Hypoplastic left heart syndrome (HLHS) is among the most severe cardiovascular malformations and understanding its causes is crucial to making progress in prevention and treatment. Genetic analysis is a broadly useful tool for dissecting complex causal mechanisms and it is playing a significant role in HLHS research. However, unlike classical Mendelian disorders where a relatively small number of genes are largely determinative of the occurrence and severity of the disease, the picture in HLHS is complex. De novo single-gene and copy number variant (CNV) disorders make an important contribution, but there is emerging evidence for causal contributions from lower penetrance and common variation. Integrating this emerging knowledge into clinical diagnostics and translating the findings into effective prevention and treatment remain challenges for the future.  It is a truism that progress in preventing and treating diseases depends on understanding their causes. Palliative surgical and medical treatment for HLHS is long and arduous , and morHLHS and congenital left-sided lesions are marked by family clustering with an estimated relative recurrence rate of 12.9-fold . RecurreDe novo mutation, an important mechanism in the genetics of HLHS, does not contribute to heritability. Observations of families and relatives led to publications that estimated broad sense heritability of left-sided lesions and HLHS ,13. UsinExamining trends in fully ascertained populations consistently shows higher rates of HLHS in males compared to females and in people of European ancestry compared to other populations ,16. TherTurner syndrome  is the most common known genetic cause of left-sided heart defects and HLHS , and accETS1. Another recent example in the HLHS literature is a novel syndrome caused by 6q25 deletions involving TAB2 as the likely driver gene for CHD [A birth defect like HLHS would have been near reproductive lethal in the era before surgical management. Based on classical mutation selection balance theory, it is natural to look for de novo genetic mechanisms as explanation for a sustained rate of occurrence. Copy number variants have higher mutation rates than other allele types and so it is a good research strategy to evaluate de novo CNV as possible causes of HLHS. It was known even before the era of routine microarray that deletions of 11q are associated with left sided lesions and HLHS (Jacobsen syndrome) . Other s for CHD ,28,29.KMT2D) is an example of the former and appears to be more common that previously appreciated [ZEB2) [KMT2D pathogenic variants among apparently non-syndromic cases emphasizes both the difficulty of the clinical diagnosis and that clinical phenotypes are often incomplete without information from genetic testing [Exome sequencing studies provide a potentially unbiased strategy for identifying de novo coding sequence variants underlying HLHS. There are two clinical classes of patients—those with syndrome presentations and those with isolated CHD. Kabuki syndrome (caused by de novo pathogenic variants in reciated . There ad [ZEB2) , and the testing ,33,34. L testing ,36,37. TNOTCH1 has been confirmed in multiple studies to underlie some familial recurrences in which there is autosomal dominant transmission [TBX5) demonstrates the clinical difficulty and strongly argues for unbiased sequencing strategies rather than narrow phenotype-specific panels in both research and diagnostic testing.Linkage mapping, candidate genes, and positional cloning have also contributed to understanding of rare familial forms of HLHS and left-sided lesions. smission ,39,40. TKMT2D in a single patient [In principle, parental germline mosaicism could be an explanation for sibling recurrence of severe birth defects like HLHS. In addition, embryonic and somatic mosaicism might allow an otherwise lethal variant to cause a severe developmental defect in a live-born infant. A recent case report highlights the joint use of methylation profiling and sequencing to establish mosaicism for  patient . LimitatFor some diseases, a long list of different genes, each acting independently, can be found as more patients are sequenced. There are many examples where subtle informative phenotypic differences among patients were only fully appreciated once this heterogeneity was discovered. Demonstrations of rare non-recurrent CNVs, multiple singleton candidate loci with de novo variants in studies that show excess burden of de novo variants, and the lack of a clear lead locus in autosomal dominant left-sided lesions all point to very complex origins of HLHS. The failure to find one or a few monogenic disorders even considering exome or genome  sequenciA consistent observation in genetic studies of HLHS and congenital heart defects, in general, is the observation of what appear to be functionally deleterious variants in genes located in known cardiac developmental pathways but transmitted from unaffected parents ,33,37,42There is also evidence, albeit incomplete, that common genetic variants contribute to left sided congenital heart defects ,49,50,51Non-genetic factors may impact the same cells and developmental processes as genetic variants . IdentifThere is substantial evidence of clinical utility for comprehensive genetic testing in the literature and that has led to expert recommendations, professional society guidelines, and adoption by a growing number of payers ,60,61. TAs with any novel medical technology, one may reasonably ask whether there are predictable or frequent harms from genetic testing. This topic that has been addressed primarily from the point of view of ethics and leading to generally accepted professional guidelines ,64. ClinAn important policy question is whether and under what circumstances hospitals and health systems should view comprehensive genetic testing as medical necessary. The main factors that one might consider are (1) superior technical performance compared to standard care; and (2) cost-effectiveness. There is already substantial support for the superiority of exome and genome sequencing compared to standard precursor genetic testing. At a purely technical and lab interpretation level exome and genome can detect essential all DNA variant types that are typically reported clinically and thus outperform all previous single tests ,67. ExomGenomic data management is getting easier and less costly with the advent of convenient cloud solutions. Storage of raw genomic information in the EHR or any other local server is neither necessary nor desirable. The rapid advance of data quality coupled with dramatic cost reductions will continue to smooth the transition from limited targeted sequencing to unbiased genome technical platforms. Interpretation of exomes and genomes is also improving and, fundamentally, the challenge of variants of unknown significance is no different than that encountered in large panels. The development of fast and accurate AI methods for variant prioritization is already reducing the hours required for professional level analysts to review long lists of DNA variants. Unlike in research aimed at novel gene discovery, clinical reporting is necessarily conservative and focused.There is a growing literature on the cost effectiveness of exome and genome sequencing ,69,70,71Because HLHS is a rare disorder and many of the underlying causes are ultra-rare, aggregation of genetic data should be an important future goal. Currently, the best such resource is ClinVar  which asFuture studies must incorporate the probable independent and joint roles for rare and common genetic variation. As costs of individual genome sequencing have plummeted, it will be increasingly attractive to use that method since it provides the coding sequence coverage of exomes, but also provides all of the non-coding variation. Short read genome sequencing is already a platform from which to identify almost all the known DNA variant types including some structural variants and repeat expansions. Very large studies, perhaps requiring tens of thousands of patients, and utilizing genome sequencing in case parent trios will likely be needed to fully catalog single gene effects and their modifiers.HLHS has several distinct clinical presentations  that haGenome sequencing technology is also moving very quickly to include long read sequencing (10–100 s of kB). These methods can give more accurate and higher sensitivity detection of large structural variants that are often invisible to short read sequencing and where the accuracy is very low ,76. It iFinally, it is important that all the recent discoveries about the genetic causes of HLHS are brought into routine clinical practice. It is especially important to detect syndrome diagnoses early as they can be very difficult to recognize and may have a large effect on neurodevelopmental outcomes. Recent publications have demonstrated the efficacy of genome sequencing in newborns and have also shown evidence for clinical utility ,59,76. G


