The ventriculoperitoneal (VP) shunt has been one of the primary methods for treating hydrocephalus for many years and is one of the most frequent surgical interventions performed in neurosurgery using a variety of techniques and different VP shunt types. Consequently, shunt insertion is associated with many complications, including insertion failure, functional failure, and mechanical failure such as shunt migration. Shunt migration to the gastrointestinal or urogenital tract is a rare and one of the most distressing complications, which can lead to ascending infection and even meningitis. We report a rare case of a 24-month-old male with a VP shunt tube that migrated and protruded from the anus, subsequently causing meningitis. A ventriculoperitoneal (VP) shunt is a medical device used to treat hydrocephalus, a condition in which there is an excessive accumulation of cerebrospinal fluid (CSF) in the brain -3. The sAfter the procedure, patients may experience some discomfort and need to stay in the hospital for a few days. They will also need to have regular follow-up appointments with their healthcare provider to monitor the shunt's function and address any complications that may arise ,9. ThereA 24-month-old male presented to the pediatric emergency department (ED) with a history of tube protruding from the anus. He had undergone a VP shunt at the age of six days for congenital hydrocephalus and was discharged home without any postoperative complications, followed by two shunt revisions at the age of 16 months and 17 months.Seven months after the last shunt revision at the age of 17 months, the child presented to the pediatric ED with a distal catheter protruding through the anus; this was noticed by his mother one hour before presentation to ED.There was no history of fever, headache, vomiting, abnormal movements, or abdominal distention. Clinical examination did not reveal any signs of peritonitis or meningitis. The peritoneal end of the VP shunt was protruding through the anus Figure .There was dribbling of CSF at the distal end of the VP shunt. The child was investigated with a VP shunt survey X-ray, a computed tomography (CT) scan of the brain, and a full septic work-up that included a complete blood count, inflammatory markers, blood culture, and a CSF sample for CSF studies, cultures, and PCR. The patient was kept nil by mouth, and empirical antibiotics (ceftriaxone and vancomycin) were started.The VP shunt survey X-ray confirmed that the peritoneal end of the shunt tube was extending well beyond the pubic symphysis; no knotting of the shunt tube was visualized. No gas under the diaphragm was noted Figure .CT scans of the brain, comparing the new brain CT Figure  to the pCBC demonstrated a high white blood cell count (WBC), normal hemoglobin, and normal platelet levels; blood culture was negative. Inflammatory markers included high erythrocyte sedimentation rate (ESR), high C-reactive protein (CRP), and high procalcitonin. The CSF sample showed a high white blood cell count, high red blood cell (RBC) count, normal lymphocytes, high neutrophils, normal monocytes, high CSF protein levels, and low CSF glucose. The CSF culture grew Providencia stuartii. After identifying the CSF culture, the antibiotics vancomycin and ceftriaxone were upgraded to meropenem Table .On Day 1 of admission, the patient was brought to the operating room for laparoscopic shunt removal, performed by pediatric surgery, and the insertion of a new external ventricular drainage, carried out by pediatric neurosurgery. In the first stage, the pediatric surgery team conducted a diagnostic laparoscopy, reporting multiple adhesions and a thick peritoneum. The site of the peritoneal shunt was facing the rectum but could not be identified due to the presence of multiple adhesions; the distal catheter was removed. No area of leakage or perforation was noted. The pelvis was found to be severely adhered. No other complications were observed.In the second stage, pediatric neurosurgery reported that the VP shunt valve was exposed at the left frontal area. The skin was opened using the same previous skin incision around the valve in a curved fashion. The valve was fully exposed, and the distal tube was cut and pulled through the anus; it was found to be free. The valve, along with the proximal catheter, was removed and sent for culture, which grew Providencia stuartii. A new external ventricular drainage (EVD) catheter was placed and secured. The CSF was released under low pressure and was tunneled through the skin, then secured using 2-0 silk sutures. Dressing was applied, and the patient tolerated the procedure well. Postoperatively, the patient was extubated and transferred to the pediatric intensive care unit in a stable condition.Subsequent CT scans of the brain showed that the tip of the VP shunt was located in the encysted hydrocephalus on the right side, with an interval decrease in the size of the supratentorial hydrocephalus. There was also an interval increase in the size of the left cerebral convexity subdural collection, along with the development of a small right cerebral convexity subdural collection Figure .After day 2 postoperatively, the patient was shifted to the regular floor with follow-up by the infectious team and daily CSF study. During the same admission, following clearance of CSF, the patient underwent another surgery by both pediatric surgery and neurosurgery for removal of the EVD and insertion of a new VP shunt.Hydrocephalus is a condition characterized by excessive accumulation of fluid in the brain, leading to increased intracranial pressure. The term "hydrocephalus" is derived from the Greek words "hydro," which means water, and "cephalus," which means head ,13. ShunThere are several types of shunts available, including VP, thecoperitoneal, ventriculoatrial, and ventriculopleural shunts. Among these, VP shunts are the most commonly used for treating hydrocephalus .However, shunt surgery is associated with many risks. The complication rate for VP shunts is reported to be between 24% and 47%. The most common complication is mechanical blockage of the shunt. Other potential issues include infection, bleeding, and over-drainage .In addition to complications related to the shunt itself, there's also a risk of abdominal complications with VP shunts, reported to be around 25%. These may include bowel obstruction, hernia, meningitis, and other issues related to the shunt tubing's placement in the abdominal cavity. It's essential to work closely with your healthcare team to monitor and manage any potential complications. Regular follow-up appointments and symptom monitoring can help ensure that any issues are identified and addressed promptly .Our patient, who was asymptomatic, presented only with a VP shunt protruding from the anus. Culture results indicated the growth of Providencia stuartii, a gram-negative organism that can cause meningitis. For any patient presenting with abdominal symptoms, an evaluation for bowel perforation is crucial. The appropriate treatment varies depending on the presence of sepsis, perforation, peritonitis, or an intraperitoneal abscess.In cases of simple bowel perforation without additional complications, a formal exploratory laparotomy may not be necessary. Instead, the shunt should be disconnected at the abdominal wall, and the lower end removed through the rectum. This can be done using colonoscopy, sigmoidoscopy, or proctoscopy to prevent contamination of the tract. The distal end of the VP shunt should not be pulled back into the peritoneal cavity. An external ventriculostomy should be established for at least three weeks, and the patient should be administered broad-spectrum antibiotics to prevent CSF infection. Once repeated CSF cultures return as sterile, a new VP shunt can be inserted on the opposite side. In more severe cases involving bowel perforation and peritonitis, an exploratory laparotomy is warranted. The shunt should be removed, the bowel wall thoroughly cleansed, and primary closure performed .The VP shunt functions by removing excess CSF from the brain's ventricles and transporting it to the peritoneal cavity, where the body can absorb and eliminate it. A valve is typically integrated into the shunt system to regulate the CSF's flow and avoid over-drainage or under-drainage. No doubt, one of the common procedures performed in neurosurgical practice is the placement of a VP shunt, but this procedure can result in several severe complications.To prevent complications with a VP shunt, it is important for patients and caregivers to be aware of the signs and symptoms of shunt malfunction or infection, such as headaches, vomiting, seizures, meningitis, and changes in consciousness or behavior. Regular follow-up appointments with a healthcare provider are also important to monitor the shunt's function and address any concerns or complications that may arise.


