Lower-Extremity Arteriovenous Malformation Masquerading as Peripheral Artery Disease.

An arteriovenous malformation (AVM) refers to an anomalous, direct connection between an artery and a vein. Typically, these two vessels are interposed by high-resistance capillary beds, the absence of which results in a high-flow system from an artery into a vein. Venous vessel walls are not designed to handle such high-pressure blood flow, and their vessel wall structure becomes permanently altered and weakened. For this reason, AVMs are at an increased risk for hemorrhages and ruptures. AVMs present with a spectrum of symptoms, ranging from skin discoloration, ischemia in distal tissues, and heart failure from arteriovenous shunting. Here, we present a case of a patient who underwent amputation of his second left toe, initially thought to be a result of peripheral arterial disease (PAD) due to his extensive smoking history. Further imaging findings revealed a rare lower-extremity AVM as the source of his ischemia, not PAD. Ultimately, the treatment of the vascular anomaly and resolution of the patient's symptoms were achieved via transarterial embolization. This case emphasizes the importance of looking beyond PAD as the cause of distal lower-extremity ischemia and provides insights into an uncommon and often missed diagnosis of extracranial AVMs.

Starting a Vascular Surgery Fellowship at a Rural Healthcare Center.

INTRODUCTION: In the United States, there is an anticipated critical shortage of vascular surgeons in the coming decades. The shortage is expected to be particularly pronounced in rural areas. Our institution serves a rural and underserved population in which the incidence and prevalence of cardiovascular disease continues to rise. Our institution maintains a general surgery residency and has all the required Accreditation Council for Graduate Medical Education (ACGME) rotations and educational infrastructure to support a vascular surgery fellowship. This study aims to analyze the vascular caseload at our institution to determine if we and other institutions with similar surgical volumes can support the creation of a 2-year vascular fellowship. METHODS: A single-site retrospective review of the number and type of vascular cases conducted at our institution between July 2016 and June 2021 was performed. The procedures were grouped into the following ACGME-defined categories: abdominal, cerebrovascular, complex, endovascular aneurysm repair, endovascular diagnostic or therapeutic, and peripheral. The total number and annual average for each category was obtained. Using the annual average, a 2-year estimate was calculated and compared to the ACGME minimum for each category. Our 2-year estimate was then compared to the national average for graduating vascular surgery fellows in order to generate a z-score for each category. RESULTS: In the specified period, 6100 total surgical procedures were performed by three vascular surgeons at our institution. Two thousand five hundred and seventy-eight of the 6100 procedures met at least one of the ACGME-defined category requirements. Our center greatly exceeded the requirements for each category except for abdominal. This is consistent with trends observed in most centers across the nation, which are seeing a decline in open repairs across all categories, especially in open abdominal repairs. Our center's vascular case volume shows no significant difference the national average in each ACGME category (P ≥ 0.05 for all). CONCLUSIONS: Despite our center's large vascular caseload and need for more vascular providers, there were not enough open abdominal cases performed to support the training of a vascular fellow. Given the continued decline in open aortic volume across the country, we anticipate that rural centers similar to our own will have difficulty establishing programs to train and recruit vascular surgeons. Flexibility in the abdominal category requirement or creation of open aortic fellowships may be necessary for smaller rural centers to train vascular surgeons and meet the future needs of the specialty.

Survival in patients with neuroendocrine tumors of the colon, rectum and small intestine.

BACKGROUND: Neuroendocrine neoplasms (NENs) of the colon, rectum and small intestine (SI) are increasing in incidence and prevalence. We evaluated the 5-year overall survival (OS), and cancer-specific survival (CSS). METHODS: The Surveillance, Epidemiology, and End Results (SEER) 18 registry from 2000 to 2017 was accessed to identify patients with colonic, rectal, and SI NENs. RESULTS: 46,665 patients were diagnosed with NENs of the colon (n = 10,518, 22.5%), rectum (18,063, 38.7%), and SI (18,084, 38.8%). By tumor site alone, patients with well-differentiated neuroendocrine tumors (NETs) of the rectum had improved 5-year OS (HR 0.72, 95% CI 0.68-0.77, p < 0.001). However, patients with rectal poorly-differentiated neuroendocrine carcinomas (NECs) who underwent oncologic resection had lower 5-year OS (35.1%) compared to colon (41.9%), and SI (72.5%). CONCLUSIONS: Surgical resection may improve 5-year OS for NECs of the SI and colon, except in the rectum where survival was reduced. More frequent surveillance and timely initiation of systemic therapy should be considered for rectal NECs.