Patients presenting with acute abdominal pain that occurs after months or years following bariatric surgery may present for assessment and management in the local emergency units. Due to the large variety of surgical bariatric techniques, emergency surgeons have to be aware of the main functional outcomes and long-term surgical complications following the most performed bariatric surgical procedures. The purpose of these evidence-based guidelines is to present a consensus position from members of the WSES in collaboration with IFSO bariatric experienced surgeons, on the management of acute abdomen after bariatric surgery focusing on long-term complications in patients who have undergone laparoscopic sleeve gastrectomy and laparoscopic Roux-en-Y gastric bypass.A working group of experienced general, acute care, and bariatric surgeons was created to carry out a systematic review of the literature following the Preferred Reporting Items for Systematic Review and Meta-analysis Protocols (PRISMA-P) and to answer the PICO questions formulated after the Operative management in bariatric acute abdomen survey. The literature search was limited to late/long-term complications following laparoscopic sleeve gastrectomy and laparoscopic Roux-en-Y gastric bypass.The acute abdomen after bariatric surgery is a common cause of admission in emergency departments. Knowledge of the most common late/long-term complications  following sleeve gastrectomy and Roux-en-Y gastric bypass and their anatomy leads to a focused management in the emergency setting with good outcomes and decreased morbidity and mortality rates. A close collaboration between emergency surgeons, radiologists, endoscopists, and anesthesiologists is mandatory in the management of this group of patients in the emergency setting. It is associated with an increased risk of mortality. The World Health Organization reported that in 2016, more than 1.9 billion adults were overweight. Of these over 650 million were individuals living with obesity  was done on members of various surgical bariatric associations. They considered tachycardia to be the most sensitive sign associated with surgical complications after bariatric surgery in the early postoperative period, and as a clinical alarm to closely investigate emergency surgical long-term complications.Another on line survey , tissue sealants, suturing systems (OverStitch System®), internal drainage techniques, and vacuum therapy. These techniques may be applied alone or in combination, and as first-line or as salvage treatment after failure of previous approaches. Unfortunately, a standardized approach that fits for all possible scenarios does not exist. The choice of one procedure over another depends on the clinical presentation, defect features, and local expertise .. Moreover, insufflation of CO2 is recommended to reduce the risk of barotraumas on surgical suture, in early postoperative endoscopy, and pneumoperitoneum or pneumomediastinum, in cases of suspected leak  and 13% vs. 5% [P < 0.01], respectively), whereas in community-acquired complicated IAIs, the most commonly isolated microorganisms were Escherichia coli, Streptococcus, and Bacteroides fragilis  and unfractionated heparin [UFH]).Unlike pharmacologic prophylaxis, mechanical prophylaxis is not associated with an increased risk of bleeding complications. Furthermore, there are few contraindications to mechanical prophylaxis, including lower-extremity wounds and severe peripheral arterial disease.Pharmacologic VTE prophylaxis is highly effective for VTE prevention in hospitalized patients.Bergqvist et al.  reportedContraindications to pharmacologic prophylaxis include active bleeding or the presence of disorders associated with a significant risk of bleeding, such as thrombocytopenia or coagulopathy.p < 0.001), the presence of metastatic cancer , urinary tract infection , and postoperative sepsis .DeWane et al.  retrospeA recent systematic review of the literature showed that using a validated system for risk assessment and prescribing LMWH for all operative and non-operative abdominal emergencies, and using mechanical prophylaxis if pharmacologic prophylaxis is contraindicated may improve the management of patients requiring an urgent surgical procedure for intra-abdominal surgical diseases .Currently there are no recommendations concerning the clinical relevance of routine anti-Xa levels monitoring for LMWH dose adjustment in patients on VTE thromboembolism prophylaxis, except in elderly, pregnant, renally impaired, with BMI > 35 kg/m2 patients, being at risk of suboptimal dosing , 118.In patients for whom LMWH monitoring is required, anti-Xa levels should be obtained 4 h after administration. A reasonable anti-Xa target range for LMWH DVT prophylaxis is suggested to be 0.2–0.5 IU/mL , 118.Scenario 1: BLEEDING(QoE: low).Intra-abdominal bleeding occurs very rarely as a late complication after bariatric surgery (QoE: moderate).The most common reason for late gastrointestinal bleeding is ulcer from the gastric sleeve and gastro-jejunostomy, gastric pouch, bypassed stomach, or duodenum after LRYGB (QoE: low).Bleeding after LRYGB and LSG is self-limiting in many patients and can be managed conservatively, with medical treatment and close monitoring and observation (QoE: moderate).In hemodynamic stable patients presenting with intra-luminal intestinal bleeding after bariatric surgery, the endoscopic assessment  is a valid and safe tool after bariatric surgery (QoE: very low).Angiography and angioembolization may be valid strategies to bleeding control (QoE: low).If endoscopic and angiographic management fail, surgical exploration is indicated, if there are signs of persisting bleeding (QoE: high).In unstable patients not responding to aggressive resuscitation, diagnostic laparotomy and surgical hemostasis are mandatory .Endoscopy is the first recommended diagnostic tool in stable patients presenting with gastrointestinal bleeding after SG and RYGB (Weak recommendation based on low level of evidence 2C).We suggest performing an angio-CT and embolization in stable patients presenting with gastrointestinal and intraperitoneal extra-luminal bleeding, when skills are available (Weak recommendation based on very low level of evidence 2D).In selected cases of hemodynamically stable bleeding peptic ulcer patients, after failure to attempt endoscopic hemostasis, we suggest the use of angiography with angioembolization if technical skills and equipment are available (Strong recommendation based on low level evidence 1C).We recommend against delaying surgical exploration in unstable patients presenting with ongoing gastrointestinal bleeding after endoscopic assessment and negative angio-CT scan for bleeding source localization (Weak recommendation based on very low level of evidence 2D).In patients selected for surgical exploration for a bleeding ulcer, we suggest planning intraoperative endoscopy to facilitate the localization of the bleeding site, using a surgical gastrostomy in case of patient with LRYGB to assess the gastric remnant and duodenum (Strong recommendation based on low level of evidence 1C).We recommend against