There are a number of scientific questions that are novel or controversial, which are clinically relevant in the real-world setting for patients diagnosed with bladder cancer, independently of the stage of disease or the histological type and grade of the tumors. These transversal topics have been discussed by a panel of expert specialists who participated in the Genitourinary Alliance Project, aimed to develop actions focused on the integration of relevant information into clinical practice. Advances in radiological imaging techniques have the potential of improving accuracy of staging methods, resulting in a more personalized planning and therapeutic option. The use of liquid biopsy will undoubtedly contribute to an increase in the efficiency of the evaluation of the clinical response and outcome of the disease. It is important to consider specific conditions of elderly people with bladder cancer, as well as the implementation of appropriate measures to enhance safe drug administration.Recommendations regarding transversal topics applicable to bladder cancer patients independent of tumor grade and stage were established by members of the Spanish Oncology Genitourinary Multidisciplinary Working Group (SOGUG). Liquid biopsy in urine and blood samples is useful in the surveillance of non-muscle-invasive and muscle-invasive bladder cancer, respectively. Multiparametric MRI is an accurate, faster and non-invasive staging method overcoming the understaging risk of other procedures. The combination of FDG-PET/MRI could improve diagnostic reliability, but definite criteria for imaging interpretation are still unclear. Hospital oncology pharmacists as members of tumor committees improve the safety of drug use. Additionally, safety recommendations during BCG preparation should be strictly followed. The initial evaluation of patients with bladder cancer should include a multidimensional geriatric assessment. Orthotopic neobladder reconstruction should be offered to motivated patients with full information of self-care requirements. Bladder-sparing protocols, including chemoradiation therapy and immune checkpoints inhibitors (ICIs), should be implemented in centers with well-coordinated multidisciplinary teams and offered to selected patients. The optimal strategy of treatment with ICIs should be defined from the initial diagnostic phase with indications based on scientific evidence. Centralized protocols combined with the experience of professional groups are needed for the integral care of bladder cancer patients. The increasing availability of novel treatment options and improved oncological outcomes of patients with urothelial bladder cancer have contributed to a recent change towards the challenge for clinical implementation of personalized medicine. Despite impressive advances in tumor biology in terms of genetic mutations and molecular subtypes providing the possibility of tailor-made therapeutic approaches for patients suffering from bladder cancer, a lot of questions remain to be answered. Although inter- and intratumoral heterogeneity represents a difficulty for the clinical implementation of personalized medicine, there are number of transversal topics that are relevant in the real-world setting and are interesting to be considered in the broad overview of bladder cancer patients. Some of these transversal topics in particular have been discussed by a panel of expert specialists, all of whom are members of the Spanish Oncology Genitourinary Multidisciplinary Working Group (SOGUG), and participated in the Genitourinary Alliance Project (12GU), aimed to develop consensus and recommendations focused on the integration of relevant information into the care of bladder cancer patients in daily practice conditions. Therefore, a set of cross-cutting topics applicable to different aspects of the management of patients with bladder cancer were discussed and selected with the aim of improving integrated cancer care, supporting specialists in a fast-changing scientific environment, and integrating scientific advances into the continuous improvement in the care and outcome of bladder cancer.The term liquid biopsy refers to the use of blood and other bodily fluids as a surrogate of tissue samples for diagnosis purposes . MateriaRecent research of diagnostic methods has focused on extracellular vesicles (EVs) that can be found in various bodily fluids. The term EVs includes all types of vesicles that exist in the extracellular space, including microvesicles, exosomes, apoptotic bodies, oncosomes, and prostasomes . EVs areLiquid biopsy is a tool for molecular profiling given the high number of non-synonymous somatic mutations reported in bladder cancer . Blood oHowever, clinical implementation of liquid biopsy presents challenges related to the robustness of samples, standardized and optimized processing, and sequencing levels of detection  Figure .The clinical usefulness of liquid biopsies in the clinical management of bladder cancer  includesBiomarkers detected in urine by liquid biopsies have shown usefulness in clinical practice for detecting primary and recurrent tumors, they are mainly used for the study of NMIBC (liquid biopsy based on blood samples are preferable in muscle-invasive bladder cancer (MIBC)), DNA/RNA urinary biomarkers account for most molecular alterations found in primary tumors, monitoring recurrence after primary treatment is the main current clinical application, the use of protein-derived urinary biomarkers is limited, and prognosis and identification of new therapeutic targets is an important area of research of DNA/RNA urinary biomarkers. A review of Lopez-Beltran et al.  reportedAdditionally, based on the interactions between circulation exosomal PD-L1 and T cells, it has been reported in melanoma patients that tracking the levels of circulating exosomal PD-L1 may help to predict a patient’s response to anti-PD-L1 therapy (pembrolizumab) . The magRecommendations and challenges:Liquid biopsy has great potential in the diagnosis, prognosis and treatment of bladder cancer, but further clinical studies are needed to confirm the efficiency of this technique in the assessment of clinical response and overall survival.Liquid biopsy of urine samples is recommended in the surveillance of NMIBC and liquid biopsy of blood samples in MIBC .Cost reduction of commercially available kits is indispensable for the full incorporation of liquid biopsies in routine clinical care of bladder cancer patients.Integration of all available radioimaging, histopathological, liquid biopsy, and molecular medicine data in multidisciplinary committees will change the diagnostic and therapeutic paradigm of bladder cancer.Ultrasound (US) is a well-accepted, cost-effective, and noninvasive diagnostic method for screening of patients with suspected bladder cancer, although accuracy depends on several factors, such as distension of the bladder, tumor size, and morphology and location of the lesions. Ultrasound may be inconclusive in the presence of bladder clots, surgical wall changes, and wall trabeculation and has a low sensitivity in the detection of small tumors (<1 cm). Contrast-enhancement ultrasound (CEUS) improves the bladder cancer detection rate of US, especially in US studies that are indeterminate. In a study of 43 patients with suspected bladder cancer, accuracy in the detection of the presence or absence of bladder cancer was higher for CEUS (88.4%) as compared with US (72.1%), but for tumors larger than 5 mm, the sensitivity was very high 94.7%), in contrast to a very low sensitivity (20%) for tumors smaller than 5 mm 4.7%, in . MagnetiIn relation to tumor staging of bladder cancer, MR urography is increasingly being used for the high spatial resolution and soft-tissue contrast to delineate tumors from the normal detrusor muscle, making MRI superior to computed tomography (CT) for differentiating non-muscle-invasive from muscle-invasive bladder tumors. Muscle invasion is usually better delineated with T2-weighted MRI than with CT, and the muscular (detrusor) layer appears as a hypointense band against hyperintense intraluminal urine and perivesical fat . The useIn reference to nodal staging of bladder cancer, conventional CT and MRI showed critical limitations for identifying lymph node metastases based on size criteria only, both techniques are unable to identify metastases in normal nodes and to distinguish large hyperplastic (benign) nodes from malignant nodes . FunctioBone scintigraphy is indicated in patients with specific symptoms or signs suggestive of bone metastases, although MRI (DWI) is more sensitive and specific for diagnosing bone metastases than bone scintigraphy . CurrentAdditionally, CT is the standard technique in the assessment of response to treatment. The Response Evaluation Criteria in Solid Tumors (RECIST) , publishRadiomics is a new field of quantitative image analysis based on the concept that biomedical images may reflect underlying pathophysiological relationships, and in which digital medical images, such as MRI, PET, or CT examinations, are converted into mineable high-dimensional data . DiagnosRecommendations and challenges:mpMRI is more accurate, faster, and a non-invasive staging method, overcoming the risk of understaging associated with transurethral resection of bladder tumors (TURBT) .MRI preoperatively could help in planning treatment, including radical complete TURBT, identification of patients without need of re-TURBT, patients suitable for bladder-sparing and chemoradiation, and replacing TURBT with mpMRI in selected patients (poor fitness).The need of frequent repeat cystoscopies at follow-up has driven mpMRI use as a non-invasive alternative.Standardization of MRI acquisition and validation in prospective studies is needed to ensure MRI reproducibility.Imaging-based biomarkers of treatment response should be explored in further studies.In relation to biological parameters, it has been shown that the presence of CTCs (using the CellSearch CTC test) was associated with increased risk of radiological metastatic disease on 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) in patients with advanced bladder cancer treated with radical cystectomy, and also with earlier progression but not of cancer-specific death . FurtherMoreover, simultaneous PET/MRI has been suggested to have a possible role to help clinicians in the management of bladder cancer. In a prospective pilot study, 22 patients underwent MR urography and FDG-PET/MRI for the evaluation of bladder cancer, and the information obtained by simultaneous PET helped to refine suspicion of tumor in all intrapelvic anatomic sites evaluated, particularly at the level of the pelvic lymph nodes, which could be associated with an improvement of clinical staging . Other metabolic radiotracers used for PET/CT include C-11 labeled tracers, such as 11C-choline, 11C-acetate, and 11C-methionine. In the case of 11C-choline and 11C-acetate, the main advantage is their low urinary excretion, although the performance of 11C-methionine is not superior to other radiotracers.18F-NaF is used only for the detection of bone disease with a diagnostic accuracy higher than standard bone scintigraphy with 99mTc-based radiotracers. The