BackgroundPreoperative anxiety is common in children undergoing surgery. When anxiety is identified or suspected, there are several strategies typically used to manage it. Perhaps the most common is anxiolytic premedication or parental presence at induction. Medications such as midazolam have been associated with adverse effects, such as a slower wakeup, and require timing of administration, while parental presence can be disturbing to the parent and divert the attention of the operating room team. A more recent option is distraction via electronic tablets. The purpose of this study was to retrospectively investigate and quantify any change in the use of midazolam, the most common anxiolytic approach at our institution, and any change in the length of time in the post-anesthesia care unit (PACU) following the introduction of tablet computers to a pediatric ambulatory surgical center.MethodsWe conducted an IRB-approved retrospective chart review of 13,790 pediatric patients ages one to 18 undergoing outpatient elective surgeries at the University of Florida (UF) Children’s Surgical Center over a five-year period. A univariate analysis was conducted using the Fisher’s Exact test and interrupted time series analysis to determine differences between midazolam administration and PACU times, with interruption occurring at tablet implementation. A multivariable analysis and sensitivity analyses were performed to confirm the findings of the univariate analysis.ResultsOn univariate analysis, tablet availability was associated with both a decreased preoperative oral midazolam administration (odds ratio (OR) 0.158, 95% confidence interval (CI): 0.140 to 0.179, P-value <0.001) and a decreased PACU length of stay . The association with decreased preoperative midazolam administration held after multivariable analysis , but PACU length of stay was not statistically significant . These results were confirmed on sensitivity analysis, with tablet availability continuing to be associated with decreased preoperative oral midazolam administration but not with reduced PACU length of stay.ConclusionOur results demonstrate that computer tablets were associated with a significant decrease in the frequency of midazolam administration and consequently may reduce preoperative pediatric anxiety. We did not find an associated change in PACU length of stay following the introduction of tablets. Tablets present a unique distraction alternative to chemical anxiolysis for institutions seeking to reduce medication use in pediatric patients. Preoperative anxiety is present in the majority of pediatric patients undergoing surgery with general anesthesia . Fear ofConventionally, anxiolytics are used to prevent and treat childhood preoperative anxiety . Oral miDistraction is a well-established technique for reducing anxiety prior to surgery ,9. SpeciThe University of Florida (UF) opened a new pediatric ambulatory surgical center in April 2016. Tablet computers loaded with popular movies and video games were purchased and made available to patients. Over the coming months, the anesthesiology faculty and staff at the surgical center noticed that pediatric patients were less frequently requiring premedication. This retrospective study investigated the frequency of midazolam use and length of time in the PACU among pediatric patients presenting for procedures at our outpatient surgical center.Tablet implementation in an outpatient surgical setting Tablet computers were made available for all patients to use while preparing for surgery at the UF Children's Surgical Center (CSC) when the new facility opened on April 1, 2016. These tablets were maintained by the information technology (IT) department, set up with a common password protection system, and loaded with games and movies that are popular among various age groups. In the interest of safety and accountability, the tablets were not able to browse the internet. The preoperative nursing staff offered tablets to patients with parental permission at the start of the patient/parent interview process, and they could be used throughout their stay, including in the recovery room. The tablet was signed out to each patient and passed along as part of the standard nursing handoff. The tablet computers were locked in protective cases that were sanitized after each patient's use. Tablets were stored overnight in a locked charging station for safekeeping.Data collectionAn IRB-approved retrospective observational chart review of 13,790 patients was conducted. All pediatric patients one to 18 years old who had an outpatient elective surgery under general anesthesia at the University of Florida, Children’s Surgical Center (CSC) between October 1, 2015, and September 30, 2020, were included in the study. Patients were divided into two cohorts: pre- and post-introduction of tablets. Data extracted from the EPIC electronic medical record included patient age, presence or absence of midazolam administration in the preoperative phase of care, surgical service, procedure type, post-anesthesia care unit length of stay, total length of stay, and length of surgery. Surgical procedures primarily included circumcisions, endoscopies, tonsillectomies, and tympanostamies.Statistical analysisThe Fisher’s Exact test or the independent t-test was used to determine univariate proportional differences or mean differences between the two cohorts, respectively. Since this was a before-after study design, interrupted time series analyses were utilized to determine differences between midazolam administration and PACU times, with the interruption occurring at the tablet implementation  . To accoIn this analysis, 13,790 pediatric patients were included, with 1,227 patients and 12,563 patients in the pre-tablet and post-tablet cohorts, respectively (Table We observed a dramatic decrease in midazolam administration at our pediatric ambulatory surgical center following the introduction of electronic tablets. This reduced rate of midazolam administration persisted for four years following the introduction of tablets. Our findings demonstrate that electronic distraction may be an effective means of decreasing premedication with midazolam. Though we did not find a significant change in PACU length of stay, decreased use of pharmacologic anxiolytics may improve long-term patient recovery following general anesthesia. This study at a large tertiary care ambulatory surgical center supports many previous studies that have demonstrated that tablets and other modes of electronic distraction significantly decrease the frequency of midazolam given for preoperative anxiety in children ,15,16. TWe recognize that there are several limitations to this study. First, we did not assess anxiety levels in patients in a formal way. We assessed in our usual manner: children who appeared anxious received midazolam, and children who did not appear anxious did not. We have no data about behavior at induction, but studies comparing electronic tablets to various different forms of distraction and behavior at induction abound in the literature. We have no data regarding the incidence of postoperative delirium or adverse effects of midazolam in these patients, but PACU length of stay was not negatively impacted in length, as one might come to expect if delirium or other adverse reactions were to occur. We also looked at all children under the age of 18 in this study. Although different ages of children will have varying levels of anxiety and be at different levels of cognitive development, the age groups were equally represented in those who had surgery prior to tablet availability and those after tablet availability. It is our local practice to start IVs starting at age 12 preoperatively and for those under 12 years of age to receive an inhalational induction, so we further subdivided our original age limit to those under the age of 12. Both the groups under the age of 12 and under 18 were equally represented in the groups before and after tablet implementation.We have no child life specialists, and parental presence at induction is not a usual occurrence at our facility. We also have no measures of patient adaptability to using tablets or taking midazolam to compare. Our patient population was also limited because we only looked at patients who were undergoing same-day elective surgeries at a free-standing outpatient surgical center. Despite these limitations, we still believe that our study has merit in its original state. Since the study occurred over a five-year period, there may be the possibility of differences in variables between cohorts not accounted for in our analysis that could confound our results. However, the interrupted time series model that was employed should minimize this potential bias. Rather than focusing on all individual factors that may be associated with changes in midazolam use, the statistical model analyzed overall rates of midazolam use over time, specifically in relation to the introduction of computer tablets. Any change in factors associated with midazolam administration over the course of the study would be controlled for in this analysis.Our study demonstrates a reduction in midazolam use after the computer tablets became available, which is something that we had suspected anecdotally and that prompted the data collection approximately one year after the tablets became available. We continued gathering data retrospectively to see if any further changes occurred. If midazolam use continued to decline, one might suspect providers were under-recognizing and under-treating anxiety, and PACU times might consequently increase due to an increased incidence of delirium. If midazolam use increased again over time, then other conclusions might be drawn. Although causation cannot be established, midazolam use did decrease. Induction behavior was not noted to deteriorate, and we did not observe an increase in PACU length of stay. Our report represents an organic description of the impact of the implementation of tablet computers on our practice. We believe that our findings confirm what almost any parent would tell you: children are distracted by tablet computers. In our setting, this distraction resulted in less midazolam use and is of interest and applicable to many other institutions with similar resources that are examining alternatives to pharmacologic anxiolysis.The fear with any attempt to decrease pharmacologic agents for anxiety is under-diagnosing and under-treating anxiety. We recognize that without a validated tool to recognize and treat anxiety in children, the decision to medicate a child is not a perfect science. As such, our facility is in the process of implementing a tool to standardize this process, which is especially important in an academic setting so that learners with different backgrounds can be placed on a more level playing field in recognizing and addressing preoperative anxiety. Future goals include predicting which patients are most likely to experience preoperative anxiety and determining the most appropriate treatment algorithm based on individual patient characteristics.The electronic tablets have proven a good investment for our pediatric ambulatory surgical center. They are still being used at the CSC, and we have had an adequate supply of electronic tablets to give to each pediatric patient scheduled for surgery. We have not had to buy any additional electronic tablets or replace any due to damage in the seven years since they were originally purchased. Some tablets have been found in linens in our laundry department, but these have almost all been recovered without damage, and only one has been lost over the seven years since their introduction. The tablets have required minimal upkeep. Aside from the original purchase, no additional money has been spent on the tablets.In summary, our results demonstrate that the introduction of computer tablets to our pediatric ambulatory surgical center was associated with a significant decrease in the frequency of premedication with midazolam for preoperative anxiety in children. This observed decrease in midazolam administration persisted for four years after tablets were made available to all pediatric patients. Tablet availability and decreased midazolam usage have not significantly impacted the PACU length of stay. We believe this cohort is the largest observational study to date to evaluate the relationship between electronic distraction and anxiolytic administration, though further studies are needed to adequately quantify the resulting change in anxiety. Pediatric ambulatory surgical centers should consider electronic tablets as a cost-effective means of reducing reliance on pharmacologic anxiolytics.