The Role of Cholecystectomy in Hyperkinetic Gallbladder: A Retrospective Cohort Study in a Rural Hospital.

Background Biliary dyskinesia is a functional gallbladder disorder in which there is an absence of a structural or mechanical cause for biliary pain. A cholecystokinin-hepatobiliary iminodiacetic acid (CCK-HIDA) scan is typically performed during workup, and cholecystectomy is the accepted treatment for low ejection fraction (EF) (less than 33%, as defined by the literature). However, few studies have examined the role of cholecystectomy in hyperkinetic gallbladder (EF ≥80%). The aim of our study was to examine symptom resolution following minimally invasive cholecystectomy in patients with hyperkinetic gallbladder. Methodology A retrospective chart review was conducted at Robert Packer Hospital in Sayre, PA. Patients who underwent minimally invasive cholecystectomy for biliary colic with EF ≥80% and who were without cholelithiasis on preoperative imaging or on final pathology were included in this study. The main outcome was symptom resolution at the postoperative visit. Data collected included age, gender, EF, body mass index, symptoms with CCK infusion, and pathology. Results A total of 48 patients were included. The mean age of patients was 41.2 years (standard deviation = 14.4), and the median age of patients was 42.2 years, with a range of 17-71 years. The majority of patients were female (83.3%). Overall, 58.3% of patients had replication of symptoms with CCK infusion. The mean gallbladder EF was 87.3%, with a median of 87.0 and a range of 80-98. In total, 33 (68.8%) patients had chronic cholecystitis on final pathology reports. There was a 95.9% symptom resolution rate among our patients two weeks postoperatively. Conclusions The overwhelming majority of patients experienced symptom resolution prior to their two-week postoperative visit following minimally invasive cholecystectomy for hyperkinetic gallbladder. These results strongly suggest a role of surgical management in patients with high EF.

A systematic review of primary ileostomy site malignancies.

BACKGROUND: This paper aimed to elucidate the etiologies of all primary ileostomy site malignancies published in the literature. METHODS: A review of the literature was conducted following PRISMA guidelines by querying PubMed, Global Health, and Web of Science for articles published before November 2020. Search criteria contained broad terminology for ileostomy site neoplasms without language, date, or publication limitations. A full-text review of the abstracts confirmed primary malignant pathologies and was evaluated for study inclusion. RESULTS: Literature search discovered 858 publications, with 76 meeting eligibility criteria. The final sample contained 91 patients, with equal males and females. The mean age of patients with ileostomy site malignancy was 62.0 ± 12.2, with an average ileostomy age of 29.4 ± 12.4. The most common indications for ileostomy creation were inflammatory bowel disease (IBD) (73.6%) and familial adenomatous polyposis (FAP) (20.9%). There was a total of eight ileostomy malignant pathologies reported, with adenocarcinoma being the most common (76.9%), followed by squamous cell carcinoma (SCC) (11.0%). Adenocarcinoma was diagnosed at a younger age than SCC (59.7 vs. 72.3) and developed over a shorter time (28.8 vs. 37.0). Patients with FAP almost exclusively developed adenocarcinoma (94.4%) at a younger stoma age (25.8 vs. 31.4) than those with IBD who developed seven diverse pathologies. With a median follow-up of 0.75 years, four patients developed disease recurrence and received oncologic resection of their cancer less often than the 55 negative patients (p = 0.04). CONCLUSION: Ileostomy site malignancies are late-appearing complications that require curative surgery. Their presentation is associated with ileostomy duration and creation indication, such as FAP or IBD. We recommend screening at a stoma age ≥ 20 or patient age ≥ 50 for patients with FAP, while stoma age ≥ 25 or patient age ≥ 60 for IBD patients.

Prognostic Factors in Gastrointestinal Leiomyosarcomas: An Analysis Using the Surveillance, Epidemiology, and End Results (SEER) Database.