prostate-specific membrane antigen (PSMA) is expressed in the neovasculature of a number of solid malignancies including urothelial carcinoma. PSMA-targeted agents such as 18F-DCFPyL may offer improved image quality relative to other conventional modalities but the relatively scant expression of PSMA by urothelial cancer limits the utility of 18F-DCFPyL imaging of this malignancy .Imaging techniques are unable to detect microscopic lymph node disease, and about one-third of patients with MIBC have lymph node infiltration (between 30% in T2 and 50% in T3 tumors). However, lymph node drainage is variable and unpredictable, with crossover lymphatic drainage in 45% of cases, and there is controversy regarding the extent of pelvic lymphadenectomy. In a systematic review and meta-analysis of sentinel node biopsy in bladder cancer based on eight studies and 336 patients with MIBC at clinical stage cT1-T4N0M0, the pooled detection rate was 91% and the pooled sensitivity 79%; however, by omitting studies that enrolled >50% of patients at a pT stage of 3 or 4, the pooled sensitivity increased to 93%. Based on the existing studies, pT1 or pT2 bladder cancer patients with clinically negative lymph nodes are the most appropriate group for sentinel lymph node mapping .Recommendations and challenges:The role of FDG-PET/CT for predicting tumor biology and prognosis is still uncertain, although results of a relationship between metabolic imaging and CTC positivity and PD-1/PD-L1 status are promising.The combination FDG-PET/MRI could increase diagnostic reliability and improve staging of patients, but methodological aspects and criteria for the interpretation of images have not been definitively established.The sentinel lymph node biopsy approach with radiocolloids in urothelial carcinoma is justified but the clinical value of the procedure is unclear, with a higher diagnostic accuracy in pT1-T2 tumors.From a safety perspective, cancer patients are vulnerable and complex to manage because of a series of interrelated factors .In this context and from a wide perspective of safety, main actions taken by the oncology pharmacy service for improving safety and optimizing pharmacotherapy include detection and prevention of drug interactions, promoting medication reconciliation programs, improvement of patients’ adherence, safe drug manipulation, and validation of drug prescription. The main predisposing factors to drug interactions are the high number and many different kinds of drugs used to treat cancer, the complex pharmacological profile of antineoplastic drugs, the deterioration of physical function of cancer patients, and the frequent use of phytotherapy.Drug–drug interactions (DDIs) comprise an important problem in medical oncology practice, and a systematic review of eight studies showed a large frequency of DDIs ranging between 12% and 63% . In a coCancer patients are also at risk of food–drug interactions, and serious patient education pitfalls in understanding treatment compliance have been identified . On the Main actions to increase safety in relation to DDI are the following: systemic review of all medications taken by the patient, analysis of interactions and assessment of the clinical significance, and definition and efficient communication of recommendations for patients and healthcare professionals.The increased use of oral cancer therapy  has been a great advance through improved outcomes and convenience of treatment administration, although long-term medication adherence is one of the challenges with this treatment modality. In a sample of 181 patients prescribed oral targeted therapy or chemotherapy, participants took only 85% of the oral therapy on average, with different percentages of poor adherence by cancer type  . In a stDrug-related iatrogenesis can be reduced by medical reconciliation, which facilitates the transmission of exhaustive data at care transition points. Medical reconciliation can be associated with important clinical benefits given the involvement of different specialists and levels of care in the treatment of patients with bladder cancer and the vulnerability of these patients to adverse drug effects. Data of 14 studies included in a systematic review showed that medical reconciliation led to the identification of drug-related problems in 94.7% of patients and discrepancies in 88% . The advHospital oncology pharmacists play a central role in the validation of prescription of anticancer treatments, checking a series of aspects to ensure that the prescribed treatment is appropriate, including treatment days, duration, and interval between cycles according to the protocol; assessment of all drugs at appropriate doses and adjusted to laboratory data and previous toxicity; assessment of supportive treatment and premedication to prevent and reduce adverse events; pharmaceutical formulations adequate to the patient’s condition ; review and prevention of interactions; encouragement of adherence to treatments, and reinforcement of information .Recommendations and challenges:An adequate prescription validation process that finally results in the administration of the prescribed treatment targeted to the established protocol and the patient’s clinical characteristic and individual laboratory data is an important step that contributes to safety of the oncological patient.Based on the large volume of cancer patients, frequency of polypharmacy, care of the patient in different healthcare levels, medication reconciliation protocols according to the profile and treatment of patients should be established.Involvement of a multidisciplinary team and improvement of communication of potential drug–drug interactions is important to ensure safety management of cancer patients.The presence of hospital oncology pharmacists as members of the tumor committees would contribute to improve safety of the drug use in cancer patients.The term “hazardous drug” was introduced in 1990 by the American Society of Hospital Pharmacy and used for the first time in an alert of the National Institute for Occupational Safety and Health (NIOSH) in 2004, referring to drugs that are known to cause harm in healthcare workers due to their inherent toxicity. NIOSH defines a hazardous drug as a drug that exhibits one or more of the following toxicity characteristics: carcinogenicity, teratogenicity, reproductive toxicity, organ toxicity at low doses, genotoxicity, and new drugs with structure and toxicity profiles to drugs defined as hazardous according to the aforementioned criteria.It is important to distinguish two types of risk: (a) chemical risk associated with chemical properties of most hazardous drugs, and (b) biological risk, which is a potentially infectious risk  for intravesical immunotherapy for treating early-stage bladder cancer). Exposure to hazardous drugs may occur during any of the different processes of reception, storage, manufacturing, transportation, administration, and waste disposal, although manufacturing and administration to a lesser extent are associated with the highest exposure risks. Inhalation and direct contact of skin with contaminated surfaces are the main exposure routes, followed by the oral route (hand-to-mouth transmission), and parenteral route .The principal sources available for information regarding hazardous drugs and their classifications are shown in On the other hand, factors associated with the risk of exposure to hazardous drugs include the intrinsic risk of the drug, the pharmaceutical formulation and the route of drug administration , the activity being performed , and the frequency of exposure .In relation to BCG, recommendations to reduce the risk of exposure include centralized preparation in the service of pharmacy inside a biological safety cabinet, avoidance of cross-contamination due to the high risk of a contaminated solution in immunosuppressed patients, coordination of BCG preparation with the service of urology due to the limited stability of liquid BCG, BCG preparation with closed systems and without the use of needles, and a closed system administration set should be used. Likewise, chemotherapeutic agents and immunotherapy drugs are considered hazardous drugs. Biological safety cabinets should be used for preparation, and closed systems for administration. Exposure of healthcare workers during drug administration can be minimized using closed systems and the personal protection equipment individualized to the risk .Recommendations and challenges:To improve safety in the use of drug treatment in patients with bladder cancer, in particular intravesical BCG therapy, diffusion of information and especially training of healthcare personnel are essential factors.It is important to implement appropriate measures during drug administration to prevent (or minimize) exposure of the healthcare personnel.BCG is a hazardous drug with biological risk and involves a potential risk in immunosuppressed patients, so safety recommendations during preparation should be carefully followed.Cancer can be considered an age-related disease because the incidence of most cancers increases with age, with persons over 65 accounting for 60% of newly diagnosed malignancies (30–40% in patients older than 70 years), and cancer-related deaths are expected to occur in the elderly population. Ageing is a heterogeneous process and geriatric deficits associated with a reduction in life expectancy and higher toxicity of anticancer treatments cannot be detected by standard oncological assessment. Some characteristics of bladder cancer in elderly individuals are shown in The provision of geriatric assessment (GA) with management recommendations to oncologists can reduce toxicity in older patients with advanced cancer treated with chemotherapy and/or other agents. In a cluster randomized clinical trial of 718 patients (mean age 77 years), the use of GA information reduced the proportion of patients with grade 3–5 toxicity from high-risk palliative cancer treatment  without compromising overall survival . In a raA recent position paper of the International Society of Geriatric Oncology (SIOG) emphasizes that age should not determine treatment, patients should be fully involved in decisions and undergo cognitive impairment evaluation and comprehensive geriatric assessment, and standard treatment for fit patients should be provided . ElderlyThe importance of geriatric evaluation in elderly cancer patients has been emphasized because findings may reveal impairments that have passed undetected in the medical history and/or physical examination . AdditioFunctioning, comorbidity, mental and cognitive status, fatigue, nutrition, geriatric syndromes, social relationships, and social support are some of the domains that should be included in the geriatric assessment. Different instruments can be used for the evaluation of these domains, the choice of which depends on preferences of the medical team, characteristics of the instruments, and availability of questionnaires . Hurria Although the integration of geriatric assessment into oncology clinics is still limited, a simple geriatric assessment can be performed in any clinical setting, regardless of the available resources, and will provide valuable data of the physiological age