Premedication in anesthesia has long been used to reduce patient anxiety, increase patient compliance, and supplement the overall anesthetic. In pediatric populations, premedication also has the indirect benefits of reducing parental anxiety as well as both the incidence and severity of emergence delirium. Oral midazolam, selected for its ease of administration, short duration of action, and reliable anxiolytic and amnestic effects, has been a favorite choice in this role for decades. The side effect profile of midazolam is also relatively benign, heavily dose-dependent, and easily managed in the perioperative setting. While midazolam appears to be an ideal adjunct in the anesthetic care of pediatric patients, there is a growing body of evidence suggesting prolonged benzodiazepine exposure causes neurodevelopmental changes in infants. This evidence, along with the 2017 Food and Drug Administration (FDA) warning labels for the use of select anesthetic medications, including midazolam in children under the age of three, has led to some debate in the anesthetic community over the continued use of this anesthetic for premedication in pediatric populations. This article aims to educate the reader on the history of midazolam as a premedication agent in pediatric populations and examine the evidence supporting and against its continued use in this role. Preoperative anxiety in children is associated with several adverse postoperative outcomes, including increased pain, sleep disturbances, and negative behavioral changes . There aThese critiques have been bolstered by studies of the effects of exposure to general anesthesia on lifelong health and behavioral outcomes  in conjuWhile this new warning highlights the correlation between early childhood exposure to midazolam and negative cognitive and behavioral outcomes, the evidence for a causal relationship remains weak. Only one human study has shown a relationship between midazolam exposure and neurodevelopmental changes in neonates . The relMidazolamMidazolam is a benzodiazepine that binds to postsynaptic γ-aminobutyric acid (GABA)-A receptors within the central nervous system, which in turn increases the flow of chloride ions through the receptor into the postsynaptic neuron . Increas-1, with mildly dose-dependent durations of onset and action at 10-20 minutes and 60-90 minutes, respectively. In children over the age of one, half-life ranges from 2.2-6.8 hours, with a clearance range of 3.2-13.3 mL·kg-1·min-1. If an IV catheter is in place, IV administration offers a shorter onset and duration of action at 2-3 minutes and 45-60 minutes, respectively, with a shorter average half-life of 2.9-4.5 hours [-1), a significant number of children achieved satisfactory anxiolysis within 10 minutes [In the setting of procedural pediatric anesthesia, oral dosing is the preferred method of administration due to its ease of administration without the need for IV access and high rate of tolerance in pediatric populations . Oral do.5 hours . There i minutes . There i minutes .Midazolam’s primary action on GABA-A receptors, slowing neurotransmission throughout the central nervous system, leads to the desired anxiolytic, sedative, anti-epileptic, and anterograde amnestic effects. The primary undesired side effect is oxygen desaturation, especially when combined with opioids and other depressant medication, which is caused by reduced respiratory drive, relaxation of airway musculature, or a combination of the two. This has been reported in less than 1% of cases and is thought to be dose-dependent, with obstructive sleep apnea as a significant risk factor . Other rOverview of perioperative and postoperative behaviors and outcomesSurgery is a traumatic life event for many children. The strange environment, sights, sounds, and stimuli induce a great deal of fear and anxiety in both the patient and the parent or guardian. This fear and anxiety have been shown to lead to immediate consequences such as increased difficulty with mask induction and even cancellation of surgical procedures in some cases . IncreasEvidence for efficacy of midazolamThe effectiveness of midazolam as a preoperative anxiolytic for pediatric patients has been well documented, and more than 80% of anesthesiologists in the US preferred midazolam as a premedication . Many hiNo medication is without side effects, however, and midazolam is no exception. The most recent criticism of midazolam follows evidence suggesting that early exposure to the medication can lead to neurodevelopmental changes in neonates . An emerIncluding midazolam in this label has led to the publication of various studies examining the link between neonatal midazolam exposure and neurodevelopmental changes. Animal models have shown a more direct link between total midazolam exposure during the neonatal period and negative behavioral changes but notably have focused on long-term sedation. In addition, the doses used are more than ten or even 100 times the weight equivalent dosing common in the neonatal intensive care unit setting ,25,26. OAlternativesAlpha-2 Agonists-1 ) have been considered replacements for midazolam in recent years [Oral clonidine and intranasal or buccal dexmedetomidine , with sedative, anxiolytic, and analgesic effects [Ketamine has also been evaluated as a potential alternative to midazolam. It has a faster onset (10-15 minutes) in the oral form  [-1 [The use of opioids, like oral transmucosal fentanyl citrate (15-20 µg·kg-1) ,31 or or-1) [-1 ), is pra-1) [-1 , showed -1. However, this can vary based on individual patient factors and the specifics of the procedure. Notably, children receiving the higher spectrum of the dosing range (20-25 µg·kg-1) displayed a significant decrease in oxygen saturation (SpO2) after 30 minutes compared to those on lower doses [Some concerns with oral transmucosal fentanyl citrate are that it causes a dose-dependent reduction in respiratory rate and the risk of respiratory depression is present, and in some cases, the postoperative administration of naloxone might be necessary. The typical dose for oral transmucosal fentanyl in pediatric patients is around 5-15 µg·kger doses . This rier doses .Another opioid option for anesthetic premedication is butorphanol, a mixed agonist-antagonist at the μ-opioid receptor with agonistic activity at the κ-opioid receptors. One study found that it has more sedation and comparable anxiolysis to oral midazolam with no increase in nausea and vomiting . FentanyParental Presence at Induction of AnesthesiaPPIA, as a part of a family-centered approach, is one of the more heavily studied forms of non-pharmacologic anxiolysis prior to pediatric surgery . ProponeBehavioral interventionsPassive video viewing, active video gaming devices, and other distraction-based interventions have also been studied. Providing a familiar alternative point of focus to the child allows them to ignore many of the unknown and anxiety-inducing sights and sounds present during the induction process. Passive video viewing and clowns (doctors or nurses in costume) have been shown to significantly reduce anxiety levels when compared to controls. However, only interactive video gaming is superior to pharmacologic premedication . These vMidazolam is used as a premedication agent in pediatric anesthesia for its proven efficacy in reducing anxiety, facilitating smoother anesthesia induction, and improving the overall experience for pediatric patients undergoing surgery. Binding to GABA-A receptors and reducing neuronal activity provides effective anxiolysis, sedation, and amnesia. However, as FDA warnings and studies highlight, its use is not without concerns, as there is an evolving understanding of the potential neurodevelopmental risks associated with benzodiazepines, which necessitates a reevaluation of its use. As the anesthetic community continues to deliberate on administrating midazolam in light of new evidence, the focus should remain on patient safety and optimizing anesthetic care for the pediatric population.The challenge in pediatric anesthesia remains to balance the benefits of effective anxiolysis against the potential risks of drug exposure, especially in very young children. While opioids like fentanyl can be used in pediatric anesthesia for their potent analgesic properties, their potential side effects, particularly respiratory depression, make them less ideal as a sole agent for premedication. Alternatives like alpha-2 agonists and NMDA antagonists offer a balance of sedation and analgesia with a more favorable side effect profile. Non-pharmacologic methods should also be considered to minimize medication-related risks. The evolving research will undoubtedly influence future guidelines and practices as clinicians embrace a patient-centered approach that weighs the benefits of midazolam against its risks, emphasizing individualized patient care. As the body of research and evidence grows, so does our understanding of the complex interplay between anesthetics, developing neurology, and long-term outcomes, guiding us toward safer and more effective management of pediatric anesthesia.


