the largest meta-analysis. Moreover, delay in treatment of AP is associated with permanent renal scarring. In children without prior urological malformation, acute complications are exceptional, even in the presence of bacteraemia. Short courses of intravenous (IV) antibiotics (2-4 days) followed by oral therapy have proved to be as efficient as longer courses (7-14 days) of IV treatment. For children aged ≥ 1 month, oral treatment alone for 10 to 14 days has proved non inferior to initial IV antibiotics (2-4 days) followed by oral therapy (total 10 to 14 days). French Paediatric guidelines recommend a short course (up to 4 days) of IV amikacin and/or ceftriaxone followed by oral therapy (total 10 days), with the possibility, for children aged \> 3 months of a 10-day course of oral cefixime \[12\]. In children initially treated IV, the oral relay occurs once the urine culture and antibiogram are available. The American Association of Pediatrics that focused on children aged 2 to 24 months recommends either an oral or a sequential IV/oral treatment for a total of 7 to 14 days, while the British NICE guidelines recommend an exclusively oral route only for children aged ≥ 3 months In practice, most centers initiate an IV treatment in a large subset of patients (ongoing practice analysis on the management of AP in children in France, personal data, to be published in 2021). An initial IV treatment is particularly used in young children, with an age cut-off varying between 3 months and 3 years according to the center. It is also used to secure the absorption of the treatment if the child vomits, is unable to take oral antibiotics or is severely unwell. The excellent short-term and the good long-term clinical outcomes in children treated for AP questions the need for a 10-day course of antibiotics. In adults, shorter treatments, such as amikacin for 5 days, have been validated for the treatment of uncomplicated AP. Recently published studies (Zaoutis 2023, Montini 2024) have compared a 5-day oral treatment vs 10-day oral treatment for AP in children. However, the first study (Zaoutis 2023) mainly included (63%) children with a non-febrile urinary tract infection (ie not an AP). The second only included children aged \> 3 month. A practice survey conducted prior to our protocol had shown that many departments were already reluctant to treat infants under 1 year old, and particularly those under 3 months old, by oral route, warranting clinical trials including children \< 3 month old. Third-generation cephalosporins (3GC), such as ceftriaxone, rapidly reduce the richness and diversity of the gut microbiota and also select subpopulations of resistant bacteria, particularly by acquisition of extended spectrum beta-lactamases, a major public health issue. There is no data on the impact of antibiotic relays on the gut microbiota. Since each antibiotic has its own anti-bacterial spectrum, a sequence of treatments could have an additive or even synergistic deleterious effect on the gut microbiota. This may in particular be the case in children treated with IV ceftriaxone for 3 days followed by cotrimoxazole for 7 days, as recommended in France in first intention. 3.0 Summary of relevant pre-clinical experiments and clinical trials 1999 Hoberman et al. Oral versus initial intravenous therapy for urinary tract infections in young febrile children This was a non-inferiority study between oral cefixime for 14 days and intravenous ceftriaxone for 3 days followed by oral cefixime for 11 days. One of the outcomes was the occurrence of renal scarring. It included children aged 1 to 24 months. A total of 306 children were included. Renal scarring at 6 months was noted in 9.8% children treated orally versus 7.2% of children treated intravenously. The study conclude that oral treatment was safe. The main limit of the study was the lower rate of renal scar in both arms compared to other studies, probably linked to a female/male sex ratio of 9:1 (with a median age of 8 months), when the sex ratio is in favour of boys before 1-year-old. 2007, Montini et al. Antibiotic treatment for pyelonephritis in children: multicentre randomised controlled non-inferiority trial This was a multicentre, randomised controlled, open labelled, parallel group, non-inferiority trial comparing oral co-amoxiclav for 10 days to parenteral ceftriaxone for three days, followed by oral co-amoxiclav for 7 days. Primary outcome was the rate of renal scarring after 12 months. A total of 502 children aged 1 month to \<7 years with clinical pyelonephritis were included. Intention to treat analysis showed no significant differences between oral (n=244) and parenteral (n=258) treatment, both in the primary outcome (scarring scintigraphy at 12 months 27/197 (13.7%) v 36/203 (17.7%), and secondary outcomes: time to defervescence, white cell count at day 3, and percentage with sterile urine at day 3 (99.5% n both arms). The results were similar in the subgroups of children older and younger than 2 years (data not shown in the paper). 2012, Boquet et al. Randomized trial of oral versus sequential IV/oral antibiotic for acute pyelonephritis in children PHRC AOM 04 105; NCT00136656 This was a non-inferiority study between oral cefixime for 10 days and IV ceftriaxone for 4 days followed by oral cefixime for 6 days on the occurrence of renal scarring. It included children aged 1 to 36 mont with a first proven urinary tract infection and procalcitonin concentration ≥ 0.5 ng/mL s. The primary endpoint was the proportion of renal scar measured by 99mTc-DMSA renal scintigraphy 6 to 8 months after treatment. The study included a total 171 children of the 698 expected. The incidence of renal scarring was 30.8% in the oral treatment group and 27.3% for children who received the sequential treatment. The trial could not demonstrate statistically the non-inferiority due to insufficient enrolment. 2023, Zaoutis et al. Short-Course Therapy for Urinary Tract Infections in Children: The SCOUT Randomized Clinical Trial PMID: 37358858 ; NCT01595529, This was a randomized clinical noninferiority trial at 2 children's hospitals. Participants included children aged 2 months to 10 years with UTI exhibiting clinical improvement after 5 days of antimicrobials. The study compared another 5 days of antimicrobials (standard-course therapy) or 5 days of placebo (short-course therapy). The primary outcome, treatment failure, was defined as symptomatic UTI at or before the first follow-up visit (day 11 to 14 A total of 664 children were randomized (639 female \[96%\]; median age, 4 years): 2 of 328 assigned to standard-course (0.6%) and 14 of 336 assigned to short-course (4.2%) had a treatment failure. There were no differences between groups in rates of UTI after the first follow-up visit, incidence of adverse events, or incidence of gastrointestinal colonization with resistant organisms. 2024, Montini et al. Short Oral Antibiotic Therapy for Pediatric febrile Urinary Tract Infections: A Randomized Trial. \[25\] PMID: 38146260 This was a multicenter, investigator-initiated, parallel-group, randomized, controlled trial. We randomly assigned children aged 3 months to 5 years with a noncomplicated fUTI to receive amoxicillin-clavulanate for 5 or 10 days. The primary end point was the recurrence of a urinary tract infection within 30 days after the completion of therapy. Secondary end points were the difference in prevalence of clinical recovery, adverse drug-related events, and resistance to amoxicillin-clavulanic acid and/or to other antibiotics when a recurrent infection occurred. The study included a total of,175 children and 142 underwent randomization. The recurrence rate of UTI within 30 days of the end of therapy was 2.8% (2/72) in the short group and 14.3% (10/70) in the standard group. The recurrence rate of fUTI within 30 days from the end of therapy was 1.4% (1/72) in the short group and 5.7% (4/70) in the standard group.