of older people with cancer .Recommendations and challenges:Chronological age alone is not a reliable indicator of the functional and physiological status of people over 65 years of age with cancer and should not be a main factor for guiding treatment decisions in patients with bladder cancer.Elderly patients should be referred to the service of geriatrics for multidimensional evaluation of cognition, nutrition, physical function, comorbid conditions, social support, and psychological status.If a geriatrics service is not available, consultation with other services are recommendable to assess the nutrition status, the risk of falls, to establish medication reconciliation, or interventions for patients with deficient social support.Geriatric assessments should be implemented in the initial evaluation of patients with bladder cancer and may constitute a validation system for clinical decision making.Replacement of the urinary bladder aimed at storage of urine at low pressure, preserving renal function, and to achieve adequate voiding and urinary continence is a major challenge in urological surgery. Types of urinary diversion surgery include orthotopic neobladder substitution (Studer “U” or Hautmann “W”), Indiana pouch heterotopic continent diversion, neobladder formed from a segment of ileum , cutaneous urinary diversion, and sigma-rectal pouch. Although an orthotopic neobladder reconstruction is an effective treatment option and remains the gold standard at many centers of expertise, the Bricker procedure  is still performed in 20–25% of patients after radical cystectomy. Age and comorbidity are critical factors in the selection of urinary diversion method, with frail older people more likely to undergo the Bricker ileal conduit diversion. Advantages of ileal conduit urinary diversion include shorter operative time, quicker recovery and ease of care by others, whereas some disadvantages are requirement of external appliance, impairment of body image, parastomal hernia, and peristomal skin irritation.Motivated patients with realistic expectations, with skills for self-catheterization, a serum creatinine level < 2 mg/dL or glomerular filtration rate > 35/mL/min, and without liver dysfunction (risk of hyperammonemia) are candidates for bladder substitution procedures. Age is not a contraindication, whereas bladder diversion surgery is contraindicated in the presence of urethral tumor invasion, tumor detection in the intraoperative biopsy, and N2–N3 stage. Relative contraindications include inability for self-catheterization, mental incapacity for self-care, complex urethral stenosis, NMIBC in the urethra or bladder neck, previous pelvic radiotherapy or incontinence, and low life expectancy.In relation to health-related quality of life (HRQOL), most research has focused on comparing HRQOL outcomes between different urinary diversion types, such as ileal conduit vs. neobladder vs. continent cutaneous diversion, the results reported have been mixed and clear evidence-based findings differentiating these techniques have not been found .Today, about 75% of patients treated with radical cystectomy are candidates for orthotopic urinary diversion, and it is reasonable to consider that when no absolute contraindications are present, a small percentage of patients eligible for a continent urinary diversion chose an ileal conduit for personal reasons . HoweverAccording to recommendations of the European Association of Urology Muscle-invasive and Metastatic Bladder Cancer Guideline Panel, patients should be referred to hospitals in which a high number of radical cystectomies are performed on an annual basis , since hospital volume influences postoperative survival and the quality of care provided to bladder cancer patients . In addiRecommendations and challenges:The choice of orthotopic neobladder reconstructions should be offered to motivated patients, with full information of self-care and self-catheterization needs.It is necessary to discuss the pros and cons of all bladder substitution techniques, even in case that the operation should be performed in another center.It is necessary to implement a centralization plan involving hospitals and surgeons, both for orthotopic neobladder reconstruction and radical cystectomy in centers with annual volumes >20 procedures.Daily practice challenges include implementation of enhanced recovery after surgery (ERAS) protocols, geriatric assessment, appropriate evaluation of HRQOL, and protocolized follow-up after radical cystectomy.Conservative management of infiltrating bladder cancer based on a trimodality approach  and the multidisciplinary involvement of different specialties is becoming a real alternative to radical surgery for bladder preservation in selected patients. It has been shown that the best results of the trimodality therapy are obtained using a strategy in which radiochemotherapy follows TURBT. Bladder preservation with radiochemotherapy is supported by numerous guidelines ,61,62. NIn relation to HRQOL, bladder-sparing trimodality therapy and radical cystectomy are both associated with good long-term outcomes in MIBC survivors , althougPrediction of chemoradiation response would enable selection of optimal candidates for bladder-sparing treatment and may ultimately improve prognosis and HRQOL of MIBC patients. The possible role of different biomarkers that can be used for predicting and improving the chemoradiation response and prognosis on bladder preservation therapy has been reported , but nonIn a study that evaluated the association between MRE11 expression (a protein involved in the DNA double-strand break repair mechanism) and outcome in patients from six NRG/RTOG bladder-sparing protocols, with tissues available from 135 patients and slides analyzed via Automated Quantitative Image analysis (AQUA), it has been shown that low expression of this biomarker was associated with significantly higher disease-specific mortality .A clinical approach of great interest has been to combine radiotherapy with radiosensitizers including synchronous chemotherapy  ,70 or hyRegarding the integration of next-generation imaging (NGI) and chemoradiotherapy, the best schemes for treatment plans remain unclear, including the role of elective nodal irradiation/treatment volume irradiation, feasibility and efficiency of an hypofractionated approach, the new modality of functional biological imaging to define volumes and contribute to personalized treatment, and adaptative radiotherapy (ART) in dose escalation focal radiotherapy.Recommendations and challengesBladder-sparing protocols based on trimodality therapy should be implemented in centers with well-coordinated multidisciplinary teams and should be offered to selected patients with an appropriate clinical profile.The use of biomarkers combined with imaging technologies  is a promising approach in the management of bladder cancer patients.Optimal schemes of immunotherapy as sensitizers for radiotherapy are still undefined but moderate hypofractionated radiation therapy seems to be a beneficial approach. Extreme hypofractionation/immunotherapy is not advisable due to the high toxicity.Based on a potential higher sensitivity to some ICI drugs, the use of small radiation therapy volumes is recommended.Immunotherapy with PD-1/PD-L1 agents is changing the landscape of treatment in the management of solid tumors including urothelial carcinoma. General classification of patients with bladder cancer and treatment approach for NMIBC, MIBC, and metastatic disease are shown in Immunotherapy is integrated in the management of patients with bladder cancer and there are ongoing clinical trials in NMIBC after TURBT, in the perioperative setting of MIBC, in first-line treatment of metastatic disease in patients eligible for cisplatin chemotherapy, and unfit patients treated with carboplatin chemotherapy. In patients with metastatic disease treated with cisplatin-based chemotherapy, the use of immunotherapy has shown to increase disease-free survival. Immunotherapy as a consolidation of maintenance treatment after first-line chemotherapy and in second-line treatment of metastatic disease has shown to increase overall survival . However, although PD-1/PDL-1 drugs have shown the potential therapeutic benefits, toxicity and high financial costs should be considered together with the fact that robust evidence from randomized clinical trials is still insufficient , althougFinally, circulating tumor DNA (ctDNA) testing is a promising minimally invasive technique to identify patients at risk of recurrence after surgery of bladder cancer receiving adjuvant immunotherapy. In the framework of the phase III IMvigor010 trial, patients in the atezolizumab arm who were positive for ctDNA had improved disease-free survival and overall survival versus the observation arm, whereas no difference in disease-free survival or overall survival between treatment arms was noted for patients who were negative for ctDNA .Recommendations and challenges:Indications of immunotherapy for the management of metastatic bladder cancer should be based on evidence rather than on availability of drugs.The optimal strategy of treatment with ICIs should be defined from the initial diagnostic phase, with clear identification of clinical entities of bladder cancer and their corresponding diagnostic and therapeutic circuits .Definition of alternatives when the better option is not available is also necessary.Patients should be fully informed regarding access and difficulties to different approved ICI alternatives.The advances in the research of radiological imaging techniques in patients with bladder cancer have made it possible to have more precise and less invasive staging methods, which could lead to better treatment planning with more personalized therapeutic options in selected patients. High-resolution micro-ultrasound (mUS) technology has been introduced very recently and the initial results indicate that mUS may have a better performance than MRI in distinguishing NMIBC from MIBC . RecentlOn the other hand, the improvement of safety and optimization of pharmacological treatments requires an adequate review and reconciliation of medication, management and prevention of interactions and a multidimensional, systematic, and protocolized evaluation in older patients, which facilitate appropriate adherence to the therapeutic plan, optimizing its efficacy and reducing its toxicity. The use of ICIs in the treatment of patients with bladder cancer should be based primarily on the available evidence for the indications and effectiveness of these drugs at each stage of bladder cancer.In relation to safety, it is also necessary to consider the implementation of appropriate measures that would allow a safe drug administration both for the patients and the healthcare personnel involved in drug treatment.Finally, patients should be appropriately and extensively informed of the currently available new surgical and radiotherapeutic options. The SOGUG group recommends the need to establish well-coordinated multidisciplinary teams and, in some cases, the implementation of centralized protocols in some hospitals according to characteristics of the center and experience of the professional groups.