Background Gastrointestinal leiomyosarcomas (LMSs) from intramural smooth muscle are extremely rare, with limited literature. This paper evaluates the epidemiology and survival and prognostic factors in LMSs of the gastrointestinal tract. Methods Clinical data from the Surveillance, Epidemiology and End Results (SEER) 18 registry from 2001 to 2016 with additional treatment fields were compared between primary tumor sites using the chi-squared test for categorical variables and ANOVA for continuous variables. A five-year survival rate analysis was performed for overall and cancer-specific survival. Hazard ratios (HRs) were calculated using univariate and multivariate Cox proportional models using the variables age group, tumor location, grade, stage, surgery, and chemotherapy. Results We identified a total of 523 patients diagnosed with LMSs of the gastrointestinal tract. The median age of diagnosis was 66 years, with no significant difference between tumor sites for age, sex, and race. The five-year overall survival was 77.3%, and the cancer-specific survival was 90.3%. In the multivariate analysis, grade and stage of tumor were the only factors significantly affecting survival in this cohort. Conclusion While surgical status significantly affected survival in the univariate analysis, when adjusted for other factors, the HR for death was not significantly different by surgical therapy. Grade 3 tumors and tumors with distant metastasis at diagnosis were associated with worse survival among these patients.

Oxaliplatin resistance in colorectal cancer enhances TRAIL sensitivity via death receptor 4 upregulation and lipid raft localization.

Colorectal cancer (CRC) remains a leading cause of cancer death, and its mortality is associated with metastasis and chemoresistance. We demonstrate that oxaliplatin-resistant CRC cells are sensitized to TRAIL-mediated apoptosis. Oxaliplatin-resistant cells exhibited transcriptional downregulation of caspase-10, but this had minimal effects on TRAIL sensitivity following CRISPR-Cas9 deletion of caspase-10 in parental cells. Sensitization effects in oxaliplatin-resistant cells were found to be a result of increased DR4, as well as significantly enhanced DR4 palmitoylation and translocation into lipid rafts. Raft perturbation via nystatin and resveratrol significantly altered DR4/raft colocalization and TRAIL sensitivity. Blood samples from metastatic CRC patients were treated with TRAIL liposomes, and a 57% reduction of viable circulating tumor cells (CTCs) was observed. Increased DR4/lipid raft colocalization in CTCs was found to correspond with increased oxaliplatin resistance and increased efficacy of TRAIL liposomes. To our knowledge, this is the first study to investigate the role of lipid rafts in primary CTCs.

Possible Predictive Factor of Acute Respiratory Distress Syndrome Development After Mild Traumatic Brain Injury: A Single Rural Trauma Center Preliminary Study.

Introduction Acute respiratory distress syndrome (ARDS) after mild traumatic brain injury (TBI) can be associated with significant morbidity and mortality. This study aimed to evaluate the potential predictive factors of ARDS development following mild TBI in trauma patients. Methods A retrospective chart review was done for adult trauma patients with mild TBI (GCS 13-15) requiring admission at our center from 2012 to 2020. Linear regression analysis and chi-square test were utilized to identify independent predictors of the association with ARDS in adults with mild TBI.  Results A total of 784 mild TBI patients were admitted during the time of interest; 34 patients developed ARDS during their index hospitalization. Patients who had ARDS were more likely to have acute kidney injury (AKI; p < 0.0001), sepsis (p < 0.01), rib fractures (p < 0.05), use of anticoagulants (p < 0.001), deep vein thrombosis (p < 0.001), transfusion during the first 4four hours upon admission (p = 0.01), intravenous fluid (IVF) resuscitation during the first four hours (p <0.05), the first eight hours (p = 0.01), the first 12 hours (p = 0.03), and intubation upon the admission (p < 0.0001). ARDS associated with mild TBI demonstrated a statistically significant increase in mortality during the index hospitalization (p < 0.0001). Conclusion ARDS after mild TBI can be associated with significant morbidity and mortality. Key risk factors identified include AKI, sepsis, anticoagulant use, deep vein thrombosis (DVT), transfusion in the first four hours, IVF resuscitation in the first four, eight, and 12 hours, and intubation upon admission.

Proper use of noncontact infrared thermometry for temperature screening during COVID-19.