delaying diagnostic laparoscopy/laparotomy in patients presenting with ongoing intraperitoneal extra-luminal bleeding, after angioembolization (Strong recommendation based on low level of evidence 1C).A biopsy of the bleeding ulcer is recommended to exclude malignancy Gastrointestinal bleeding after LSG is a rare late complication which is caused essentially by a gastric ulcer.Several studies –121 haveBleeding gastric ulcers after LSG can be treated similar to a bleeding upper gastrointestinal ulcer occurring in the general population. According to the WSES guidelines , if the After LRYGB, the marginal ulcer is the most common complication. The incidence of marginal ulcers (MU) ranges from 0.6 to 16%. It can lead to bleeding and perforation and may require surgical urgent treatment. It has been estimated that 1% of LRYGB patients will suffer from a perforated marginal ulcer in their life. Patients with a history of smoking, immunosuppression and preoperative non-steroidal anti-inflammatory drugs use were significantly more likely to develop a MU requiring surgical revision. Patients undergoing revision had a resolution of their symptoms in only 36% of the cases, while 57% developed a recurrent ulcer .Marginal ulcers are classified into early and late ulcers depending on the timing of the diagnosis.an early marginal ulcer, which occurs 1 to 10 months after surgery, is more likely to be associated with local factors , while late marginal ulcers are likely related to increased acid exposure of the gastro-jejunal anastomosis developing over time [The development of ver time . For botver time .Recurrent marginal ulcers refractory to medical therapy are often due to local problems such as enlargement of the gastric pouch over time or presence of a gastro-gastric fistula with subsequent increased acid exposure of the jejunal mucosa. The presence of a Zollinger–Ellison syndrome has to be ruled out in these patients. It was reported that refractory marginal ulcers after gastric bypass demand revisional surgery. The operation consists of resection and reconstruction of the gastro-jejunal anastomosis with or without partial remnant gastrectomy.The management of marginal ulcers complicated with bleeding, in the emergency setting, should follow the WSES guidelines: In hemodynamically stable patients, the first assessment should be by endoscopy, which may achieve hemostasis and reduce re-bleeding, the need for surgery, and mortality . AngiogrThe management of bleeding from excluded segments of post-RYGB, such as gastric remnant and duodenum, is more challenging. Endoscopy is considered the first-line approach for the diagnosis and treatment of upper gastrointestinal bleeding, but the access is limited due to the altered anatomy of the gastric remnant and duodenum. In the presence of an experienced endoscopists, the gastric remnant and duodenum can be reached with a pediatric colonoscope in up to 68% of cases . This raIn emergency situations, the endoscopic assessment of the duodenum and gastric remnant can be achieved by performing a temporary laparoscopic surgical gastrostomy through the gastric remnant allowing to perform a transgastric endoscopy assessment . In any (QoE: low).Stenosis after LSG in stable patients presenting with gastrointestinal symptoms should be assessed by endoscopy, and the treatment must be tailored according to the clinical status of the patient and endoscopic findings (QoE: moderate).Endoscopic pneumatic dilation is a safe and effective first-line treatment of gastric stenosis after SG and gastro-jejunostomy strictures after RYGB. Perforation is a potential complication of this treatment and may necessitate surgical intervention (QoE: low).After RYGB, the most common causes of small-bowel obstruction (SBO) are internal hernia, adhesions, incisional hernia/trocar site hernia, intussusception, volvulus, obstruction localized at the jejuno-jejunostomy (JJ), twisted alimentary limb, alimentary limb mesenteric ischemia, and adhesions proximal to the JJ (QoE: low).In case of SBO after RYGB, an exploratory laparoscopy is mandatory in the first 12–24 h in stable patients presenting with persistent abdominal pain and inconclusive clinical and radiological findings (QoE: very low).Diagnostic laparoscopy in pregnant women with SBO after bariatric surgery is effective and is associated with a good maternal and fetal outcome (QoE: very low).Surgical exploration in patients after LRYGB should start from the ileocecal junction  toward the inspection of the jejuno-jejunostomy and of the 3 potential site locations of internal hernia: the traverse mesocolon (in retrocolic bypasses), Petersen’s space (Petersen’s hernia) and the jejuno-jejunostomy mesenteric defect , and then the remnant stomach. (QoE: very low).If an internal hernia is found, an assessment of intestinal viability should be undertaken; if intestinal ischemia is present, surgical resection is performed. The closure of the mesenteric defect should be performed with non-absorbable material in running or interrupted suture (QoE: very low).Indocyanine green (ICG) fluorescence angiography may be a valid tool in the evaluation of the extent of bowel resection and anastomosis perfusion, when it is available (QoE: very low).If no internal hernia or other evident causes of SBO are found, the entire small intestine should be assessed given that there are other causes of intestinal obstruction  (QoE: very low).In case of intra-operative findings of intussusception, the surgical treatment may be limited to reduction if the small bowel is viable, but resection of the affected segment is recommended since it seems to result in fewer recurrences (QoE: very low).In the emergency setting, when SBO is due to a bezoar located in the stomach, the first approach could be endoscopy. If the bezoar is located distally in the small bowel, surgical intervention is required to milk the bezoar into the cecum or remove it by creating an enterotomy (Strong recommendation based on low level of evidence 1C).In the presence of symptoms of proximal SBO after LSG and LRYGB, endoscopic assessment is recommended in stable patients Strong recommendation based on low level of evidence 1C).In the presence of SBO after RYGB, we recommend performing an exploratory laparoscopy in the first 12–24 h in stable patients with a history of bariatric surgery presenting with persisting acute abdominal pain after inconclusive laboratory, radiological and endoscopic results in the emergency setting ((Weak recommendation based on low level evidence 2C).We suggest considering limited intestinal resection and anastomosis in case of clear intestinal segmental ischemia in hemodynamically stable patients, or damage control and open abdomen approach in cases of extended intestinal ischemia/peritonitis in hemodynamic unstable patients Gastric obstruction after SG occurs in 0.2–4% of cases and most cases of obstruction present within 6 weeks after surgery . It can The endoscopic management of these strictures with balloon dilatation or stent placement, is reported to be successful in 88–94% of cases –134. WheIn the emergency setting, patients presenting with symptoms of obstruction such as nausea, vomiting, and intolerance to solid food intake after SG may benefit from a naso-gastric tube placement to decompress the stomach, before assessing the SG by endoscopy.After RYGB, the overall incidence of SBO ranges from 6 to 9.6%, and it could occur late (more than 30 days after surgery), usually resulting from an internal hernia or adhesions, or early (within 30 days of surgery) which is more commonly attributed to technical problems with the Roux limb, such as kinking or obstruction at the jejuno-jejunostomy , 136.After RYGB, patients rarely present with vomiting because of the small size of the gastric pouch. If bilious vomiting is present, it is a sign that the origin of the obstruction is at the jejuno-jejunostomy. More rarely, SBO could be due to a gastro-gastric fistula which allows the passage of the bile from the remnant stomach to the gastric pouch .The most common