The Healthy Homes and Neighbourhoods (HHAN) integrated care initiative was designed to break intergenerational cycles of social and health inequalities and enhance access to and engagement with health and social services for vulnerable families in the Sydney Local Health District. We sought to unearth the initial programme theory of the HHAN initiative to inform rollout to other relevant areas.We conducted a critical realist evaluation using steps. (1) Exploring the events around the HHAN initiative development. (2) Explore consumer experiences. (3) Identifying the entities and associations characterising the HHAN initiative and related outcomes. (4) Searching for different theoretical perspectives and explanations (abduction). (5) Hypothesising the mechanisms and [context] conditions that might have activated the generation of the HHAN outcomes (retroduction).We identified three central mechanisms; trust, buy-in and motivation, and understanding family dynamics operating across consumer, provider and systems levels of the HHAN initiative.These programme theories reveal that to achieve the goals of HHAN, interpersonal dynamics, fostering buy-in and ensuring motivation of both the consumers and care workers should be sought and sustained at all levels.The programme theories unveil that integrated care initiatives should foster positive relationships at all levels to ensure favourable consumer outcomes. Despite existing government initiatives designed to address the social, health and well-being inequities of Australian children and families who live in disadvantaged communities, inequality continues to grow and subsequently transferred to the next generation . ConsequIn July 2015, the Sydney Local Health District (SLHD) implemented an integrated care initiative, the Healthy Homes, and Neighbourhoods (HHAN), for vulnerable families in the inner West of Sydney, Australia. The HHAN initiative was designed as a population-based and family-centred care-coordination network operating across agencies to assist vulnerable families in navigating the health and social care system . The HHAMultiple core and non-core agencies work with vulnerable families over a sustained period (5 years).Co-design and co-production of the initiative in partnership with families and service partnersAll the needs of enrolled families are in the scope of the intervention, including housing, employment, income support and legal adviceAn early intervention and public health approach to interrupting cycles of family disadvantage, poor health, and psychological traumaEfficient use and leveraging from existing family, societal and government resources, including Medicare scheduled servicesUse of evidence-informed integrated care methods by service partners, including family case conferencing, and wrap-around care deliveryEncouraging families to have a ‘health home’ for all their health needs and supporting progress toward self-efficacyProviding a supporting structure for general practice providers to care for families is often considered ‘too difficult.’Development and implementation of shared assessment tools and referral criteriaImplementing family assessment and engagement tools to monitor the health and well-being of family members” .For the HHAN initiative to be successful, the original design embedded consumer-centeredness, participation, and care coordination as its central tenets. To this end, the HHAN initiative includes the following intervention modalities – activities: identification of vulnerable family cohorts; care coordination; evidence-informed intervention(s); general practice engagement and support; family health improvement; placed-based neighbourhood initiatives; interagency system change and collaborative planning; monitoring of individual and family outcomes; and evaluation . The impA preliminary big data outcome-based evaluation of the pilot HHAN initiative indicated a significant reduction in potentially preventable hospitalisation, emergency department visits, admissions and length of stay for members of HHAN families . The eva8The translation research design of HHAN adopted the four phases of the 2008 Medical Research Council Framework  for the 13We adopted a critical realist theoretical paradigm to generate the initial programme theories of the HHAN initiative. The initial programme theories were based partly on the realist theory and propositions of neighbourhood, context, stress, depression and developmental origins of health and disease . The valCritical realism focuses on developing theories and models to explain social events, including how and why programmes work or not. According to McEvoy and Richards , criticaCritical realism posits that reality comprises the domains of the Empirical – experienced and observed events; Actual – events which occur but may or may not be observed/experienced; and Real – structures and mechanisms with the potential to produce events under certain conditions . In realcontingent causality [Central to critical realist methodology is the identifying and conceptualising of mechanisms and structures considered as the causal elements of events . A multiausality .Owing to the multi-component nature of the HHAN initiative, we found it helpful to adopt the Context-Intervention-Mechanism-Outcome (CIMO) heuristic tool to develop the initial programme theories of the HHAN initiative. Based on the critical realist understanding of causality, mechanisms (M), context (C), and outcomes (O) are predominantly used to express how and why programmes work or fail to work . Other aOur overall methodology followed guidelines proposed by Thapa and Omland : (1) ExpThe steps described above followed an iterative process indicated in The review of the development of the HHAN initiative was achieved by thoroughly examining relevant policy documents, implementation documents, and notes. Vital documents that were consulted include:https://www.slhd.nsw.gov.au/sydneyconnect/plans.html particularly the Community Health Services Strategic Plan, Inner West Sydney Youth Health and Wellbeing Plan, District Strategic Plan 2018–2023, and Child Health and Wellbeing Plan 2016–2021.SLHD Plans: NSW Ministry of Health Vulnerable Families Transformation Plan: This document is the implementation plan that the Ministry wrote, based on the HHAN model.https://www.slhd.nsw.gov.au/pdfs/HealthyHomesAnnualReport.pdf.Inner West Sydney: Healthy Homes and Neighbourhoods – 2015–2016 Annual Report In addition to the review of the documents, zoom meetings were held with some stakeholders, including medical practitioners (4), researchers (6) and programme designers (3) working at the SLHD to discuss how the HHAN initiative was designed to achieve its aims. Monthly zoom meetings were conducted for three months to unpack the aims and objectives of the HHAN initiative. The goal of these zoom meetings was to assess the initiative’s progress, plan to address the barriers to implementation, and enhance the implementation of what is working well. These zoom sessions were recorded with permission from all participants. Meeting notes and summaries were prepared after each meeting and analysed thematically.We meticulously read through the HHAN initiative documents, and in tandem with the meeting discussions, we abductively started formulating the programme theories of the HHAN initiative. Abduction at this stage was applied to generate hypotheses about the possible generative mechanisms that might operate, given the structure of the HHAN initiative and how it was designed to work.YouTube videos of HHAN care coordination consumers and their journey with HHAN were also used to substantiate the evidence obtained from the other sources. For ethical reasons, these videos will not be made publicly available. They were created by SLHD Strategic Relations and Communications for the SLHD Innovations Symposium. These stories were selected as they demonstrated “care in the community”, which was the symposium’s theme. Making these videos allowed families to share their experiences from their perspectives and homes where they received their care from HHAN. The families were then invited to the symposium as well.These various sources of information, including the YouTube videos, were analysed thematically guided by the search of constructs that represent context conditions, generative mechanisms and reported behaviour or outcomes, especially in line with the different components offered by the HHAN intervention.The second step we adopted was critically examining the existing theories of change (ToC) of the vulnerable family co-design project and the developed and piloted HHAN initiative. This exercise aimed to identify the critical programmatic components of each model and the goals that these components strive to achieve in isolation and synergistically. Another essential element that examining the ToC aimed to delineate was the various activities (inputs), which usually require the cooperation and co-production of service providers and service users. Such interactions can highlight potential mechanisms of the HHAN initiative. The activities also shed light on some contextual elements, such as the availability of resources for integration-related activities.Based on the framework presented in Following the review of the ToC, we delineated three levels of potential programme theories: consumer, provider, and service. While the consumer level speaks to the adoption of the HHAN initiative components by the families, the provider level relates to issues around the buy-in and consequent implementation of the HHAN initiative by the different providers, including health practitioners, case managers and social services providers. The programme theory at the service level deals with the coordination and organisation of separate independent systems to achieve integration. Since the inception of the idea of developing HHAN, the critical realist approach to understanding how it will work, for whom and under what health system conditions has been considered 26. The e1122728415The goal was to achieve theoretical constructs that would then be used to abductively and retroductively construct explanatory models of how and why the HHAN intervention works. Most importantly, this step allowed us to identify the other programme modalities and how they are operationalised at the consumer (user), provider and service levels. The findings of this step are presented in This step is the culmination of the activities that we conducted from step 1 through step 4. This final step entailed the discursive reviewing of the developing initial programme theories from step 1. This step involved a discussion led by one of the authors with a group of researchers working on the HHAN intervention from SLHD since its inception and working on other integrated care programmes in Australia. This team of six was engaged in a discursive exercise reflecting on the developing programme models obtained from steps 1–3. Through these discussions, the causal links of the different CIMO chains were examined, and these chains were confirmed, discarded or revised. The exact process was also used to refine the developing programme theories.We present here three programme theories aligning with the three levels: consumer, provider and service . For eacThe programme theory developed from the consumers’ perspective is essential to understand the dynamics around the adoption of the programme. Of course, without the intended users adopting the intervention, the programme cannot achieve its goals. Following the abductive and retroductive process, we constructed the programme theory model at the level of the HHAN initiative consumers – The initial programme theory at the consumer level indicated that rapport building with all family