Chemotherapy (CTx) with targeted therapy (TT) have increased the overall response rate (ORR) and improved survival in unresectable or borderline resectable metastatic colorectal cancer (mCRC). However, the resection rate is an endpoint with often suboptimal expert involvement. The aim was to investigate whether the improvements in ORR have translated to improved resection rates (RR).A systematic literature search was performed using the PICO process.Odds ratios, and 95% confidence intervals  were analyzed for ORR and RR using dichotomous values with the Mantel-Haenszel method. Progression-free survival (PFS) and overall survival (OS) were analyzed using the inverse-variance method and displayed as hazard ratios and 95% confidence intervals .p = 0.002) and with triplet CTx + TT versus doublet CTx + TT . PFS and OS were improved by use of TT . The overall RR was low (< 15%) and did not improve in the same way as the other endpoints.The literature search returned 469 records. Sixteen articles with 5724 patients were selected for analysis. The qualitative analysis revealed low and moderate risk of bias endpoints. Higher ORR was observed with CTx + TT versus CTx only (OR: 0.62 , The ORR and survival rates in unresectable and borderline resectable mCRC were improved by modern CTx and TT that did not translate into higher RR, mostly due to the lack of expert involvement.The online version contains supplementary material available at 10.1245/s10434-023-14049-3. Therefore, systemic treatment with CTx and TT can be used to try to convert initially oligometastatic unresectable mCRC to resectable disease.6 Most of the randomized controlled trials (RCT) published so far do not consider the metastasis resection rate (RR) as a well-defined endpoint supported by expert decision making, and have focused instead on ORR, progression-free survival (PFS), and overall survival (OS). This is a systematic literature search and meta-analysis to explore the relationship between ORR and metastasis RR in patients with initially unresectable or borderline resectable mCRC. The hypothesis was that the RR did not improve in the same way that ORR, OS, and PFS did with the use of modern CTx and TT.Metastatic colorectal cancer (mCRC) is a major cause of morbidity and mortality. Patients with mCRC can be treated with surgery, ablative techniques, chemotherapy (CTx) and targeted therapy (TT) with anti-epidermal growth factor (EGFR) or anti-vascular endothelial growth factor (VEGF) drugs. Surgical removal of metastases is potentially curative; however, only a minority of patients with mCRC are initially suitable for resection and the concept then is instead to reach a prolonged chronic state of disease control improved by surgical and other interventional therapies such as ablation or radiation therapy.Do improvements in ORR with modern CTx and TT translate to higher metastasis RR in patients with upfront unresectable or borderline resectable mCRC?Population: Adult patients older than 18 years with mCRC.Intervention, Comparator: Use of different types of antineoplastic agents for systemic treatment of mCRC.Outcomes: ORR, RR, PFS, OS.Timing: 1 January 2000 to 1 January 2020.Study type: RCT.The following elements were employed in the literature search strategy:A systematic literature search of the MEDLINE/Pubmed electronic database using the Medical Subject Headings (MeSH) “colorectal neoplasms,” “neoplasm metastasis,” “antineoplastic agents,” and “randomized controlled trial” was carried out to find appropriate articles. The results were limited to English articles published in the time period between 1 January 2000, and 1 January 2020. Additionally, the references of the chosen articles were screened to minimize the risk of missing relevant publications. For multiple publications reporting on the same patient population, the most recent publication was used.Included patients were adult humans older than 18 years with mCRC.Included patients had upfront unresectable or borderline resectable metastatic disease.6Included patients in the trials received current ESMO and German S3 mCRC guideline adherent first-line treatment with CTx and TT.The studies were designed as RCT.All outcomes of ORR, RR, PFS, and OS were reported in the results.The following inclusion criteria were used to select the relevant articles for analysis:Any studies in which patients received non-standard of care or experimental treatments .Studies with second line, reduced dose, maintenance, disease control or palliative treatments.The following articles were excluded from the analysis:Three of the authors  independently reviewed the titles, abstracts, and full texts to determine study eligibility for inclusion. Differences in eligibility assessments were resolved by consensus among all three authors. Data extraction was performed by two of the authors (JZ and CH) and independently verified by two other authors . The following data points were extracted from each of the eligible trials: manuscript information, antineoplastic agents used , number of patients included, ORR, RR , PFS, and OS. Data on KRAS mutation status were also collected where applicable to ensure anti-epidermal growth factor (EGFR) drugs were given according to the guidelines. Data included in the final analysis reflected the intention-to-treat population of each trial.7 Two other authors  independently reviewed the bias assessments. Any discrepancies were resolved by consensus among all four authors. The RoB2 tool was used to make judgments on five standard domains of bias  that can possibly affect the results of randomized trials. A final overall judgement of either low risk, some concerns of bias, or high risk of bias was also derived using the RoB2 tool.All individual trial results included in the meta-analysis were assessed for bias using the Cochrane risk-of-bias tool for randomized trials version 2 (RoB2) by two of the authors (JZ and CH).The statistical analysis was carried out by extracting the hazard ratios (HR) and 95% confidence intervals (95% CI) for OS and PFS as well as the percentages for ORR and RR. The HR were determined for the time-dependent variables OS and PFS with their corresponding 95% CI and displayed in forest plots. For ORR and RR, the odds ratios (OR) with their corresponding 95% CI were identified and displayed in forest plots. The HR and OR were analyzed using a random-effects model as a large heterogeneity between the individual trials was assumed. The meta-analysis was carried out with Review Manager (Rev-Man) version 5.3.5 .In total, 469 records were identified from the initial database search. No duplicates were identified. After initial screening of the titles and refinement of the search strategy, two authors (JZ and AAS) assessed the full texts of 65 articles for eligibility. All the included studies used ESMO and German S3 guideline adherent treatment regimens with doublet or triplet CTx with or without anti-EGFR and anti-VEGF TT Table . For stuFrom the included studies, 16 primary and 35 secondary outcomes were selected for risk of bias assessments with RoB2. A visual presentation of the bias assessments is presented in Supplementary Table 1. Three of the included primary outcomes were judged to be at a low risk for bias, 12 were judged to have some concern for bias, and one was judged to be at a high risk of bias. The main areas of possible concern were the randomization process and the measurement of the outcomes. Specifically, most studies did not report whether the allocation sequence was concealed until participants were enrolled and assigned to the interventions. Another area of possible concern was the frequent omission of blinded and centralized radiological review which could affect ORR and PFS results. An overall judgment of high risk of bias was made for one of the primary outcomes due to the baseline differences between groups, suggesting a possible problem with the randomization process and possible selection of the reported results. For the 35 secondary outcomes, a similar distribution of bias risk was observed (Supplementary Table 1).19 Three trials included patients with liver-limited disease.22 The range