causes of SBO after RYGB are internal hernia, adhesive disease, jejuno-jejunostomy stenosis or kinking, incisional hernia, intussusception, and bezoar .Husain et al.  retrospeThe incidence of SBO caused by internal hernia is higher with retrocolic Roux placement when compared with antecolic Roux placement. In patients with antecolic Roux placement, the most common cause of obstruction is adhesive bands or stenosis at entero-enterostomy .When suspecting an internal hernia, in hemodynamically stable patients, early explorative laparoscopy is mandatory to avoid late diagnosis, intestinal vascular compromise, and bowel resection.It is suggested to begin the exploration from the alimentary limb at the gastro-jejunal anastomosis. This limb must be followed distally to its junction with the transverse colon where Petersen’s space will be evaluated. The exploration should be carried on through the alimentary limb to the jejuno-jejunal anastomosis to assess the inter-mesenteric defect.Internal hernia can be easily reduced from the ileocecal valve, distal to the obstruction, where the intestine is less dilated and can be handled much safer by laparoscopy. After reducing the hernia, if the bowel loops are viable, all the mesenteric defects and Petersen’s defect have to be closed with non-absorbable sutures.If an intestinal resection is required because of vascular compromise, indocyanine green (ICG) fluorescence angiography can support surgical decision making in evaluating intestinal perfusion and may help to define resection margins more accurately .If no internal hernia is found, the entire small intestine should be assessed given that there are other causes of SBO  that should be discarded in these patients. .Another cause of obstruction after RYGB is stenosis at the GJ. It has a reported incidence ranging between 3 and 27% . Risk faGJ strictures can be classified based on the mechanism of formation and endoscopic evaluation. These classifications can guide decision making. For example, membranous strictures are easily treated by endoscopic hydrostatic balloon dilatation; cicatricial strictures are characterized by intense fibrosis and respond unpredictably to endoscopic balloon dilation; granular strictures, that seem to result from secondary intention healing, or from tissue necrosis, require an early endoscopic approach .If the endoscopic treatment fails, surgical revision is an option to consider with an expert bariatric surgeon. Laparoscopic revision of a strictured anastomosis is a technically challenging procedure because of adhesion formation and difficulties in anatomical identification, even if an antecolic antegastric route of the Roux limb may make this attempt easier.In the emergency setting, SBO due to GJ stenosis can be managed by decompressing the gastric pouch with the placement of a naso-gastric tube and an endoscopic assessment to provide diagnosis and treatment.SBO after LRYGB could be due to intussusception, with an incidence estimated range of 0.1% to 0.3% . The patIntussusception can be classified in antegrade when the lead point is usually identifiable and can involve either limb; and retrograde , which is the most common form after LRYGB. It is characterized by a featureless entry point beginning a few inches below the intestinal anastomosis, with the intussusceptum traversing the entero-enterostomy into either the biliary or Roux limb .Type I—Afferent loop intussusception (antegrade);Type II—Efferent loop intussusception (retrograde);Type III—combined form of intussusception.The anatomical classification for jejunogastric intussusceptions which is widely accepted was proposed by Schackman et al.  which caThe management of jejunogastric intussusception could be endoscopic in selected cases, considering that the endoscopic reduction of intussusception is associated with an increased rate of recurrence . SurgicaHowever, there is no consensus about the best surgical treatment of intussusception after LRYGB. Gentle manual reduction of intussusception could be possible with high risk of recurrence. If there is intestinal necrosis, the nonviable segment should be resected with the creation of a new anastomosis when it is allowed (patients without signs of hemodynamic instability). If the involved segment includes the jejuno-jejunostomy, the latter will need reconstruction. Other described surgical techniques include anchoring of efferent limb to surrounding structures like parietal peritoneum and the Noble enteropexy. Reversal of the gastric bypass and conversion to another procedure like sleeve gastrectomy may be an option, but it has to be evaluated by an experienced bariatric surgeon in a multidisciplinary approach .To our knowledge, resection of the invaginated segment is the treatment of choice for avoiding recurrences. Laparoscopy or open surgery can be used, depending on the experience of the surgeon and the setting.Another rare cause of SBO after LSG or LRYGB, is the occurrence of a bezoar.Risk factors for bezoar formation are reduced gastric motility, loss of pyloric function, hypoacidity, low mastication and high consumption of high-fiber foods. After RYGB, the relatively restricting gastro-jejunostomy and a small gastric pouch are risk factors for presenting phytobezoar , 151.The management of patients presenting with SBO due to bezoar includes non-operative strategies such as chemical or endoscopic fragmentation and removal, and surgical removal, according to the site of obstruction , 151.Chemical dissolution and endoscopic removal is the primary treatment of choice when the bezoar is located in the stomach. Bezoar dissolution could be obtained through oral or endoscopic injection of Coca-Cola or papain , 151.Bezoars in the small bowel usually require surgical exploration and removal either by milking the bezoar into the cecum or alternatively, and less commonly, by enterotomy , 151.In the emergency setting, when SBO is due to a bezoar located in the stomach, the first approach could be non-operative by endoscopy, that will allow also a balloon dilation if an anastomotic or pouch stricture is found. If the bezoar is located distally in the small bowel, surgical intervention is required to milk the bezoar in the cecum or remove it by enterotomy.(QoE: low).Stable patients with perforated gastro-jejunal ulcer after LRYGB should be managed with laparoscopic primary repair by suturing and omental patch which are safe and feasible and associated with decreased operative time, blood loss, and length of stay (QoE: low).In patients presenting with marginal ulceration and perforation at the jejuno-jejunal anastomosis, laparoscopic primary suturing is a valid option in selected patients  QoE: very low).If a gastro-gastric fistula is found at surgical exploration for a perforated ulcer, surgical options include simple resection of the fistula, resection of the fistula with revision of the gastro-jejunal anastomosis (GJA), resection of the fistula with remnant gastrectomy ± revision of GJA, or gastrectomy of the remnant stomach ((QoE: low).After LRYGB, a perforated remnant stomach may be managed by primary suture and omental patch or stapled resection, If there is concern for significant postoperative ileus due to peritonitis, a gastrostomy tube could be placed in the gastric remnant proximal to the site of the perforation to decompress the stomach and allow a postoperative endoscopic access (QoE: low).If diffuse peritonitis is due to a perforated excluded gastrointestinal segment (stomach or duodenum), it is recommended to explore the jejuno-jejunostomy (stenosis) or the gastric remnant (gastro-gastric fistula) (QoE: very low).Surgical treatment of a duodenal perforation depends on the hemodynamic stability of the patient, size of the perforation and extent of native tissue loss Strong recommendation based on low level of evidence 1C).We recommend performing immediate surgical exploration in unstable patients presenting with peritonitis without delay (Strong recommendation based on low level of evidence 1C).We recommend assessing all anastomoses after