members engenders mutual respect and trust (M) and encourages consumers to engage in their goal settings, consequently improving the uptake of social and health services. Case-based discussions fostered knowledge sharing and awareness of available activities leading to knowledge acquisition, encouragement, and empowerment. These three mechanisms have been found to promote positive outcomes such as consumer independence, an improved outlook, and community acceptance of the programme. Under contexts and conditions where vulnerable families experienced distrust of past health and social services—and low levels of trust in providers, authorities and the overall policy environment—a whole-of-family care approach can allow consumers to feel supported in their community.The second programme theory we developed is at the provider level. This programme theory speaks to the implementation phase of the HHAN intervention as the success of the implementation of the HHAN intervention is mainly dependent on the care providers. Care providers are directly involved in delivering the HHAN intervention. Thus, they are considered the central actors vis-à-vis the implementation of the HHAN intervention. The service organisation-level deals with the interplay between policymakers and the rollout of the intervention at the implementation sites. This level highlights the complexity of how the integration of services is supposed to be achieved during implementation. Byng and colleagues  propose In this study, we employed a multi-method approach to elicit the initial programme theories of the HHAN initiative at three levels . We formOverall, trust—which emanates from favourable interpersonal relations—buy-in from the co-design and co-identification of problems and solutions, and motivation owing to knowledge acquisition were found to be overarching mechanisms, under which secondary modes of intervention at consumer, provider and system levels emerged. The centrality of trust, motivation and buy-in as enablers of service engagement and provider motivation to collaborate has also been highlighted in the recent literature 3536. The35We found that at the consumer level, critical mechanisms include awareness of family dynamics, knowledge acquisition, self-efficacy and encouragement embedded in trust. A recent realist review to identify causal mechanisms on how and why community-based integrated care initiatives work found five bundles of mechanisms at the consumer level (1) motivation, (2) perceived interpersonal trust, (3) user-empowerment, (4) perceived accessibility to required services, and (5) self-efficacy and self-determination . These mAt the provider level, we found that if there is a good level of trust between care providers and the authorities, the presence of transformational leadership, and buy-in from the programme managers, shared learning among the professionals can be achieved, and the buy-in by staff and agency will increase. Thus, leading to perceived benefits of cooperation between professionals and agencies, experiential learning, mutual respect, and trust. To this end, while implementing or rolling out the HHAN intervention, strategies must be devised to improve stakeholder engagement and drive further collaboration. Evidence-based practice and family accompaniment, which meant working at multiple levels simultaneously and maximising partnership opportunities, activated shared and experiential learning mechanisms through multiagency shared casework. Leveraging learning from experiences and transferring learnings from the service level to the system level can enforce the transition from service collaboration to service integration. A realist evaluation of another integrated care initiative to improve the diagnoses and management of chronic conditions indicated that the initiative increased the confidence of the primary care professionals through improved person-centred conversational skills and increased patients’ active engagement .In siloed health systems, strong interagency cooperation, high vulnerability, and the complex nature of the HHAN initiative, proper service integration can only be achieved if there is buy-in, shared responsibility, and perceived cooperation among the authorities and service providers. Smeets and colleagues  observedThe notion of emergence captured in the principles of critical realism alludes those structures and mechanisms are usually unobservable, and their operations depend on situations with causal tendencies. Emergence occurs when a whole possesses one or more emergent properties. Within the systems in which the HHAN initiative operates, operations arise within and across different levels. The operations of mechanisms and structures at one level can have implications or create conditions for how the mechanisms operate at another level. In some instances, the outcome of one level constitutes the context conditions for the next level. For example, at the systems level, where outcomes such as the breakdown of silos, collaborations and recognition of service partners are achieved, can constitute favourable conditions for triggering the mechanisms at the service provider level. Therefore, the outcomes achieved at one level constitute situations with causal tendencies at the next level. Practically, this notion of emergence, as applied in this circumstance, suggests that relevant stakeholders should ensure that the outcomes at the higher levels are successfully achieved to create favourable conditions for attaining those at the lower levels.While we attempted to capture the complexity around the implementation and uptake of the HHAN initiative, we also want to recognise that the continuous activation of essential mechanisms such as buy-in, trust and motivation, and acceptance for favourable outcomes are also contingent upon how things play out over time. This time consideration is in line with the temporospatial dynamics of events captured in the critical realist philosophy of science. In keeping with the notion that the world is changing and that social structures, mechanisms, and causes operate in a complex system , we apprWe propose, therefore, that structures should be set in place to ensure affective, continuance and normative commitments at all levels, with the relevant stakeholders operating at each level. Meaningful engagement can be achieved by assessing the programme’s success, addressing existing barriers, fostering existing relationships and encouraging active participation and co-decision-making (service providers – consumers) at all levels. Such engagements can be achieved through frequent meetings and re-evaluating the aim and commitment of the different service providers and stakeholders. Ensuring the resources for implementing various levels and aspects of the HHAN programme is also critical to sustaining buy-in, trust and motivation.The study was conducted based on the critical realist philosophy of science, which offers a multilevel perspective fostering the investigation of different levels of mechanisms operating at the psychological level of self, the level of situated activity, and the levels of intermediate and macro-level services. This feature of the critical realist methodology allowed us to unearth the programme theories of the HHAN initiative at three levels: consumer, care provider and service provision.Another strength of the critical realist-informed evaluation approach is that as opposed to outcome-based evaluations, where contextual elements are eliminated to establish the association between the programme modality and the observed outcome, retroductive theorising is inclusive of the contextual elements in its evidence package . ObtainiThe study, however, has some limitations. Constructing CIMO configurations for each significant element requires abductive thinking and retroduction to link the different elements, which makes replication of such studies challenging, requiring a high level of expertise. Although we engaged in discursive and iterative discussions, the risk of misattribution of causality remained, primarily because the study is conducted in an open system within a multi-component programme. In our comprehensive methods, we included respondent feedback/discussions with the programme architect and team to revise and confirm our causal links to minimise such misappropriation of causality. Several analytical methods were employed through theory gleaning, refining, and consolidating.We adopted a complex systems-sensitive approach to evaluate the HHAN integrated care initiative. Capturing the central mechanisms at work at each level using a causality-based evaluation approach helps us understand how mechanisms at one level can impact the implementation and adoption of the different components of HHAN integrated care at other levels. These programme theories revealed that to achieve the goals of the HHAN integrated care initiative, interpersonal dynamics, fostering buy-in at all levels and ensuring motivation of both the consumers and care workers should be sought during implementation. The programme theories unveil that integrated care service design should focus on fostering positive relationships at all levels to ensure good consumer outcomes, which could be achieved through scheduled collaborative meetings.


Since the beginning of ages, pathogens have circulated worldwide, with many causing significant morbidity and mortality in humans . Much ofA frequent cause playing a role in infectious diseases emergence is the involvement of multiple host, vector, or infectious agent in complex ecological communities, hampering control and mitigation efforts that target particular hosts for management . DespiteBesides this, ecological changes can sometimes drive evolution and change the complex interplay between hosts-environment-pathogens, ultimately favoring transmission. A good example can be seen in the El Niño events in the 90’s that led to the emergence of human hantavirus cases in the US, through an ecological cascade: increased precipitation led to growth of vegetation, which sustained increased populations of rodents, facilitating hantavirus transmission between rodents and from rodents to humans.In this sense, community ecology wraps up the complex interplay and multitude of factors that generate the emergence of infectious agents in animals by examining the interactions between pathogens and their host organisms within an ecological context. It provides a pathway to understand how the dissemination and impact of infectious diseases is affected by factors such as population density, biodiversity, and environmental conditions, and how these factors in turn affect the distribution and evolution of species. This field of study helps bridge the gap between the micro-scale processes of individuals and populations and the macro-scale patterns of species distribution and evolution.Disease community ecology hence combines the disciplines of epidemiology and community ecology to address the multispecies nature of many contemporary disease threats. The approach focuses on identifying the factors that govern the structure and dynamics of communities composed of multiple hosts, vectors, and symbionts, isolating the drivers of heterogeneity, and understanding how processes and patterns link across multiple scales of biological organization. A broader knowledge of these factors will facilitate more effective management of emerging infections, as complete eradication may not be successful .This issue plans to collect the most recent advances in Animal infectious diseases epidemiology. Original research articles and comprehensive reviews that cover the community ecology and pathogen dynamics, including molecular aspects, transmission, infection, and pathology are welcomed.