Over 90% of adult males develop lower urinary tract symptoms (LUTS) secondary to bladder outlet obstruction by age 80, rendering benign prostatic hyperplasia (BPH) the most common proliferative abnormality in humans. LUTS secondary to BPH negatively impact the quality of life of 210 million men globally, accounting for significant life years lost, in addition to costing the US healthcare system over $4 billion per year. Medical therapy for the management of BPH, which includes α-adrenergic blockers (e.g., doxazosin, terazosin, tamsulosin or alfuzosin) and 5α reductase inhibitors (5ARI, i.e., finasteride or dutasteride) targets both stromal and epithelial cells in the prostate gland. Utilization of 5ARI remains ineffective in many patients, leading to invasive therapies in many patients. 5ARI's are the only class of BPH-related drugs that reduce prostate size for the alleviation of LUTS. However, the Medical Therapy of Prostatic Symptoms (MTOPS) trial, which randomized 3047 men, showed that 34% of BPH patients did not respond to individualized treatment with finasteride or doxazosin, while combining the 5ARI and α-blocker relieved LUTS in 66% of BPH patients. Resistance to 5ARI therapy is a major factor limiting the effectiveness of these agents in the management of BPH. Therefore, understanding the molecular pathogenesis of 5ARI resistance is a High-Priority Recommendation of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Prostate Research Strategic Plan. However, it is not yet possible to predict responders vs. non-responders to 5ARI therapy, which creates a significant gap in our ability to effectively manage patients with BPH. 5α reductase (5-AR) plays a critical role in the normal development of the human prostate and in the pathogenesis and progression of prostatic diseases. There are three types of 5-AR isozymes, Steroid 5 Alpha-Reductase 1, 2 3 (SRD5A1, SRD5A2 and SRD5A3), which are encoded by three distinct corresponding genes, SRD5A1, SRD5A2 and SRD5A3. Many studies suggest that all three 5-AR enzymes are expressed in prostate tissues; however, SRD5A2 is the predominant enzyme responsible for prostate development and growth. In addition, since the most commonly prescribed 5ARI, finasteride, is an inhibitor of SRD5A2, regulation of SRD5A2 will remain the focus of this study. It was previously shown that the mechanism of somatic suppression of SRD5A2 during adulthood is dependent on epigenetic changes in the promoter region of the SRD5A2 gene. DNA methylation is one of the most common epigenetic mechanisms affecting gene expression. Methylation of Cytosine-Phosphate-Guanine (CpG) islands has been associated with the regulation of genes during development, cancer initiation, and metastasis. Since the prostate is the only solid organ that grows during adulthood as a result of androgen exposure, it can be considered a benign tumor growth throughout adulthood. Therefore, similar to the neoplastic initiation and progression of many cancers, including prostate cancer, epigenetic changes and variable expression of SRD5A2 in benign prostate tissue is a plausible molecular mechanism. Finasteride, the most commonly prescribed 5ARI, is an inhibitor of SRD5A2. Finasteride has been shown in several large clinical trials to reduce prostate size by 20%, improve urinary flow rate, and improve urinary bothersome symptom scores in men suffering from bladder outlet obstruction caused by BPH. Despite their widespread use and clinical effectiveness, 25% to 30% of patients are resistant to the therapeutic effects of 5ARIs and another 5% to 7% of patients develop worsening symptoms and ultimately may require surgery. Given their age and comorbidities, these patients are often not ideal candidates for surgery. Therefore, understanding the mechanisms of 5ARI treatment failure may pave the way for the development of new medical therapies appropriately targeted to these specific patient groups and is a desirable way to move forward with precision medicine. This proposed work is based on the premise that epigenetic changes to SRD5A2 account for the significant number of patients who are unresponsive to 5ARI therapy. The goal is to assess SRD5A2 methylation and expression as a gene signature to predict which patients will respond to 5ARI therapy. The information gained from this proposal will pave the way toward the development of predictive biomarker assays that can be used to evaluate resistance to BPH-related therapies and allow clinicians to select alternate therapies for managing the most common proliferative disorder affecting men worldwide.