LRYGB, the remnant stomach and the excluded duodenum (Strong recommendation based on low level of evidence 1C).In the presence of a perforated ulcer, we recommend performing biopsies of the perforated ulceration to exclude malignancy ((Strong recommendation based on low level of evidence 1C).We recommend performing primary suture with omental patch in laparoscopic approach in stable patients presenting with a perforated marginal ulcer or gastric remnant or duodenal perforation of less than1cm, whenever technically possible (Weak recommendation based on low level evidence 2C).We suggest considering damage control surgery and open abdomen in hemodynamically unstable patients Common causes of peritonitis in the general population may also occur after bariatric surgical procedures. We restricted our review to assess proper causes of peritonitis after SG and RYGB.A perforated gastric or marginal ulcer should be managed according to the WSES guidelines . PerforaA perforated gastric ulcer or marginal ulcer should be treated with laparoscopic suture repair followed by reinforcement using an omental patch. This is a safe and effective therapeutic option even in patients who have undergone bariatric surgery , 154.A gastro-gastric fistula has to be suspected in the presence of a marginal perforated ulcer following gastric bypass. This has to be ruled out by exploring the gastric remnant, to decrease recurrent marginal ulcers. If a GGF is detected, it may require revision bariatric surgery by an experienced bariatric surgeon.In the emergency setting, for a perforated ulcer it is recommended to perform laparoscopic suture repair reinforced with an omental patch. If a gastro-gastric fistula is recognized, an omental or jejunal interposition, may decrease the gastro-gastric fistula recurrence postoperatively, but only if this procedure is judged to be safe and will not extend the time of surgery.Recently, the robotic approach in the management of bariatric surgery postoperative complications showed promising results: it was reported that it is easier to repair a perforated ulcer or an anastomotic leak assisted by robot , 156.Perforation of an ulcer in the gastric remnant and in the excluded segment of the duodenum after LRYGB is rare. There are 29 cases of perforated gastric remnants reported with a perforation prevalence ranging from 0.12 to 0.84% . Of thosWhen the perforation is found at the gastric remnant, there is no consensus about the surgical treatment. It should be kept in mind that gastric remnant perforation could be secondary to back pressure of mechanical/functional bowel obstruction, consequently the jejuno-jejunostomy has to be assessed.Plitzko et al.  reviewedIf a stricture or an anomaly such as kinking or twisting is found at the jejuno-jejunostomy, it has to be resected to avoid the high risk of vascular compromise and perforation.In case of intestinal ischemia, it is recommended not to delay the surgical exploration using laparotomy if the patient is hemodynamic unstable. Laparoscopy can be used if skills are present, and the patient is hemodynamically stable. According to the extent of intestinal ischemia, principles of damage control surgery may be applied using the open abdomen by evaluating each case individually , althougA very small number of cases of duodenal perforation after bariatric surgery are reported in literature. There is no consensus on the surgical management of this situation. According to the experience in the management of duodenal perforation in trauma patients , surgicaDamage control surgery should be considered in hemodynamically unstable patients. Primary repair should be considered whenever technically possible in small size duodenal perforations.In managing large duodenal perforations (> 2 cm), there is no consensus on optimal surgical treatment. The selection of the appropriate techniques is based on the presence of an experienced surgeon, significant duodenal tissue loss, the presence of hemodynamic instability of the patient, and other operative and situational factors.Clinch et al.  have recThe WSES guidelines  suggest Damage control options, such as pyloric exclusion, gastric decompression, and external biliary drainage, should be considered contemporary to primary repair of the perforated duodenal ulcer.(QoE: low).Damage control surgery may be a tool to consider in the management of the acute abdomen in patients presenting with persistent hemodynamic instability because of severe peritonitis and septic shock (QoE: low).The open abdomen is an option for emergency surgery patients with severe peritonitis and severe sepsis/septic shock in the context of an abbreviated laparotomy due to severe physiological derangement, the need for a deferred intestinal anastomosis, a planned second look for intestinal ischemia, persistent source of peritonitis (failure of source control), or extensive visceral edema with concerns for the development of abdominal compartment syndrome (Weak recommendation based on low level evidence 2C).We suggest the use of damage control surgery with open abdomen in hemodynamic unstable patients secondary to an intra-abdominal source of infection, to extensive intestinal ischemia and massive hemoperitoneum Damage control surgery (DCS) represents a staged surgical approach to the treatment of critically ill patients. It has 3 stages: an abbreviated initial operative procedure with temporary abdominal closure (TAC), continued resuscitation and management of physiologic and acid–base derangements, and definitive treatment and closure .At present, there are no good quality published prospective studies focused on the implementation DCS in the management of patients with a previous history of bariatric surgery. There is basic science data that open abdomen management with negative pressure peritoneal therapy may fundamentally affect the propagation of inflammatory biomediators in severe complicated intra-abdominal sepsis, although there are certainly risks to the open abdomen use. Thus, ongoing studies such as the closed or open after laparotomy for severe complicated intra-abdominal sepsis trial are attempting to answer these questions and bariatric surgery patients are not excluded from enrollment.The threshold to operate patients in the emergency setting because of late complications of bariatric surgery, if the radiological findings are inconclusive, should be lower if they present with acute abdominal symptoms  and/or persistent tachycardia.Surgery is mandatory in the first 12–24 h, to obtain a good outcome and decrease morbidity and mortality rates. Laparoscopy is considered a safe technique if skills are present and if the patient is hemodynamically stable –165.Acute care surgeons diagnosing surgical emergencies in patients with a previous history of bariatric surgery must not overlook the common causes of a surgical acute abdomen . For theDecompressive laparotomy is indicated in abdominal compartment syndrome if medical treatment has failed after repeated and reliable intra-abdominal pressure measurements .The open abdomen is an option for emergency surgery patients with severe peritonitis and severe sepsis/septic shock under the following circumstances: abbreviated laparotomy due to severe physiological derangement, the need for a deferred intestinal anastomosis, a planned second look for intestinal ischemia, persistent source of peritonitis (failure of source control), or extensive visceral edema with concerns for the development of abdominal compartment syndrome .Experience from DCS in trauma and non-trauma patients suggests that the severity of inflammation and physiological impairment  are important factors to consider when deeming patients eligible for DCS , 174.The acute abdomen after bariatric surgery is a common cause of admission in emergency departments. Knowledge of the most common late/long-term complications  following LSG and LRYGB and their anatomy leads to a focused management in the emergency setting with good outcomes and decreased morbidity and mortality rates in a multidisciplinary approach.