Theory and research informed a framework of best intergenerational practice that has proven effective in the field of community programs. Reflecting a number of AFU principles, this set of proven practices can promote positive intergenerational contact in college classrooms as well. Here, we present evidence-based and promising practices salient to the AFU, offering examples from the classroom and suggesting low- and high-tech solutions. For example, the intergenerational practices of offering meaningful roles and engaging youth and older adults in a novel activity can support AFU principle 4 reciprocal sharing of expertise between learners of all ages. Stakeholders, including instructors, university students, older adult learners, and community partners, benefit from preparation for the distinctive needs and opportunities of intergenerational learning experiences in higher education. Effective implementation of intergenerational strategies helps both younger and older learners to reimagine aging, offering the potential to address a critical need of individuals and communities.


Antimicrobial pharmaceuticals are classified as emergent micropollutants of concern, implying that even at low concentrations, long-term exposure to the environment can have significant eco-toxicological effects. There is a lack of a standardized regulatory framework governing the permissible antibiotic content for monitoring environmental water quality standards. Therefore, indiscriminate discharge of antimicrobials at potentially active concentrations into urban wastewater treatment facilities is rampant. Antimicrobials may exert selective pressure on bacteria, leading to resistance development and eventual health consequences. The emergence of clinically important multiple antibiotic-resistant bacteria in untreated hospital effluents and wastewater treatment plants (WWTPs) has been linked to the continuous exposure of bacteria to antimicrobials. The levels of environmental exposure to antibiotics and their correlation to the evolution and spread of resistant bacteria need to be elucidated to help in the formulation of mitigation measures. This review explores frequently detected antimicrobials in wastewater and gives a comprehensive coverage of bacterial resistance mechanisms to different antibiotic classes through the expression of a wide variety of antibiotic resistance genes either inherent and/or exchanged among bacteria or acquired from the reservoir of antibiotic resistance genes (ARGs) in wastewater systems. To complement the removal of antibiotics and ARGs from WWTPs, upscaling the implementation of prospective interventions such as vaccines, phage therapy, and natural compounds as alternatives to widespread antibiotic use provides a multifaceted approach to minimize the spread of antimicrobial resistance. However, biotransformation and mineralization have been observed with both pure and mixed cultures in different redox  conditions . A bacterial strain, Stenotrophomonas maltophilia DT1, capable of degrading TET, has been isolated from TET contaminated sites  are broad spectrum antibiotics commonly used in livestock production. They are poorly biodegradable due to their complex chemical structures; However, numerous studies have explored chemical processes  for their degradation  and sul1 gene at the 3′ conserved sequence. Between the 5′ and 3′ conserved sequences, gene cassettes can be found. The integrase has the ability to capture and integrate antimicrobial resistance genes into the gene cassettes. The promoter of the integron contributes to the expression of genes located in the gene cassettes. The aacE∆ and sul1 genes are responsible for resistance to quaternary ammonium compounds and sulfonamides, respectively  that carry genes have high mobility and are easily transferable between strains and, in some cases, taxonomic classes , for example, acquires a gene cassette that transfers multiple ARGs simultaneously  alteration or modification of the antibiotic target site leading to reduction of drug affinity to the binding sites like the modified penicillin binding proteins (PBPs), (2) decreased drug accumulation due to decreased permeability or to expression of active efflux pumps which transport specific or multiple antibiotics out of the cell  are quite common, indicating widespread occurrence in the human gut , has been found to be the most widespread and dominant ARG in metagenomic resistome profiles of humans and cynomolgus monkeys , and vancomycin are more abundant compared to resistance gene types such as bacitracin, chloramphenicol, fosmidomycin, and polymyxin, while six tetracycline resistance genes , cephalosporins (cephems), carbapenems, and monobactams that interfere with the synthesis of the bacterial cell wall. β-Lactams inhibit the penicillin binding proteins (PBPs), which catalyze the transpeptidation process during peptidoglycan synthesis and thus prevent the cross-linking that forms a cell wall structure that is closely knit. The common mechanisms of β-lactam resistance are alteration of target sites (mutations in PBPs) and direct deactivation by β-lactamases  form a group of enzymes that confer significant resistance to penicillins, aminopenicillins, oxyimino-cephalosporins , and monobactam (aztreonam) and their activity is inhibited by β-lactamase inhibitors such as clavulanic acid  , the decoding centre on the 16S rRNA of the ribosome, thus inhibiting protein synthesis. The most clinically relevant members commonly used against infections caused by Gram-negative bacteria are gentamicin (GEN), amikacin (AMK) and tobramycin (TOB) Bartlett . ResistaaadB and aadA, respectively, both of can be part of gene cassettes carried in class 1 integrons while Streptomycin resistance is mediated by APH(6)-Ia and APH(6)-Id aminoglycoside phosphotransferases encoded by the strA and strB genes respectively  which promote target protection by methylating the 16S rRNA of the 30S ribosomal subunit at the A site, which interferes with aminoglycoside binding and results in high-level resistance to aminoglycosides . Theqnr genes, including A, B, C, D, S, and VC families that occur on plasmids, encode proteins that prevent quinolones from entering cleavage complexes by binding to DNA, which decreases the action of DNA gyrase and topoisomerase IV, with the resultant effect of low level fluoroquinolone resistance  . Sul3 is linked to a type of class 1 integron only known to be associated with a gene cassette that includes dfrA12 , tetM, tetO, tetQ, tetS, tetT, tetW, tetX and decrease in intracellular drug concentration achieved through active efflux from the cell due to proteins coded by genes such as. tetA, tetA(C), tetA(P), tetB, tetC, tetD, tetE, tetG, tetH, tetJ, tetK, tetL, tetV, tetY, tetZ , tetA(2), tetJ, tetQ, tetV), plasmids , tetC, tetD, tetE, tetK, tetY), transposons and ICEs   or on the chromosome and plasmid (e.g. tetL)  antibiotic inactivation by modifying enzymes—macrolide phosphotransferases (MPH) coded by mph (A) and mph (B) genes on plasmids; and (3) active efflux of the drug from the cell coded by genes such as mefA and msrA  and mph(B) were found in effluent and activated sludge  have been shown in vitro to select for antibiotic resistant bacteria based on mutations carried by specific strains  from the point of view of advancing the technologies applied in the removal of antibiotics and ARGs during wastewater treatment   are viruses that infect and kill bacteria through lysis  and Pantocin A, produced by the clinical strains of Pantoea agglomerans Tx10, a cystic fibrosis isolate, have also shown the ability to inhibit the growth of a wide range of multi-drug resistant Gram-negative and Gram positive bacteria, including Enterobacter, E. coli, Klebsiella, Kosakonia, Pseudocitrobacter, Salmonella, Staphylococcus, and Streptococcus , which has recently shown the capability to reduce biofilm formation of Bacillus subtilis 1556WTNC for the successful removal of beta-lactams; cephalexin, ceftaroline, ampicillin, and amoxicillin from wastewater  and/or quantitative polymerase chain reaction (qPCR)) and have contributed to the expansion of knowledge on the ARGs’ diversity, and abundance in aqueous environments as antimicrobial resistance reservoirs. In addition, intensifying the application of targeted functional and sequence-based metagenomics and new metagenomics-based studies are likely to reveal more insights into the occurrence and distribution of ARGs in wastewater.To reduce the threat of the escalation of antimicrobial resistance facilitated by the aqueous environment, strict threshold limits for antibiotic release from point sources such as hospitals and animal husbandry, as well as thresholds for release of other pharmaceuticals, and biocides that drive co-selection of resistance, need to be established and applied universally. Further, diverse studies on the role of environmental antibiotic contamination and its correlation to the development of antibiotic resistance would aid in the formulation and strengthening of the intervention measures.Given the threats posed by antimicrobial resistance to human health, it would be useful to intensify research on the prospective bioremediation approaches to remove environmental antibiotics to complement the variety of technologies that are applied to remove antibiotics and ARGs in wastewater treatment facilities.Although a combination of approaches to remove antibiotics and ARGs from WWTPs has yielded promising outcomes, the adoption of novel therapeutic strategies, either alone or in conjunction with traditional therapies to control bacterial infections, offers a multifaceted approach to slow down the rapidly growing resistance to antimicrobial drugs in bacteria.The environment constituted by hospital effluents and wastewater treatment plants is rich in antimicrobial micro contaminants and creates selection pressure, leading to the emergence of antimicrobial resistance by providing an ideal platform for the residence and interaction of antibiotics, bacteria, and resistance genes. The absence of standardized regulations to monitor these microcontaminants has contributed to the escalation of antibiotic resistance in the environment. Evidence suggests that effluent from WWTPs is a reservoir of ARGs and is pivotal in their dissemination to both commensal and pathogenic bacteria in the receiving environments facilitated by horizontal gene transfer. The development of antimicrobial resistance spurred by antibiotics and other stressors in the environment raises concern due to the likelihood of simultaneous transmission of virulence and resistance determinants to multiple antibiotic classes by mobile genetic elements in bacteria, which may directly or indirectly reach human and animal hosts. The progression of AR in the environment presents a considerable challenge to the successful achievement of the One Health initiative envisaged by the World Health Organization as well as the full realization of the United Nations Sustainable Development Goals. Meanwhile, advanced technologies applied to eliminate antibiotics and ARGs from WWTPs are important to mitigate the adverse effects of such toxicants on aquatic environment.