of liver-only metastasis was between 18 and 33% for the studies, including patients with multiple sites.Thirteen trials included mCRC with single or multiple sites that were primarily unresectable or borderline.22 Four trials with 868 patients compared triplet CTx + TT versus doublet CTx + TT.20 Three trials with 589 patients compared triplet CTx versus doublet CTx only.21 Two studies with 762 patients compared doublet CTx + anti-EGFR TT  versus doublet CTx + anti-VEGF TT (bevacizumab).23Seven trials with 3505 patients compared doublet  or triplet (FOLFOXIRI) CTx + TT  versus doublet or triplet CTx only.p = 0.003); Fig. 19 triplet CTx versus doublet CTx only ; Fig. 22 and triplet CTx + TT versus doublet CTx + TT ; Fig. 20 were associated with statistically significant differences in ORR. No differences in ORR were observed regarding the type of TT given (anti-EGFR versus anti-VEGF) ; Fig. 23The ORR ranged from 29 to 87% . The comparisons of doublet/triplet CTx + TT versus doublet/triplet CTx only . The overall RR was better in patients that received CTx + TT versus CTx only; Fig. 19 The RR in patients with liver-limited disease ranged from 13 to 67% . However, no difference in RR for patients with liver-limited disease treated with doublet CTx + TT versus doublet CTx only was observed; Fig. 22Only three of the included RCT reported detailed criteria for metastasis resectability and how the decision for resection was made by the multidisciplinary team.p < 0.001) and in patients treated with triplet CTx + TT versus doublet CTx + TT . No differences in PFS were observed for studies which compared doublet versus triplet CTx only , and CTx + anti-EGFR TT versus CTx + anti-VEGF TT . Data are displayed in Supplementary Figs. 1a to d.PFS was better in patients treated with CTx + TT versus CTx only , patients treated with triplet CTx + TT versus doublet CTx + TT , and in patients treated with doublet CTx + anti-EGFR TT versus doublet CTx + anti-VEGF TT . No differences in OS were observed for patients treated with triplet versus doublet CTx only . Data are displayed in Supplementary Figs. 2a to d.OS was better in patients treated with CTx + TT versus CTx only  in patients with liver-limited disease. Both ORR and RR were higher in patients who were treated with both CTx and TT.24 Modest et al. also published a similar blinded post-treatment review of 448 patients included in the FIRE-3 trial.25 In the review by Modest et al, eight experienced surgeons and three medical oncologists centrally reviewed CT and MRI examinations from the FIRE-3 trial. Included patients were considered resectable if at least 50% of the reviewers selected surgical intervention. Surgical intervention was retrospectively considered possible in 22% of patients at baseline and 53% at best response. However, the actual resection rate achieved in the FIRE-3 trial was 13%. Again, the discrepancy between potential and actual resection rates demonstrates the necessary impact of expert involvement in determining resectability of mCRC.25 The recently published CAIRO05 trial adds new evidence for the strategy in removing metastases from the liver and thus prolonging tumor-free intervals, with a positive impact on overall survival. In this trial an expert panel evaluated the tumors before chemotherapy and judged that approximately 82% to 88% may become resectable (or treatable with ablation). After the chemotherapy, patients with mutations in either RAS or BRAF underwent ablation (37% of patients) or surgery (51% of patients), whereas patients with RAS/BRAF wild-type underwent complete local treatment with either surgery and/or ablation in 68% (RAS) and 69% (BRAF) of the cases.26 This finally implements the findings of the CLOCC trial into a common approach and equipoise of resection and ablation in a high-quality clinical trial.3Previously published RR for oligometastatic disease range from 5 to 22%. The overall RR in this meta-analysis matches the previously published oligometastatic RR; however, patients with liver-limited disease have higher RR. Few RCT have reported RR for liver-limited mCRC. One of them is the CELIM trial published by Folprecht et al. in 2010 which compared treatment with cetuximab and FOLFOX6 versus cetuximab and FOLFIRI in patients with unresectable colorectal liver metastases. The CELIM trial was not included in this analysis as it did not compare regimens with TT versus regimens without TT. Folprecht et al. reported an ORR of 62%. This was similar to the ORR for patients treated with doublet CTx and anti-EGFR TT in this meta-analysis (Supplementary Table 2). Folprecht et al. reported an R0 RR of 34% which is again similar to observed RR for liver-limited disease in our meta-analysis. More interestingly, Folprecht et al. also reported the results of a blinded post-treatment surgical review of resectability using CT and MRI scans. The post-treatment review involved seven senior hepatobiliary surgeons. They judged that 60% of the patients included in the CELIM trial could have undergone potentially curative resection after systemic treatment. This represents a major potential increase in resectability.27 However, most included publications shaped the guidelines over time and were the basis for improved treatment strategies. One other important limitation is that the location of the primary tumor or biomarkers other than KRAS were not considered in this meta-analysis. There is accumulating evidence in the literature that the location and biomarker status of both the primary tumor and metastases play a significant role in choosing the right systemic treatment with CTx, TT, or immunotherapy.30 However, with the currently available RCT data, further subgroup analyses were not possible. The meta-analysis also has several strengths. Only RCT were included and the guidelines published in the Cochrane Handbook, which is considered the gold standard for systematic reviews, were followed.31 The standardized qualitative assessments of the included RCT revealed a predominantly low to moderate risk of bias. The included 16 RCT comprised 5724 patients which provided a large sample size for quantitative analysis.The current meta-analysis has several limitations. One is risk of inclusion bias due to missed publications or mistakes in determining whether a study was eligible for inclusion in this meta-analysis. However, this specific risk was minimized by having three of the authors perform the literature search and study selection independently and strictly defining the inclusion and exclusion criteria. In judging whether studies used guideline-adherent treatments we followed the ESMO guidelines which are considered the gold standard for treatment of mCRC.5 There will probably never be a sufficient answer to what resectability or unresectability is, as this question requires multiple considerations for each individual patient. However, the toolbox definitely must include the following: an experienced liver surgeon; an interdisciplinary discussion based on oncologic principles, including mutational status; a risk-benefit evaluation of patient factors and patient will; and a repeat discussion after every restaging and change of therapies.In conclusion, the evolution of the treatment of mCRC has improved outcomes over the last 20 years. Nonetheless, there is still potential for improving treatment decisions regarding resection of mCRC. Our meta-analysis has shown significant variability in RR which is consistent with previously published findings. Furthermore, few RCT reported how decisions regarding resectability were made. In our opinion, this strongly advocates for the indispensable involvement of surgeons experienced in the management of mCRC and borderline resectable tumors in all multidisciplinary teams. The exact composition and qualifications of the members of the multidisciplinary treatment team should receive special attention in the design of future RCT to improve RR, which has been shown to improve overall survival significantly.Supplementary file1 (PPTX 1322 kb)Supplementary file2 (DOCX 15 kb)Supplementary file3 (XLSX 20 kb)Below is the link to the electronic supplementary material.