Simultanagnosia is a common symptom of posterior cortical atrophy, and its association with brain structural and functional changes remains unclear. In our study, 18 posterior cortical atrophy patients with simultanagnosia, 29 patients with Alzheimer’s disease and 20 cognitively normal controls were recruited and subjected to full neuropsychological evaluation, including simultanagnosia tests, and structural and resting-state functional MRI. The gray matter volume was assessed by voxel-based morphometry, while the intrinsic functional connectivity was evaluated using the reduced gray matter volume regions of interest as the seed. In contrast to the patients with Alzheimer’s disease, those with posterior cortical atrophy showed the following: (1) markedly lower simultanagnosia test scores, (2) an altered regional gray matter volume of the left middle occipital gyrus and ventral occipital areas, and (3) lowered intrinsic functional connectivity with the left middle occipital gyrus, left lingual gyrus and right middle occipital gyrus separately. Additionally, the gray matter volume of the left middle occipital gyrus and left inferior occipital gyrus were each correlated with simultanagnosia in posterior cortical atrophy patients. The intrinsic functional connectivity of the left middle occipital gyrus with the right superior occipital gyrus and that of the right middle occipital gyrus with the left superior parietal gyrus were also correlated with simultanagnosia in posterior cortical atrophy patients. In summary, this study indicated that simultanagnosia is associated with gray matter reductions and decreased functional connectivity in the left middle occipital gyrus and the left inferior occipital gyrus in patients with posterior cortical atrophy. To mitigate the influence of the severity of other cognitive dysfunction, we enrolled typical AD patients matched for disease course and clinical dementia rating (CDR) scores as well as cognitively normal controls (NCs) to characterize the unique correlate in PCA patients. Using this design, we attempted to explore the onset locus of simultanagnosia and explain its causes, providing a basis for further research on the diagnosis and treatment of this syndrome.From August 2017 to June 2018, 18 patients with PCA, 29 patients with typical AD and twenty NCs were recruited by the Department of Neurology in Xuanwu Hospital. We obtained written informed consent from the individuals or their families to participate in this study according to the Declaration of Helsinki. The informed consent form was approved by the Ethics Committee of Xuanwu Hospital, Capital Medical University on Human Clinical Research.., All the participants completed detailed clinical history interviews, physical examinations and neuropsychological assessments. Each patient with PCA fulfilled the diagnostic criteria developed in 2017  and Montreal Cognitive Assessment (MoCA). Episodic memory was evaluated by the World Health Organization University of California-Los Angeles Auditory Verbal Learning Test (AVLT), including the AVLT learning, delayed recall and cued recall subtests , which asks the subject to name each individual object that overlaps with each other in a given figure  at Xuanwu Hospital, Capital Medical University. During the scanning, the participants were asked to remain quiet with closed eyes and to think of nothing in particular. High-resolution T1-weighted structural images and resting-state functional images were acquired from all the participants using the following parameters: structural data were collected using 3D magnetization prepared rapid gradient echo sequences , and functional data were obtained using an echo-planar imaging sequence over 8 min . FLAIR sequences were also acquired from all the participants to exclude the presence of lesions.www.neuro.uni-jena.de/cat) was used to preprocess the images using all default settings. The images were bias-corrected, tissue classified, and normalized to the Montreal Neurological Institute (MNI) space at 1.5-mm isotropic voxel resolution using linear (12-parameter affine) and nonlinear transformations within a unified model including the high-dimensional Diffeomorphic Anatomical Registration Through Exponentiated Lie Algebra (DARTEL) normalization  correction for multiple comparisons. The mean values of significant clusters identified were then extracted for further analyses.The CAT12 toolbox , adjusted for the effects of age, gender, years of education and TIV; Monte Carlo simulation was applied to correct for multiple comparisons  to achieve a cluster-level false-positive rate of 0.05. For significant clusters found in pairwise comparisons, the mean iFC over a given cluster was extracted for subsequent correlation analyses with simultanagnosia measures within the PCA group.To inspect how group differences in GMV affect cortical functional coupling, clusters that significantly differed between typical AD and PCA in the above VBM analyses were used to construct resting-state iFC maps. Briefly, 5-mm-radius balls centered at the peak coordinates of VBM clusters were drawn and defined as seed regions, and then the raw iFC map for each seed region was constructed by extracting the mean rs-FMRI time series from each seed region and correlating them to the time series of every other voxel in the brain using Pearson’s correlation. After Fisher’s r to z transformation, the normalized iFC maps for each seed region were compared among groups by voxelwise ANCOVA in the Statistical Parametric Mapping toolbox . To explore the relationships between the neuroimaging findings and simultanagnosia, partial correlation analyses were performed in the PCA group between the results of simultanagnosia tests and GMV and the iFCs after regressing out covariates such as age, sex, years of education, disease duration and the TIV (for VBM findings) or GMV of seed regions (for iFC findings). A statistical significance level of p < 0.01), reading test  and facial agnosia test  among the three groups; the PCA group performed worse than the other group. Additionally, no significant difference was found in the disease duration, immediate or delayed memory and CDR scores between the PCA and typical AD groups.  ; the PCA group showed significantly lower scores than the typical AD group , while no apparent differences were found in the computer local shape test scores among the three groups  and clinical groups . Additionally, the time of the computer-based local shape test in the PCA group was significantly longer than that of the typical AD group , while the time of the computer-based global shape test was not different   Table .Table 2Sp = 6.64e − 8), left lingual gyrus , right fusiform gyrus , right middle occipital gyrus , and left inferior occipital gyrus , particularly the left middle occipital gyrus and ventral occipital areas , the GMV of the left inferior occipital gyrus was correlated with the accuracy rate of the computer global shape test (r = 0.778; p < 0.001; Fig. Partial correlation analyses associated measures of simultanagnosia with GMV clusters corresponding to atrophy in the PCA group relative to the typical AD group. In PCA group, the GMV of the left middle occipital gyrus was associated with PGOF (r = 0.670, p = 0.028; r = 0.605, p = 0.008; Fig. Regarding iFC indices from the seed regions that GMV clusters corresponding to atrophy in the PCA group compared with those in the typical AD group, we found that in the PCA group, the iFC between the left middle occipital gyrus and right superior occipital gyrus, together with the iFC between the right middle occipital gyrus and left superior parietal gyrus, were associated with the computer global shape test score (r = − 0.517, In the present study, PCA patients were selected as the experimental group to examine the imaging abnormalities of simultanagnosia in not only brain structure but also brain iFC. The typical AD group was included in this study to specifically eliminate the impact of irrelevant variables.Our results showed that compared with the typical AD group, reduced GMV in the PCA group occurred in five different brain regions, mainly in the left middle occipital gyrus and ventral occipital area, which were positively correlated with the scores of the PGOF or computer global shape test. Among these atrophic brain regions, only the left middle occipital gyrus, left lingual gyrus and right middle occipital gyrus showed decreased functional connections. Furthermore, we found correlations