Both entropy and complexity are central concepts for the understanding and development of Information Theory, playing an essential role in the increasingly numerous applications in a huge diversity of fields. Adequate methods of quantifying the entropy of physical systems and processes have been the object of design of numerous researchers for more than a century, usually based on a probabilistic description using discrete or continuous variables depending on the analysis framework considered. In this sense, Shannon entropy deserves a special mention as a pioneering measure; this has also given rise to the subsequent birth of, e.g., the Rényi and Tsallis entropies, or the relative entropy between distributions in close connection with the ‘mutual information’ among descriptive variables.The quantitative handle of the notion ‘complexity of a system’ (or process) arose much more recently, in the mid-1990s. The pioneering measure of complexity  includes the Shannon entropy, together with the distance to equiprobability or ‘disequilibrium’. Among the representative properties for any appropriate measure of complexity, it reaches its minimal value in the limits of extremal order and disorder. Complementary to LMC complexity, additional product-like complexity measures have been subsequently defined. Let us emphasize recent generalizations in terms of Rényi entropies, as well as those enclosing the content of gradient of the distribution as a local property to determine the searched complexity.This Special Issue encloses different applications of information-theoretical concepts for the analysis of physical systems, based on their specific descriptors and variables. The aforementioned applications consider both theoretical and numerical analyses, some of them for arbitrary dimensionality, and the results are systematically interpreted in terms of physically relevant magnitudes and concepts, for instance: energy, correlation, coupling, uncertainty, and reactivity, among others.Some specific physical systems have been considered in the present Special Issue. Such is the case of many-fermion systems, at times generically handled by means of solvable models , allowinAnother kind of multifermionic system is the atomic systems, here considered for a wide range of electron numbers. An appropriate description requires the use of realistic models to handle an appropiate wavefunction, making possible the simultaneous study of the position and momentum conjugated spaces . Taking In opposition to the previous examples, single-electron atoms  are also considered in this Special Issue, providing an in-depth analysis of especially interesting frameworks . All thiCombined theoretical and numerical analyses are particularly interesting, as happens with the work dealing with the entropic study of the transformation from the LS-coupled configuration space to the jj-coupled one . ShannonIn spite of the advantages of dealing with specific systems and/or processes, studies affording a generic treatment of many-body systems are always welcome, an example being the information-theoretical description based on the local-energy concept, emphasizing its interpretation for the analysis of molecular systems and chemical reactions . DiffereIn summary, these papers constitute a diversity of apportations to the information-theoretic abilities and applications in a variety of physical fields, focusing on fermionic systems as considered from different perspectives, including analytical and numerical ones. The relevancy of entropic and complexity measures is revealed, together with their interpretation in terms of physically relevant properties and concepts. Some results regard both conjugate spaces, different energetic states, and/or arbitrary dimensionality.


Mental health in children is intricate with psychological, social, and physical environments acting as key factors influencing the health status and the opposing outcomes and hence difficult to forecast. Important contextual risk factors such as natural calamities, migration, political conflicts, and socioeconomic adversities could produce negative mental health outcomes in childhood. Recent medical literature is abundant with empirical studies reporting adverse mental health symptoms and health behaviors among children and adolescents during the COVID-19 pandemic .Studies addressing the pandemic-related effects on mental health  by measuring psychological distress and well-being have shown that the initial outbreak of the COVID-19 pandemic led to a notable deterioration from existing mental health-related trajectories among young adults . AnalysiHowever, concerns have been raised regarding the relevance and validity of reported systematic reviews as well as the fact that most studies do not meet the PTSD exposure criterion among pediatric and adolescent populations , 5. The It may also be pertinent to consider historical experiences from previous large-scale communicable disease outbreaks to address the persuasive issues threatening the validity of the results from current systematic reviews. During the severe acute respiratory syndrome (SARS) pandemic in 2003, the prevalence of PTSD in adult survivors was reported as high as 38.8% 1 year after recovery . HoweverAmong adults with COVID-19, the prevalence of PTSD as high as 96.2% during the hospital stay fell to 12.4% at the time of discharge, and after discharge, the severity of PTSD was aggravated , 11. It DSM-5 symptoms, the questions on direct vs indirect exposure and the eligibility of the pediatric population to meet the PTSD exposure criteria need to be addressed [The aforementioned points of contention, therefore, make a strong case for reporting and corroboration of diagnostic screening for PTSD and follow-up to assess the “true burden” of PTSD among young children, adolescents, and adults. In addition to the use of It is remarkable that in studies concerning other disasters such as terrorism, floods, earthquake, and hurricane, self-reported measures are more frequent than other-reported measures . Therefon = 12,262) have shown that the pandemic had a significant impact on youth mental health and was mainly linked with depression and anxiety [About half of the world’s children confronted school closures during the COVID-19 pandemic with a negative cascading effect of social isolation. The stress involved in online learning compounded by poor network connectivity, logistic issues, inadequate technical support, etc. brought about unprecedented fluctuations in their social life. With schools’ reopening subsequently, separation anxiety, stress, frustration, sadness, and struggle enhanced by fear of life, and uncertainty of the pandemic could result in behavioral dysregulation and affect the mental well-being of young children. On the other hand, data from adolescent cohorts (12 studies, The present and past pandemic disasters have demonstrated that socioeconomic and environmental impacts of large-scale infection outbreaks and subsequent medical and public health responses may produce a stressful state of mental health that families and children find traumatic. Among the associated factors that could deepen the traumatic effect of the pandemic and influence outcomes such as PTSD, the issue of child maltreatment and psychological and physical abuse of the young remains at the forefront .There is overwhelming evidence suggesting that most people are resilient after a disaster . ConsideConsequently, prompt identification of early pointers to psychological distress and provision of mental health services and clinical interventions to help remediate their symptoms need prioritization. As part of future pandemic preparedness, appropriate physician and parental educational activities need to be planned to prevent, detect, and treat early warning symptoms of PTSD.