Among the myriad of challenges healthcare institutions face in dealing with coronavirus disease 2019 (COVID-19), screening for the detection of febrile persons entering facilities remains problematic, particularly when paired with CDC and WHO spatial distancing guidance. Aggressive source control measures during the outbreak of COVID-19 has led to re-purposed use of noncontact infrared thermometry (NCIT) for temperature screening. This study was commissioned to establish the efficacy of this technology for temperature screening by healthcare facilities. We conducted a prospective, observational, single-center study in a level II trauma center at the onset of the COVID-19 outbreak to assess (i) method agreement between NCIT and temporal artery reference temperature, (ii) diagnostic accuracy of NCIT in detecting referent temperature [Formula: see text] and ensuing test sensitivity and specificity and (iii) technical limitations of this technology. Of 51 healthy, non-febrile, healthcare workers surveyed, the mean temporal artery temperature was [Formula: see text] ([Formula: see text] confidence interval (CI) = [Formula: see text]). Mean NCIT temperatures measured from [Formula: see text], [Formula: see text], and [Formula: see text] distances were [Formula: see text] [Formula: see text], [Formula: see text] [Formula: see text], and [Formula: see text] [Formula: see text], respectively. From statistical analysis, the only method in sufficient agreement with the reference standard was NCIT at [Formula: see text]. This demonstrated that the device offset (mean temperature difference) between these methods was [Formula: see text] ([Formula: see text]) with 95% of measurement differences within [Formula: see text] ([Formula: see text]) and [Formula: see text] ([Formula: see text]). By setting the NCIT screening threshold to [Formula: see text] at [Formula: see text], we achieve diagnostic accuracy with [Formula: see text] test sensitivity and specificity for temperature detection [Formula: see text] by reference standard. In comparison, reducing this screening criterion to the lower limit of the device-specific offset, such as [Formula: see text], produces a highly sensitive screening test at [Formula: see text], which may be favorable in high-risk pandemic disease. For future consideration, an infrared device with a higher distance-to-spot size ratio approaching 50:1 would theoretically produce similar results at [Formula: see text], in accordance with CDC and WHO spatial distancing guidelines.

A novel protocol to maintain continuous access to thawed plasma at a rural trauma center.

BACKGROUND: Early administration of plasma improves mortality in massively transfused patients, but the thawing process causes delay. Small rural centers have been reluctant to maintain thawed plasma due to waste concerns. Our 254-bed rural Level II trauma center initiated a protocol allowing continuous access to thawed plasma, and we hypothesized its implementation would not increase waste or cost. METHODS: Two units of thawed plasma are continuously maintained in the trauma bay blood refrigerator. After 3 days, these units are replaced with freshly thawed plasma and returned to the blood bank for utilization prior to their 5-day expiration date. The blood bank monitors and rotates the plasma. Only trauma surgeons can use the plasma stored in the trauma bay. Wasted units and cost were measured over a 12-month period and compared with the previous 2 years. RESULTS: The blood bank thawed 1127 units of plasma during the study period assigning 274 to the trauma bay. When compared with previous years, we found a significant increase in waste (p < 0.001) and cost (p = 0.020) after implementing our protocol. It cost approximately US $125/month extra to maintain continuous access to thawed plasma during the study period. DISCUSSION: A protocol to maintain thawed plasma in the trauma bay at a rural Level II trauma center resulted in a miniscule increase in waste and cost when considering the scope of maintaining a trauma center. We think this cost is also minimal when compared with the value of having immediate access to thawed plasma. Constant availability of thawed plasma can be offered at smaller rural centers without a meaningful impact on cost. LEVEL OF EVIDENCE: Economic and Value-based Evaluations, Level III.

Addition of Advanced Practice Providers May Improve ABSITE Scores Through Enhanced Resident Education.