between the bilateral middle occipital gyrus and computer global shape test scores. Overall, our findings suggested that simultanagnosia is related to the left middle occipital gyrus and left inferior occipital gyrus.In our study, the PGOF and computer-based global shape test scores were adopted as the principal standards to evaluate the presence and severity of simultanagnosia, the specificity of which is worth noting, considering that PCA usually exhibits many other visual deficits except simultanagnosia concurrently.., As reported, the PGOF has been used to assess figure-ground segregation, visuospatial function and visuo-perceptual function (Glick-Shames et al., In contrast to the PGOF, the computer-based simultanagnosia test has a low requirement on the subject's ability in object perception but focuses on the patient’s ability to recognize the global and local shape of objects. Combined with our research results, the global computer test score of PCA patients was significantly lower than that of typical AD patients, while the local computer test score showed no significant difference, indicating that the basic visual function of PCA patients was the same as that of typical AD patients but with severe simultanagnosia rather than with excessive visual crowding.., Most previous imaging studies on PCA patients did not correlate the imaging results with their clinical manifestations or merely explored the relationship between the MRI results and visual perception disorders in general, without focusing on a complex and characteristic symptom (Glick-Shames et al., Our results showed that the brain regions with significantly reduced GMV in PCA patients were the left middle occipital gyrus, whose iFC to the right superior occipital gyrus, bilateral postcentral gyrus, left precentral gyrus, right inferior parietal gyrus, left superior parietal gyrus and left superior temporal gyrus also decreased distinctly, and ventral occipital areas including the left lingual gyrus, left inferior occipital gyrus, right fusiform gyrus and right middle occipital gyrus. Additionally, both reductions were positively correlated with simultanagnosia, providing evidence that simultanagnosia is related to atrophy of the left middle occipital gyrus and left inferior occipital gyrus. Although both PCA and typical AD showed atrophy in part of the lateral posterior temporal lobe compared with normal participants, no significant atrophy was identified in PCA compared with typical AD in posterior temporal regions Fig. . This fiAnother interesting finding of our current study was the negative correlation of simultanagnosia with the iFC between the left middle occipital gyrus and right superior occipital gyrus. With the lack of other possible interpretations and need for additional studies, this finding suggests the presence of a compensatory mechanism. The increased connectivity between the right middle occipital gyrus and left superior parietal gyrus of PCA patients reinforced our conclusion. Simultanagnosia was more dependent on iFC malfunction between the occipital cortex and higher visual processing cortex and negatively correlated with functional connectivity within the occipital lobe. Additionally, the right middle occipital gyrus was atrophic in the PCA group, with a decreased iFC to the left superior parietal gyrus, consistent with the observed positive correlation with simultanagnosia. Again, because of the limited number of samples and requirement for direct hypothesis-based evidence, additional studies are needed to confirm our findings, particularly the role of the right middle occipital gyrus in simultanagnosia.The primary visual cortex of humans is located in the Brodmann 17 area, which is the neural basis for the earliest processing of visual stimuli and visual features, including directional movement, spatial frequency, parallax and color (Tang-Wai et al., ., Some studies have attributed simultanagnosia to the lesion of the unilateral region along the ventral visual pathway, and others have found an association between simultanagnosia and the dorsal pathway (Fink et al., ., The results of this study may help distinguish visual functional impairment characterized by simultanagnosia and other ocular dysfunctions, contributing to the diagnosis of PCA. This conclusion may also provide a target cerebral region for further studies on the treatment of patients with simultanagnosia. Thus, we are exploring the therapeutic effects of different targets under transcranial alternating current stimulation in AD and PCA patients (Ritzinger et alThis study indicated that simultanagnosia is associated with gray matter reductions and decreased functional connectivity in the left middle occipital gyrus and left inferior occipital gyrus in PCA.


The resulting travel restrictions have exerted pressure away from hosting international faculty visiting from abroad to focusing on international diversity within the local faculty.-,The recognition of unprofessional behaviour is a universally important topic which features prominently in faculty development programmes. Although all faculty members engaging in medical education are encouraged to monitor and address unprofessional behaviours encountered among medical students and staff, the recognition and assessment of such behaviours has proven difficult due to unclear definitions of what constitutes unprofessional behaviour,,However, such studies have been done with diverse groups of participants all working within their native contexts with participation as part of a longitudinal programme.the session content and subsequent reflection by the facilitators on the key ideas for international transferability and adoption in future programmes.The faculty development session was conducted online via Zoom in August 2021 at a Japanese medical school with 16 international faculty members , where all official information is communicated in Japanese. Nine medical education faculty members, including a native English-speaking clinical educator from the U.K., were involved in developing the session. We sent a bilingual email, in Japanese and English, announcing the session to the entire faculty, including the 16 international faculty members of our university. In order to encourage the participation of international faculty members, the lead researcher also sent individual personalised emails to these members.We implemented a lecture and clinical vignettes in a video-based discussion format, which has been shown to be effective in the discussion of context-specific professionalism dilemmas.Forty-one local faculty  and four international faculty members  participated. Among local Japanese participants, the departments of clinical medicine (18), basic medicine (12), social medicine (10) and the department of laboratory medicine (1) were represented. The international faculty was comprised of members from the departments of clinical medicine (1), basic medicine (2), and social medicine (1), with countries of origin spanning the U.S., Russia, and China. Twenty-nine of 41 participants responded to the post-programme feedback (response rate 70.7%), and 28 respondents (96.6%) rated the faculty development session as "very good" or "good".We found our online cross-cultural faculty development session on the topic of unprofessional behaviour to be a beneficial and rewarding experience for both international and local faculty in terms of overcoming cultural and linguistic barriers to increase accessibility.The bilingual handouts and group work facilitation were practical for smooth communication and ensured mutual participation by the international and local faculty members. In conducting the session within a limited time frame for participants with diverse language proficiencies, we found it effective to prepare materials in both languages and encourage participants to refer back to specific lecture slides in their stronger language, allowing focus on the discussion to be maintained. Discussion in participants' stronger languages enabled both local and international groups to share their opinions freely, deepening the cultural insights revealed about the topic.In our session, the facilitators included members with cross-cultural experience as educators and clinicians. They played the role of cultural mediators, an essential component for successful international facilitation.Video clips effectively minimised language barriers, despite being recorded in Japanese. Supporting this, the use of video illustrating real-life