PeriPREVENT is a prospective, multi-centre, controlled, open-label, 1:1 randomized superiority trial with two parallel groups. In the intervention group patients will undergo a routine peripheral angiographic intervention (PVI) using a maximally contrast medium sparing strategy with an automated CO2 injection system including iodinated CM as bailout option in case of insufficient image quality or patient's intolerability of CO2 angiography. The control intervention is routine PVI using iodinated contrast media (CM) as standard of care. All patients are followed up until 12 months after the PVI.

* At the time of consent, participants will be given 20 mg/kg of the antibiotic, ciprofloxacin. If the participant has symptoms of a UTI or have a positive urine culture at enrollment, they will take the antibiotic every 12 hours for 14 days. If the participant does not have symptoms of a UTI at enrollment, the antibiotic will be taken only if needed at home upon the first occurrence of a UTI. * At the time of consent, participants will also be given 250 mg of the probiotic, S. boulardii, taken once daily for 6 months, irrespective of symptoms. \- Throughout the study, participants will receive their standard clinical care for recurrent UTI treatment, which includes bowel and bladder dysfunction management and other prescribed non-antibiotic interventions at the managing provider's clinical discretion.

A prospective Danish national registry of percutaneous transluminal renal angioplasty (PTRA) in high-risk patients with renal artery stenosis selected on the basis of common national criteria, and with a common follow-up protocol for all three Danish centres offering PTRA

The ENVELOP study aims to assess cardiorenal outcomes following enavogliflozin administration compared with dapagliflozin or empagliflozin in Korean patients with type 2 diabetes, representing the first large-scale SGLT2 inhibitor outcome study targeting this population.

Adult patients admitted to EICU of our hospital who met the diagnostic criteria for sepsis were included in the study. Patients with intra-abdominal sepsis were divided into survival group and death group for case control. Exclusion criteria: open chest and abdomen injury, advanced tumor, uremia, pregnancy. The primary endpoint was survival. Extraction time: ICU (0h), ICU (6h, that is, after fluid resuscitation), ICU (24h), ICU (48h, 08:00 a.m.), ICU (72h, 08:00 a.m.), ICU (120h, 08:00 a.m.); Monitoring indicators: antral cross-section area, colon diameter, colon peristalsis frequency, renal artery resistance index, CVP, ScvO2, IL6, blood lactic acid, blood creatinine, fluid intake, bladder pressure. The primary endpoint of the study was survival rate, and statistical analysis was performed to evaluate the progression of enterorenal syndrome, provide reliable objective basis for subsequent clinical decision-making, and improve the success rate of rescue.

This study will consist of two parts. Part 1 - Dose regimen selection: An open-label, 30 patient, 3-arm PK assessment of: Arm 4 (previously 1): LBP-EC01 (approximately 2×10\^12 PFU) given by IU administration on D1 and D2 and LBP-EC01 (approximately 1×10\^11 PFU) IV given as a 1 milliliter (mL) bolus QD from D1 through D3 concomitantly with oral trimethoprim/sulfamethoxazole (TMP 160mg/SMX 800mg) BID from D1 through D3 (6 doses); Arm 5 (previously 2): LBP-EC01 (approximately 2×10\^12 PFU) given by IU administration on D1 and D2 and LBP-EC01 (approximately 1×10\^10 PFU) IV given as a 1 mL bolus QD from D1 through D3 concomitantly with oral TMP/SMX BID from D1 through D3 (6 doses); Arm 6 (previously 3): LBP-EC01 (2×10\^12 PFU) given by IU administration on D1 and D2 and LBP-EC01 (approximately 1×10\^12 PFU) IV given as a 100 mL IV infusion over 2 h on D1 through D3 concomitantly with oral TMP/SMX BID from D1 through D3 (6 doses). Part 2 - Efficacy, Safety, Tolerability and Pharmacokinetics: A blinded, 288 patient, 1:1 randomized evaluation of the Arm 4 dose regimen, selected from Part 1, versus placebo + antibiotic (TMP/SMX -160 mg TMP and 800 mg SMX) given orally BID on Days 1 through 3.

This clinical trial consists of 2 parts. Part 1 will consist of antigen dose-escalation (start with least dose with gradual increase in dose) Safety Lead-In (SLI) in healthy participants. Part 2 (Proof of Principle \[PoP\]) will start after the safety review of all safety data in Part 1 and will consist of participants with history of at least 1 episode of urine culture confirmed E. coli UTI in the last 12 months prior to the study intervention administration.