CSF was obtained through CSF diversion procedures and lumbar punction and analyzed for protein concentrations according to the institution’s laboratory standards. We found significantly decreased CSF protein levels in patients suffering from AQS (0.13 mg/dL [0.1–0.16 mg/dL] p = 2.28 × 10−8) and from PC (0.18 mg/dL [0.12–0.24 mg/dL] p = 0.01) compared with controls (0.34 mg/dL [0.33–0.35 mg/dL]). Protein levels were not altered in patients suffering from commHC and NPH compared with neurologically healthy individuals. We propose that a decrease in CSF protein levels is part of an active counterregulatory mechanism to lower CSF volume and, subsequently, intracranial pressure in specific diseases. Research regarding said mechanism and more specific proteomic research on a cellular level must still be performed to prove this hypothesis. Differences in protein levels between different diseases point to different etiologies and mechanisms in different hydrocephalic pathologies.CSF protein levels are altered in neurological disorders, such as hydrocephalus of different etiologies. In this retrospective observational study, we analyzed cerebrospinal fluid (CSF) samples in hydrocephalic diseases such as aqueductal stenosis (AQS,  Cerebrospinal fluid (CSF) contains a significant number of proteins and other molecules that are crucial for brain function. There is active protein secretion from the choroid plexus to maintain vital functionalities, e.g., transthyretin, as well as significant clearance of molecules to maintain an optimal environment dedicated to guaranteeing neuronal function ,2. In-deAn increase in the total protein concentration is usually observed in states of blood–brain barrier (BBB) breakdown during inflammatory or autoimmune reactions but has largely been attributed to changes in CSF flow rate . HoweverTherefore, the aim of this study was to examine the differences in the total protein concentrations in hydrocephalus patients compared with control subjects without hydrocephalic configuration.Patients who underwent CSF diversion procedures were routinely examined for their total CSF protein content at time of surgery. Furthermore, radiological MRI data and clinical data were available, including data from follow-up examinations from at least 3 months afterward. We categorized the hydrocephalus recorded in the literature according to the following pathologies: aqueductal stenosis (AQS), normal pressure hydrocephalus (NPH), communicating hydrocephalus (comm HC) and pseudotumor cerebri (PC). Diagnoses were confirmed radiologically and by clinical presentation. Furthermore, commHC was suggested in patients with signs of chronically increased intracranial pressure without radiological CSF flow obstruction. PC was defined after proof of disease was confirmed by intracranial pressure monitoring and consistent MRI without ventricular enlargement.CSF specimens from 95 patients without hydrocephalic configuration served as controls. These were obtained during routine neurological diagnostics undertaken with lumbar punction in both neurological and neurosurgical departments and remained without proof of neurological disorders. Lumbar punction was undertaken in these cases to rule out neurological/CSF pathologies. In all patients and controls, CSF infection, preceding trauma or hemorrhage were ruled out. An overview of demographic data of each group is given in t-test with IBM SPSS Statistics 29 . Significance level was set at 0.05.Statistical analysis for the groups was performed using Welch’s All patients or caregivers gave their informed consent for the collection of clinical, CSF and radiological data. A local ethics committee approved the study (Ethikkommission Universität Leipzig Az 330-13-18112013) in November 2013.p < 0.01). Pseudotumor cerebri patients showed a trend of lowered CSF protein concentrations (p = 0.01). There were no differences between control and hydrocephalic entities in general  of CSF is formed and secreted in the choroid plexus 0% of CSF. It is iAlthough they share some features, the different hydrocephalic entities in the present cohort vary in their pathophysiologies: AQS causes a CSF flow disruption with consecutively raised intracranial pressure, which is more likely to be detected at a young age . PC exhiGiven that the traditional assumption is that CSF is merely a blood ultrafiltration and that the main regulatory parameter for CSF secretion should be intracranial or intraventricular pressure, differences in CSF proteomics would seem unlikely. However, the reduction in overall CSF protein concentrations in AQS and PC patients compared with controls possibly reflects a counterregulatory mechanism that attempts to reduce intracranial CSF volume and, subsequently, intracranial pressure. Given these assumptions, our findings support the recent conclusions of Krishnamurthy et al. , who desThe reasons explaining the unchanged protein concentrations in NPH and communicating HC patients are unclear, but other abnormalities, and even possible treatment, have been described ,25. ImpaFurther studies with detailed proteomic examinations of CSF components are necessary to further elucidate the nature and mechanisms of the reduction in CSF protein concentrations. These studies will also have to enroll even larger numbers of patients. Additionally, longitudinal sampling during prolonged treatment periods under CSF diversion procedures should be undertaken. A clear distinction between chronic and acute hydrocephalus, clarification of the side of the obstruction, if present, and inclusion of hypersecretory pathologies would further elucidate part of the problem—assuming that CSF protein concentrations are but a symptom. Alternatively, these desiderata would further elucidate the body’s solution to pathological intracranial pressure. We therefore see great diagnostic and therapeutic potential in CSF proteomics.The total CSF protein concentrations are significantly lower in patients with aqueductal stenosis and pseudotumor cerebri compared with other chronic hydrocephalic conditions. The nature of this reduction remains unclear and warrants further investigation.


The metropolitan area of Lima, Peru has a third of the nation’s population living in slum dwellings that are hypothesized to contribute to inefficient household hygienic practices. The purpose of this study was to quantitatively assess which living conditions have the greatest impact on handwashing practices.A cross-sectional epidemiological design of participants ≥16 y of age from San Juan de Miraflores, a slum on the outskirts of Lima, Peru, was used. Poisson regression was applied to assess the impact of living conditions on handwashing practices.We could not demonstrate a relationship between living conditions  and reported handwashing. The reported lack of handwashing is associated with the number of children in the home (those with children <5 y of age were more likely not to report washing their hands) and length of stay in the slum in years.Living conditions play an important role in one’s health, therefore improved study designs are needed to determine which strategies are likely to be the most effective in improving outcomes for slum dwellers. Additionally, such interventions are typically evaluated relative to urban or rural health,10 but less is known about the impact on slum health. This is particularly the case for living conditions in regard to personal hygiene and handwashing.Improvements in social determinants of health such as economic stability, healthcare, living conditions and education generally have been shown to improve health.1 Conversely, improved hand hygiene practices at the individual and community level have had a major role in reducing morbidity and mortality.12 Handwashing with soap is the most cost-effective intervention for many illness, can reduce diarrheal disease by 47% and has the potential to improve millions of lives.13 Several studies have highlighted that handwashing accompanied with basic hygiene behaviour  can prevent cholera, norovirus, listeria, salmonella, diarrheagenic Escherichia coli and acute respiratory infection.Slums are synonymous with poor living conditions and with health outcomes that are worse when compared to neighbouring urban or rural areas.This study population consisted of 251 families living in the Minas 2000 area of San Juan de Miraflores, Lima, Peru; a young town populated by people who moved to the urban area in order be close to the urban centre of Peru. The Minas 2000 community is an informal settlement with community-defined boundaries that is located on the edge of the city of Lima in the San Juan de Miraflores District . In 201117 The area is a high risk due to frequent landslides as a result of soil instability, and homes are mostly built with unstable materials such as mats, plywood, drywall or cardboard, without technical criteria to evaluate the homes’ potential for low durability.Most residents live in homes made of a variety of material; some have electricity, but many lack running water or plumbing. Additionally, residents in San Juan de Miraflores use 10 times less water than families with running water but paid nearly 10–15 times more for it and were forced to store it in private cisterns, plastic barrels or garbage cans outside their homes.Data collection occurred from August to November 2011. Approval from the Institute of Nutritional Research Institutional Review Board (IRB) for the protection of human subjects was obtained to perform the study. All 270 households within the Minas 2000 boundary were included in the assessment. The entire community was recruited for the study through their contacts with project facilitators employed at the Institute for Investigational Nutrition (IIN) located in the La Molina area of Lima, Peru. The Minas 2000 community’s commune chief ensured that all residents participated in the study, with 19 of the initial 270 not answering the primary outcome variable about handwashing with soap. Employees and consultant field staff of the IIN were trained with the required human ethics course (IRB) and how to administer the survey questionnaire. The Spanish-language questionnaire contained closed and open-ended questions that were pretested on a comparable population not participating in the study and later modified to improve questions found to be unclear. The topics covered in the questionnaire included hygiene and sanitation practices, water for drinking, disposal of used water, people living in the home and materials used to build the house. An additional observational study and a microbial surface sampling study took place while this survey questionnaire was administered.18 The results of the in-home sampling were published18 and indicated an increased risk for Listeria monocytogenes infection as the proportion of clean surfaces decreased.Additional data were collected through in-home sampling (swabbing of frequently touched surfaces in latrines and kitchen areas) and direct observations that lasted for a typical 8-h work day.19 To activate the memory of handwashing, the survey asked several related questions about hygiene practices in the home before asking for the frequency of handwashing with soap.The outcome variable in this study, handwashing with soap, was collected through a self-reported response to the question, ‘How many times per day did you wash your hands with soap and water or detergent?’ Two methods were used in this study to minimize bias in self-reported handwashing. The first method was written into the survey questionnaire process and asked the question using the strategy of activity recall to reduce overreported handwashing behaviour.18 published earlier. The substudy validated the handwashing variable by conducting 48 in-home observations among randomized households within the survey population. Each observation lasted 8 h in the home, and was undertaken by an investigator who was trained by the lead social scientist at the IIN to document hygiene-related observations. The observed and non-observed groups were measured for significance on the handwashing frequency variable. The study used a Mann–Whitney U test of independent means within SPSS Statistics for Windows, version 26  and did not find a significant difference . This established that the self-reported frequency was not significantly higher than the mean rate among the observed households that had handwashing frequencies validated by trained personnel. The sample size and power assumptions for this internal validation were checked with G*Power 3.120 a priori for the Wilcoxon–Mann–Whitney test, assuming an asymptotic relative efficiency method distribution. The actual power was calculated to be 0.99, with a type 1 error probability assumed to be 0.05 for the given subsample size of 48. This power was found to be sufficient to detect a difference in means using the above self-report validation method.The second method to minimize self-report bias used an internal validation of the primary outcome variable. This internal validation relied on the substudy that was part of the larger parallel risk assessmentThe outcome variable  was created by summing reports of whether respondents washed their hands after defecating and urinating, before cooking, before eating and while sneezing in the midst of cooking. For instance, if a person used the restroom once in the 8-h recall period, began cooking, ate and sneezed over the course of a day, they should have washed their hands four times in that day. This variable was created from multiple synchronous variables to help minimize recall bias, as described above. This variable was then inversed for analysis and therefore predicted the number of times a person did not wash his/her hands.hueco in the front yard to dispose of grey water and if a bathroom was within the house). Some of these variables, overcrowding,22 water,24 children <5 y of age,24hueco 25 and education,26 were associated with hygiene practice and health in previous studies. Crowding is related to the conditions of the dwelling as well as the space it provides—in this case it was measured in terms of the average living area per person in the place of residence.27A Poisson regression was used to analyse the relationship between handwashing and living conditions. Handwashing was adjusted for confounding factors such as age, education, income, parental status, number of children <5 y of age in the home and length of stay in the slum (in years), while measuring the impact of crowding within the household and water availability per day and home infrastructure  predicted handwashing.28 In this community, homes are built of materials such as cardboard (4.38%) and timber (86.85%), as well as sustainable materials such as brick (3.59%) and corrugated steel roofs (5.18%). The floors of the homes range from dirt (19.52%) and false floors  to cement (54.98%) or tile flooring (2.79%). The living conditions of participants, including kitchen/cooking arrangements and bathrooms, vary. There is no indoor plumbing and therefore each home purchases water. The amount of water each home has depends on the household income. Residents of San Juan paid 10–15 times more for water than those in Lima with running water. The storage containers are in some cases covered and at other times exposed to the elements, where mosquitoes can lay eggs. If possible, residents boil the trucked-in water before using it for cooking or drinking, but this adds to the financial strain they are already experiencing.Participants ranged from 16 to 69 y of age, with 51% having an education level less than high school and the majority (45%) of participants having a monthly income of 600–899 soles  homes receive 0–100 litres of water per day, 31.47% received 101–200 litres and the remainder (16.73%) receive >201 litres but <643 litres per day. At a recommended rate of 50–100 litres of water per person per day needed to ensure that most basic needs are met and few health concerns arise,30 With this in mind, the handwashing practices of other adults were assessed in comparison with the mother. As outlined in Mothers are hypothesized to have better handwashing practices because their hygiene behaviour directly impacts the health of their children.hueco, location of the restrooms or makeup of the restrooms.In the second model, shown in 31 that are preventable. Previous research33 has shown that changes to one’s environment, whether in the home or at school, enables improved handwashing behaviour, and structural factors such as time, accessibility of water and high-quality facilities influence how likely it is that people wash their hands. Therefore, since a key motivating factor for adoption of handwashing is environmental conditions ,34 our hypothesis sought to assess if those with poor house structures or less access to water supply and excreta disposal sources would have poor hand hygiene practices. Previous studies in other populations36 have indicated that less water access is associated with lower handwashing rates. However, our results showed no significance in spite of the low levels of available water.This study aimed to assess the impact different living conditions have on reported hand hygiene in an urban slum settlement and found that although some do have an impact, others do not. Slum dwellers spend most of their time in housing and environmental conditions that have a direct link to their health. Unhygienic practices affect quality of life and educational development and in many cases can result in diseases37 With areas in the home serving as reservoirs for microbial colonization, hand hygiene is important, especially in slum environments.38 Our results revealed that although hand hygiene behaviour is a complex interaction of many factors, no one theory can reliably predict handwashing behaviour.39 Studying hand hygiene has to take into consideration the behavioural, cultural and social factors in the context of housing and infrastructure. Although a home’s structure might influence factors of health such as handwashing, understanding what motivates hand hygiene behaviour in a slum culture38 might be critical to understanding if housing and infrastructure truly play a role in handwashing. For instance, in Bangladesh there is a culturally acceptable time period during the day for personal hygiene,40 in a study among Koreans, cultural normative attributes were identified as factors that predict handwashing41 and in settings where people are internally displaced, the disruption of cultural norms can alter handwashing practices.42 Culture, to some extent, strongly influences attitudes regarding handwashing and is worth exploring. Additionally, we could not find the hypothesized associations with overcrowding, water, grey water disposal practices and education.Although we tested for a relationship between the home infrastructure and handwashing, we could not demonstrate an association. Living in a house made of cardboard as opposed to brick showed similar hand hygiene behaviours. In this population, the house infrastructure had no bearing on one’s hygienic practices. As a factor of the built environment, building and housing structures have a major influence on health.43 One’s length of stay in the slum (in years), although significant to handwashing, had little increased difference in risk. It has been found that people born within slums, in close proximity to slums or who have resided in slums for longer periods of time tend to remain in them or move to them due to social ties related to common culture, language and similar income-generating activities.44 Behavioural practices, such as handwashing, within such a context also happen to be uniform; and since poor handwashing among slum residents has been shown to be prevalent,46 based on our results we inferred that if one stays in the slum for an extended time, poor hand hygiene practices become habits that are difficult to break. Additionally, the longer one is immersed in an environment, the more prone one is to adopting the cultures and norms of that environment and the more one’s health is affected. For instance, in a study assessing two types of slums in Kenya—one where a quarter of the residents were born in the community and had resided there longer and the other where only 5% of the residents were born in the community and were more recent residents—it was found that demographic indicators such as length of stay affect economic and health outcomes.47 Without a clear understanding of the cultural contexts that influence individual and societal behaviours, health and hygienic practices are only going to be partially understood.48 In the literature, crowding has been reported to be an indirect measure of hand hygiene practices;50 however, in our study we were unable to find a link.The handwashing associations that we did confirm are related to the number of children in the home and the length of stay in the slum. Those with one or more children <5 y of age were less likely to wash their hands. Past findings have indicated that with children <5 y of age in the home, the gap between knowledge and the practice of handwashing is more apparent.51 Mothers with more younger children are also more likely to not wash their hands compared with mothers with older children,52 and that may be the reason why these mothers are less likely to wash their hands. Another reason could lie in the fact that, due to the scarcity of water, mothers use less water on themselves in order to preserve the little they have for their children and family. Additionally, although mothers may have intended to improve their handwashing behaviour, their physical environment, social relations or constructed attitude towards handwashing may prevent them from doing so.51 For instance, a perception of poor water quality may be why some wash their hands and others do not.Compared with mothers, other adults in the home were found to have better handwashing habits. This could be influenced by the fact that handwashing appears to be an aspirational behaviour rather than a health concern and therefore the perception of handwashing among non-mothers might be different.We believe this study provides an important background for additional research into the effects of living conditions on hygienic practices. Past studies have indicated that one crucial motivating factor for adoption of safe hygienic practices is living conditions. As population growth continues to be particularly rapid in urban areas of less developed regions, health burdens will continue to increase unless an intervention is put in place to affect all determinants of health. Understanding how hand hygiene and living conditions are correlated will allow for better built interventions to assist with the health burdens among slum dwellers.19 that can be used to help explain the overreporting of handwashing that commonly occurs in hygiene assessments. The data were also collected through an interview procedure, which may have added some interviewer bias into the study. Therefore, in light of such biases, further detailed investigation is needed.The results of the current study should be interpreted in light of several limitations. First, we relied on self-reporting; it is possible that social desirability and recall bias might have influenced the responses of our participants. To rectify this, we relied on an observational substudy to validate the reported handwashing rate. This is one of many methodsThere are many issues concerning all aspects of hand hygiene that remain unresolved. While hand hygiene practices are simple, compliance with handwashing is about human behaviour and discovering what influences such behaviours. Living conditions can influence hygienic practices and therefore studies on how living conditions affect hygiene practices within slum populations need to be conducted. Living conditions should also be assessed beyond the house infrastructure and neighbourhood, including security, safety, family and social relations, conditions in school and economic and material resources. A better understanding of such factors will provide gateways to understanding which strategies are likely to be the most effective in improving outcomes for slum dwellers.