In mammals, odor information detected in the olfactory epithelium is converted to a topographic map of activated glomeruli in the olfactory bulb. Odor signals are then conveyed by projection neurons to the olfactory cortex for decision making. Odor information is processed by two distinct pathways, one is innate and the other is learned, which are separately activated during exhalation and inhalation, respectively. There are two types of odor signals, exteroceptive and interoceptive, which are also processed in different phases of respiration. Exteroceptive sensory information whether attractive/pleasant or aversive/stressful, is evaluated by the valence regions in the amygdala. Stress is an alert signal telling the body to take an action so that the normal condition can be recovered. When the odor quality is negative, the brain sets up a behavioral strategy to avoid the danger or to improve the situation. In this review article, we will describe the recent progress in the study of olfactory perception focusing on stress responses to external and internal odors. In mice, odor signals detected by olfactory receptors (ORs) are converted to an odor map, a combinatorial pattern of activated glomeruli . The gloOdor information comes from not only the outside environment but also from inside the body. Exteroceptive/orthonasal odors are essential in searching food, finding for mating-partners, and detecting dangers. Interoceptive/retronasal odors are important for evaluating the quality of chewing food, whether it should be swallowed or not. Furthermore, retronasal odor is useful for checking the physiological condition of the body. In the OB, there are two sets of mirror-symmetrical sensory maps, lateral and medial, that may be separately used for interpreting outside and inside odor information, respectively .via two distinct neural pathways: the direct pathway for innate decisions and the multi-synaptic pathway for memory-based learned decisions  axis and the other for the anterior/posterior (A/P) axis of the OB . For D/Vs, whereas glomerular segregation is controlled in mature OSNs by firing spikes with a different type of G protein, Golf  and repulsive  axon-sorting molecules are involved, whose expression levels are determined by OR-specific neuronal activity with cAMP . How is in, Golf .II) is located in the postero-dorsal OB whereas the aversive domain (DI) is separately mapped next to the DII  but in the fear (DII) domain. For optogenetic experiments, the channel rhodopsin gene was inserted into Olfr1019. Interestingly, photo-illumination of the knock-in (KI) mice induced immobility (freezing), but not avoidance behavior. Furthermore, the postero-medial part of the cortical amygdala (pmCoA) and amygdalo-piriform transition area (AmPir) were not activated in the photo-illuminated KI: the pmCoA and AmPir are responsible for inducing avoidance behavior . Then, what is responsible for imposing the positive quality on the imprinted odor memory?Among various hormones expressed in neonates, Each OB contains two mirror-symmetrical maps of glomeruli: lateral map in the dorsolateral region and medial map in the ventromedial region . We receWe hypothesize that the medial map of the OB conveys exhalation-phased retronasal odor information mainly to the medial areas of the OC including the medial and posterior parts of the AON , ventral and dorsal tenia tecta , and dorsal peduncular cortex (DP)  (m (VPrm)  and di-sm (VPrm) . These pm (VPrm) .The DP and TTd are located in the medial part of the olfactory peduncle. They project to the dorsomedial hypothalamus (DMH) that targets to sympathetic premotor neurons in the brainstem . This obWe hypothesize that the lateral map mainly conveys inhalation-phased orthonasal/exteroceptive odor information to the lateral part of the OC including the external and lateral parts of the AON , ventral and dorsal parts of the anterior piriform cortex , posterior piriform cortex (PPC), cortical amygdaloid areas (CoA), and lateral entorhinal area (ENTl) , suggesting that these areas process orthonasal odor information. The OTl projects their inhibitory axons to the rostrolateral part of the ventral pallidum (VPrl) that sends inhibitory axons to the central part of the mediodorsal nucleus of the thalamus (MDc), anterolateral part of the ventral tegmental area  and LH . These pStress-inducing sensory information can be classified into two categories: internal stressors such as low body temperature and external ones such as the sight of a predator . The olfAs illustrated in I domain and the fear DII domain in the lateral map of the OB convey the external odor signals either directly or indirectly via AON and APC to the negative valence networks in the AmPir and pmCoA. The AmPir neurons responding to predator odors activate the corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVH) for stress-hormone release , and rostral ventrolateral medulla (RVLM)  . BecauseThe afferent and efferent connections of the DP and TTd  suggest In the behavior of eating natural foods such as nuts, rodents rapidly repeat the sequence of “orthonasal examination of the external food  and negative (stressful/aversive) during the primary projection of OSNs to the OB. For instinctive decisions, odor signals are directly transmitted to the valence regions in the amygdala In addition to negative signals inducing stress, positive valence-signals also inspire the animal to achieve goals. The goal-oriented attractive behavior is induced by a desire mechanism that is mediated by dopamine, adrenaline, and other hormones. Thus, the positive-valence signals are not just for satisfaction, but also to induce the attractive behavior to accomplish a goal. Recent studies demonstrated that during odor-reward association learning, OT neurons rapidly acquire reward-selective responses and encode the positive-valence of conditioned odor  and thatOlfactory circuitry in the OB, OC, CoA, and OT plays a crucial role in perceiving the external and internal odors and judging the valence of odor inputs. When the animal inhales the orthonasal odors of a predator, the lateral stream may process the external odor information for predicting the presence of danger and driving aversive behaviors to avoid it. When the animal perceives retronasal odors of tasty foods in the oral cavity, the medial stream may process the internal odor information for predicting nutrients and driving eating behaviors, e.g., chewing and swallowing, as well as secreting saliva and gastric fluid. Although the immediate reflex-like responses to internal stressors are generated unconsciously by the autonomic networks in the hypothalamus, brainstem, and spinal cord , corticaBoth authors listed have made a substantial, direct, and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


This systematic review aims to analyze existing literature of the effects of transcranial direct current stimulation (tDCS) on motor skills learning of healthy adults and discuss the underlying neurophysiological mechanism that influences motor skills learning.This systematic review has followed the recommendations of the Preferred Reporting Items for Systematic reviews and Meta-Analyses. The PubMed, EBSCO, and Web of Science databases were systematically searched for relevant studies that were published from database inception to May 2022. Studies were included based on the Participants, Intervention, Comparison, Outcomes, and Setting inclusion strategy. The risk of bias was evaluated by using the Review manager 5.4 tool. The quality of each study was assessed with the Physiotherapy Evidence Database (PEDro) scale.The electronic search produced 142 studies. Only 11 studies were included after filtering. These studies performed well in terms of distribution, blinding availability and selective reporting. They reported that tDCS significantly improved motor skills learning. The main outcomes measure were the improvement of the motor sequence tasks and specific motor skills. Nine studies showed that tDCS interventions reduced reaction time to complete motor sequence tasks in healthy adults and two studies showed that tDCS interventions improved golf putting task performance.The included studies showed that tDCS can help healthy adults to improve the motor skills learning by activating different brain regions, such as the primary motor cortex, left dorsolateral prefrontal cortex and right cerebellum. However, the number of included studies was limited, and the sample sizes were small. Therefore, more studies are urgently needed to validate the results of current studies and further explore the underlying neurophysiological mechanisms of tDCS in the future. Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique that uses a stable, low-intensity direct current (1-2 mA) to regulate the activity of cortical neurons  to collect and find duplicate records automatically.Studies were included following the inclusion criteria of the Participants, Intervention, Comparison, Outcomes, and Study design.Participants: The participants were healthy adults without a history of musculoskeletal injury and obvious neurological diseases. The age range of healthy adults is 18–56 years old.Intervention: The intervention method was tDCS regardless of stimulation type, intensity, duration or electrode position.Comparison: The comparison was with sham tDCS.Outcomes: The main outcomes measure were the improvement of the motor sequence tasks and specific motor skills, such as serial reaction time task (SRTT), sequential finger tapping tasks (SFTT), sequential visual isometric pinch task (SVIPT), and golf putting tasks. Improvements in motor skills learning are assessed through sequential task reaction times and golf putting scores.Study design: The study included randomized, crossover, and sham controlled designs. Animal studies and non-English studies were excluded. Comments, case reports, letters, opinions and conference abstracts were also removed .Two researchers independently examined the search results and resolved differences through discussion (QS and ZL). The abstracts and full texts of relevant articles were read carefully and only those that qualified were selected. Then, the researcher further confirmed the selected articles and discussed possible disagreements. If disagreements remained, a fifth researcher was consulted, and the results were evaluated (XW).Microsoft Excel  was used to summarize the original data from the included articles. The author, sample, age, anodal/cathodal location, current intensity, electrode size, current density, duration, work tasks, and main outcome measures were all summarized.The Physiotherapy Evidence Database (PEDro) scale was used to evaluate the quality of each study . After removing duplicate publications and identifying irrelevant studies by reviewing the titles, abstracts and full texts of the articles, 11 articles were included in this systematic review. These studies investigated the effects of tDCS on motor skills learning.Eleven studies investigated the effects of tDCS on motor skill learning. A total of 383 people were recruited .2 , dorsal (PMd) and ventral premotor (PMv), SMA and posterior parietal cortex (PPC), as well as the cerebellum and basal ganglia . In view of the complexity involved in motor skills, multiple regions of the brain may be involved in the regulation and limitation of motor skills, including M1, DLPFC, SMA and the cerebellum  in the brain and the adjustment of brain network functional connections to regulate brain function  can help improve motor skills learning, and its underlying neurophysiological mechanisms are related to the changes in cerebral excitability, neurotransmitters, synaptic plasticity, and brain network functional connections. However, future studies with large sample sizes and experimental designs with increased rigor are needed to confirm the current findings.The original contributions presented in the study are included in the article/SQ contributed to study design, data collection, drafting, and revising the manuscript. YL and XW contributed to supervising study design, completing data analysis and interpretation, and revising the manuscript. ZL and ZW revised the manuscript. All authors have read and approved the final version of the manuscript and agree with the order of the presentation of the authors.This work was supported by a grant from the key program of Natural Science Foundation of China (No. 11932013).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.