BACKGROUND: Resident work hour restrictions and required protected didactic time limit their ability to perform clinical duties and participate in structured education. Advanced practice providers (APPs) have previoulsy been shown to positively impact patients' outcomes and overall hospital costs. We describe a model in which nurse practitioners (NPs) improve resident education and American Board of Surgery In Training Examination (ABSITE) scores by providing support to our trauma and acute care surgery (ACS) service thereby protecting resident didactic time. MATERIALS AND METHODS: A new educational model aimed to improve ABSITE scores was created, increasing protected resident didactic time. The addition of three full-time NPs to the ACS service allowed implementation of this redesigned academic curriculum to be put into effect without neglecting patient or service-related responsibilities that were previously fulfilled by resident staff. Resident ABSITE results including standard score, percent correct, and percentile were compared before and after the educational changes were instituted. RESULTS: Eleven residents' scores were included. For each ABSITE score, we used a mixed model with time and postgraduate year (PGY) level as fixed effects and subject ID as a random effect. The interaction term between PGY level and time was not significant and removed from the model. A significant main effect of PGY level and of time was then observed. A statistically significant improvement in ABSITE scores after intervention was observed across all the PGY levels. Standard score increased 77.3 points (P-value = 0.001), percent correct increased 5.9% (P-value = 0.002), and percentile increased 23.8 (P-value = 0.02). Following the educational reform, no residents scored below the 35th percentile. CONCLUSIONS: Utilization of NPs on our ACS service provided adequate service coverage, allowing the implementation of an educational reform increasing protected resident education time and improved ABSITE scores.

Successful Retrieval of a Retained Rectal Foreign Body in the Emergency Department.

Rectal foreign bodies are a common presenting complaint in the emergency department. Anal eroticism is the major reason for the majority of cases of rectal foreign bodies. A high index of suspicion is required to accurately diagnose a rectal foreign body as patients are often embarrassed about their condition and may not present in a timely fashion to be evaluated or volunteer their history. Extraction techniques include transanal, endoscopic, and laparotomy with repair of complications. Here, we present the case of successful transanal manual removal of a retained dumbbell in the rectum of a middle-aged man.

Anal Melanoma in an Elderly Woman Masquerading as Hemorrhoid.

Anal melanoma is a rare and aggressive neoplasm of the anal canal seen in the elderly population in the six or seventh decade of their lives. Presentation is usually nonspecific and diagnosis is often delayed or missed initially. The management is surgical and prognosis is poor. Here we present a case of anal melanoma in an elderly patient masquerading as hemorrhoid.

Comparison of conventional and nonconventional strictureplasties in Crohn's disease: a systematic review and meta-analysis.

BACKGROUND: The Heineke-Mikulicz and Finney techniques are conventional strictureplasties that have been used to manage short (<10 cm) and medium-length (>10 cm and <20 cm) strictures from Crohn's disease. Nonconventional strictureplasty techniques have emerged to facilitate bowel conservation for atypical strictures. These techniques include the modified Finney, combined Heineke-Mikulicz and Finney, modified Heineke-Mikuliczs, Michelassi, and modifications of it and others. OBJECTIVE: The aim of this study is to compare conventional vs nonconventional strictureplasties with respect to short-term complications and long-term results. DATA SOURCES AND STUDY SELECTION: A MEDLINE search was performed using "Crohn's disease", "surgical therapy", "strictureplasty", "complications", "reoperation", and "recurrence" as medical subject headings. Studies conducted between 1975 and June 31, 2010 were found via PubMed, Ovid, Embase, and Cochrane databases and categorized into 3 groups. These groups consist of centers performing conventional strictureplasties, nonconventional strictureplasties, or both. Studies with at least 3 patients were reviewed. INTERVENTIONS: A mixed-effects meta-analysis for each outcome was performed by use of Supermix software by SSI Scientific Software International. MAIN OUTCOME MEASURES: We focused on immediate and long-term complication rates among the groups. The 6 immediate complications include small-bowel obstructions, sepsis, other infections, reoperations, early postoperative GI bleeds, and other early complications. The 5 long-term complications include recurrent strictures, small-bowel obstructions, reoperations, carcinoma, and deaths. RESULTS: We reviewed 32 studies with 1616 patients who underwent 4538 strictureplasties. One thousand one hundred fifty-seven patients underwent conventional strictureplasties with an early complication rate of 15%; 459 patients underwent nonconventional strictureplasties with an early complication rate of 8%. A late complication rate of 29% for the conventional strictureplasty group and 17% for the nonconventional strictureplasty group was noted. LIMITATIONS: We are limited by the data published with the inherent risk of finding and analyzing mostly articles with positive results. CONCLUSION: The nonconventional strictureplasty techniques were noninferior to the conventional strictureplasty procedures with respect to all prespecified outcomes.

A comprehensive review of strictureplasty techniques in Crohn's disease: types, indications, comparisons, and safety.