Pneumonia remains the leading cause of death among children aged 1–59 months. The early prediction of poor outcomes (PO) is of critical concern. This study aimed to explore the risk factors relating to PO in severe community-acquired pneumonia (SCAP) and build a PO-predictive nomogram model for children with SCAP.We retrospectively identified 300 Chinese pediatric patients diagnosed with SCAP who were hospitalized in the Affiliated Hospital of Southwest Medical University from August 1, 2018, to October 31, 2021. Children were divided into the PO and the non-PO groups. The occurrence of PO was designated as the dependent variable. Univariate and multivariate logistic regression analyses were used to identify the risk factors of PO. A nomogram model was constructed from the multivariate logistic regression analysis and internally validated for model discrimination and calibration. The performance of the nomogram was estimated using the concordance index (C-index).P < 0.0001), requiring invasive mechanical ventilation (IMV) , and ALB < 35 g/L . Results of the internal validation confirmed that the model provided good discrimination . The calibration plots in the nomogram model were of high quality.According to the efficacy evaluation criteria, 56 of 300 children demonstrated PO. The multivariate logistic regression analysis resulted in the following independent risk factors for PO: co-morbidity (OR: 8.032, 95% CI: 3.556–18.140, The nomogram facilitated accurate prediction of PO in children diagnosed with SCAP and could be helpful for clinical decision-making. In 2017Among the predictive statistical models, nomograms are recognized to provide risk estimations with high accuracy, which enable clinicians to standardize clinical decision-making , 9. To o2.2.1.This retrospective case-control study focused on children with SCAP, aged 1–59 months, who were diagnosed in the Department of Pediatrics of Affiliated Hospital of Southwest Medical University from August 2018 to October 2021. All patient clinical data were obtained from the hospital information system.Pneumonia was diagnosed based on clinical signs or symptoms of acute infection  and/or acute respiratory illness , as well as radiographs  . CAP wasThe following inclusion criteria were met by all children in this study: (1) diagnosed with SCAP; (2) aged 1–59 months; and (3) complete medical records available. Patients were excluded if (1) diagnosed with HAP; (2) experienced non-infectious pneumonitis, such as aspiration, uremic, or hypersensitivity pneumonitis; (3) cases with a history of recent hospitalization; (4) cases with severe immunosuppression; (5) cases with incomplete data. The children were divided into PO and non-PO groups. Children with SCAP who died and whose respiratory tract signs and symptoms of infection  did not improve or worsen at the time of discharge were included in the PO group.The study was approved by the ethics committee of the Affiliated Hospital of Southwest Medical University (No. KY2022004). Informed consent was not required for the retrospective analysis of patient data.2.2.2 (PaO2) that was <60 mmHg in room air at sea level or an oxygenation index (OI) <300), as well as radiological data, such as chest x-ray and/or chest CT, were collected , and respiratory failure .Microbiological tests were also performed. Bacterial cultures from blood, sputum, bronchoalveolar lavage fluid, and hydrothorax were conducted. Immunoglobulin M (IgM) serology tests of 9 common respiratory pathogens (2.3.χ2 test or Fisher exact test was used to compare the two patient groups. Continuous variables were presented as median with interquartile range (IQR) or standard deviation (SD) and tested using the Mann–Whitney U-test. The occurrence of PO was designed as the dependent variable. Univariate and multivariate logistic regression analyses were performed to determine the risk factors influencing the occurrence of PO in patients with SCAP. Independent variables were not included in the model, especially if inconsistent with previous research results and clinical practice.Analyses were conducted using R software (V.4.1.2). Categorical variables were presented as frequency and percentage. The A nomogram was constructed based on the results of the multivariate analysis. The nomogram set the corresponding score value The nomogram utilized the regression coefficient of each variable in the multivariate logistic regression equation, which is representative of the contribution of each influencing factor to the efficacy, to set the corresponding score for each influencing factor. Then, the sum of the score of each influencing factor was used to calculate the total score.p-value < 0.05 was considered statistically significant.The effect of individual predictors on PO was reported by using the odds ratios (OR) and the corresponding 95% confidence intervals (95% CI). The performance of the nomogram was estimated by the concordance index (C-index), which is analogous to the commonly reported area under the receiver operating characteristic (ROC) curve. A C-index of 1 indicated perfect concordance. The C-index of most models is 0.7–0.85 , 2.1–19]. There were 181 (60.33%) boys. Moreover, 102 (34%) children had greater than or equal to 1 co-morbidity . Congeni3.2.influenza virus was detected in 2.3% of children and Mycoplasma pneumoniae in 6%. A total of 112 strains of pathogenic bacteria were detected from sputum, blood, bronchoalveolar lavage fluid and pleural effusion. Streptococcus pneumoniae was the dominant bacterium. There were also 26 strains of Streptococcus pneumoniae, 17 strains of Staphylococcus aureus, 10 strains of Escherichia coli, 10 strains of Klebsiella pneumoniae, 9 strains of Haemophilus influenzae, 8 strains of Moraxella catarrhalis, and 32 strains of other uncommon bacteria identified.The 3.3.p < 0.05). Laboratory data between the two groups did not demonstrate a statistically significant difference for procalcitonin (PCT), C-reaction protein (CRP), WBC count, creatine kinase-MB (CK-MB), and alanine aminotransferase (ALT) (p < 0.05). Additionally, the proportion of hydrothorax did not differ significantly between the two groups (p > 0.05).se (ALT) . In cont3.4.P < 0.0001), the need for IMV , and ALB < 35 g/L  were independent risk factors of PO in children with SCAP.Significant variables from the univariate analysis were considered as the independent variables. PO was designated as the dependent variable. These variables were included in the multivariate logistic regression analysis . The res3.5. < 35 g/L, pH < 7.35, and IMV) from multivariate logistical regression analysis were used to establish a nomogram for the risk of PO . The area under the ROC curve was 0.876 . Importa4.CAP is the most common infectious disease during childhood, Nevertheless, no validated nomogram model exists to predict the risk of PO caused by SCAP. Although vaccination has significantly reduced the incidence and mortality of severe pneumonia in children in recent years, vaccination is not universally available. Pneumonia remains the leading cause of death among children, aged 1 month to 5 years . There arespiratory syncytial virus  that may be meaningful to risk factors analysis due to missing data. It is necessary to validate our results with those of other centers. In the future, a prospective multi-center in-sample study to further confirm the reliability of the nomogram is warranted.5.A prognostic nomogram for predicting the risk of poor outcomes in children with SCAP was constructed. The nomogram demonstrated good discrimination and calibration in our study. The nomogram may be used to predict patient outcomes as early as at the time of admission, which may contribute to improving the clinical management of SCAP.