INTRODUCTION: Crohn's disease is one of the chronic inflammatory diseases of the gastrointestinal tract that is often complicated by stricture formation with resulting obstructive symptoms. The technical repertoire of strictureplasty procedures has increased over the years in an effort to manage the diverse presentations of this condition while limiting the need for bowel resection. In this comprehensive review, we describe, compare, categorize, and appraise the strengths and weaknesses of 15 unique strictureplasty techniques. METHODS: To identify all unique strictureplasty procedures, a Medline search utilizing "Crohn's disease," "surgical therapy," "strictureplasty," "enteroenterostomy," "Heineke-Mikulicz," and "side-to-side isoperistaltic" strictureplasty as medical subject headings was completed. PubMed, Ovid, Embase, and Cochrane database searches were conducted. Relevant articles between 1980 to December 2010 were reviewed. We initially selected 58 articles, but only 18 introduced novel surgical procedures related to 15 types of strictureplasty in Crohn's disease. RESULTS: We identified 15 types of strictureplasty techniques. These were categorized into three main groups. The revised nomenclature will facilitate the reader to understand the differences and utility of each technique. These groups include the Heineke-Mikulicz-like strictureplasties, the intermediate procedures, and the enteroenterostomies. Heineke-Mikulicz strictureplasty was the most frequently used technique. CONCLUSION: Various techniques of strictureplasty have been reported in the published literature. Strictureplasty has been shown to be a safe and efficacious technique that is comparable to bowel resection for stricturing Crohn's disease. This technique spares bowel length and puts the Crohn's disease patient at a lower risk of developing short bowel syndrome with repeated resections.

Full-thickness skin graft anoplasty: novel procedure.

We describe a novel technique to treat anal stenosis by reconstructing the anal canal by the use of a full-thickness skin graft from the abdominal wall. This treatment was successfully applied in our institution and showed positive results.

Biliary dyskinesia: how effective is cholecystectomy?

INTRODUCTION: Studies on biliary dyskinesia have been based on short-term surgical follow-up and do not take into consideration that most patients are discharged from surgical follow-up after the first postoperative visit and that for persistent or recurrent symptoms they are frequently seen by primary care providers and subsequently referred to gastroenterologists. We aimed to study this pattern and assess which factors predict patients that will benefit from cholecystectomy. METHOD: This is a retrospective analysis of medical records of patients who underwent cholecystectomy for biliary dyskinesia from February 2001 to January 2010 with a minimum postoperative follow-up of 6 months. RESULTS: At initial surgical follow-up, 19 of 141 (13.4%) patients said they had persistent symptoms. However, when subsequent visits were analyzed, 61 of 141 (43.3%) patients with persistent or recurrent symptoms saw their primary care provider. These symptoms were epigastric or right upper quadrant pain in 43 patients or 30% of those undergoing cholecystectomy. The only factor that distinguished patients with and without resolution of symptoms after cholecystectomy was the pathologic finding of inflammation (p = 0.02). CONCLUSION: Cholecystectomy does not appear to be as effective for biliary dyskinesia when long-term follow-up is evaluated.

Ventral hernia repair: outcomes change with long-term follow-up.

BACKGROUND AND OBJECTIVES: Ventral hernia repairs continue to have high recurrence rates. The surgical literature is lacking data assessing the time trend to hernia recurrence after ventral hernia repairs and whether over time the recurrence rates change with laparoscopic technique compared to open repairs. Our aim was to carry out a long-term comparative analysis of ventral hernia repairs performed at our hospital over the last 10-y period to assess if outcomes change during the follow-up period. METHODS: We conducted a retrospective observational study analyzing electronic medical records of all consecutive patients who had a ventral hernia repair from January 2001 to February 2010 at our hospital. RESULTS: During the study period, 436 ventral hernia repairs were performed: laparoscopic repairs (n=156; 36%), laparoscopic converted to open (n=8; 2%), and open repairs (n=272; 62%). We analyzed the time distribution to hernia recurrence after surgery and found that 85% of recurrences after laparoscopic repairs and 77% of recurrences after open repairs occurred within 2 y of surgery. We did a Kaplan-Meier analysis for the subgroup of patients for whom we had a minimum 4-y follow-up and found that there continued to be a low subsequent yearly recurrence rate for open repairs after the initial 2-y follow-up. CONCLUSION: Most hernia recurrences occur within 2 y after surgery for ventral hernias. There appears to be a continued although low subsequent yearly rate of recurrence for open repairs.