scenarios has been shown to be effective when engaging a culturally and linguistically diverse audience,As session facilitators, we encountered several difficulties. Firstly, we sadly could not accommodate real-time discussion across languages because provision for simultaneous translation was not available. The participants, therefore, reported a brief summary of their group discussion rather than an interactive exchange of ideas in open discussion. Secondly, although we designed the 75-minute evening programme to accommodate those with a heavy clinical schedule and reduce time barriers to attendance, it was not sufficient for participants to gain a deep understanding of each other's mutually complex contexts.We conducted an online cross-cultural faculty development session for the recognition of unprofessional behaviours at a medical school in Japan. In order to improve cultural accessibility, we introduced several strategies to reduce barriers to participation, including bilingual materials, video clips of real-life scenarios and group discussions facilitated by cultural mediators to give everyone a voice. Through the introduction of basic purposeful steps to improve accessibility, we brought faculty members of different nationalities and languages, as well as different specialities, closer together in authentic discussion united in the goal of recognising cultural differences associated with unprofessional behaviours.While the internationalisation of medical education principles is a hot topic, clear guidance on approaching the challenges associated with low cultural diversity in faculty development training is lacking. Although we successfully conducted our cross-cultural session through focusing on language and cultural barriers, continuous dialogue with both international and local faculty on obstacles faced when navigating multicultural training could reveal further challenges.Reflection by facilitators identified further aspects for improvement, such as giving international participants the option of which language to participate in. Although most international faculty is stronger in English, others may prefer Japanese, and likewise, native Japanese speakers may wish to participate in English, particularly while current opportunities to use English in academic settings are limited. Such consideration is important to promote cultural mediation expertise within participant groups and develop an inclusive ethos for future faculty development sessions. The online format may also permit the use of translation tools, which could support participants in future bilingual sessions, mainly if they are not native Japanese or English speakers.In this report, we show how low numbers of international faculty should not be an excuse for failure to embrace widening access and cultural accessibility within the medical faculty. Diversification is vitally important in recognising and addressing global issues such as unprofessional behaviour where cultural context is highly significant; therefore, increasing participant diversity through encouraging the attendance of marginalised internal faculty groups is an essential goal for future faculty development programmes.Such changes foster cultural awareness through facilitating new perspectives on culturally sensitive, context-dependent topics within medical education. Widening access to faculty development training in this way not only promotes an atmosphere of inclusivity in training and increased self-awareness but leads the way for concrete and context-sensitive globalisation of the medical education workforce.The authors declare that they have no conflict of interest.


The study recently published in the European Journal of Epidemiology by Frisch and Simonsen, which reports that non-therapeutic circumcision of boys in Denmark does not reduce risk of HIV infection and other sexually transmitted infections , does noThe authors do not consider or discuss that a man’s risk of anogenitally acquired sexually transmitted infections depends on his partner’s use of condoms and his partner’s circumcision status. It is not anatomically possible for a man’s circumcision status to influence his risk of STI/HIV acquisition if he is the receptive sexual partner in anal intercourse.Low-risk genotypes of human papillomavirus (HPV) is the infectious agent responsible for causing anogenital warts. Only when the insertive partner is circumcised, conferring a lower risk of harbouring persistent HPV infection , will thSince 2007, WHO and UNAIDS have recommended integrating male circumcision services into ongoing HIV prevention programs in 15 countries in sub-Saharan Africa. This recommendation is based on compelling evidence from rigorous randomised controlled trials conducted in South Africa, Kenya, and Uganda that demonstrated an approximately 60% reduction in heterosexually acquired HIV infection in men .Since the data from Frisch and Simonsen were drawn from administrative databases, it was not possible to adjust for the role of sexual orientation and sexual-behavioural factors and this introduces a major limitation that undercuts the authors’ attempts to generalise their findings to voluntary medical male circumcision programs in Africa. In Denmark, cases of HIV among homosexual men during the period 1990–2004 accounted for 69.7% of all HIV infections among men , whereasThe authors also focus on differentiating between male circumcision in infancy or childhood and adult male circumcision. However, there is no reason to believe that male circumcision in infancy or childhood will not result in equivalent HIV risk reduction for males, when they do become sexually active, as was seen in the randomised controlled trials among adult men. The biomedical explanatory models of friction-induced microtears allowing HIV access to susceptible target cells in the inner mucosal surface of the prepuce would account for the higher risk of HIV infection in uncircumcised males as compared to circumcised males, irrespective of whether their circumcision was carried out in childhood or later in life.Attempting to generalize the findings of this observational study in Denmark to HIV prevention programs in sub-Saharan Africa, regardless of whether male circumcision is carried out in infancy, childhood or later in life, is potentially dangerous if it risks undermining effective HIV prevention programming for males.


Genetic heterogeneity of metastatic dissemination has proven challenging to identify exploitable markers of metastasis; this bottom-up approach has caused a stalemate between advances in metastasis and the late stage of the disease. Advancements in quantitative cellular imaging have allowed the detection of morphological phenotype changes specific to metastasis, the morphological changes connected to the underlying complex signaling pathways, and a robust readout of metastatic cell state. This review focuses on the recent machine and deep learning developments to gain detailed information about the metastatic cell state using light microscopy. We describe the latest studies using quantitative cell imaging approaches to identify cell appearance-based metastatic patterns. We discuss how quantitative cancer biologists can use these frameworks to work backward toward exploitable hidden drivers in the metastatic cascade and pioneering new Frontier drug discoveries specific for metastasis. While we have made enormous progress regarding our understanding of cancer, it is still a leading cause of death worldwide. The cause of this high lethality is primarily due to the metastatic stage of the disease; metastasis occurs when cells from the primary tumor leave the local environment and colonize a distant organ . MetastaSubtle changes in metastatic cell states should manifest themselves in detectable phenotypic changes. This change is due to the morphological connection to the cytoskeleton changes necessary for invasion in the metastatic cascade. Initially, these changes were quantified through static shape morphometrics and connected to changes in metastatic potential. Cell appearance is a reliable monitor of cell signaling pathways  due to tversus elongation, shape variability, nuclear size, and nuclear shape. They noted that high metastatic potential cells differ from their low potential counterparts in projected cell area and cell volume, which were experimentally validated. Examining only the nuclear shape features showed no low versus high metastatic potential trends. This highlights the pitfalls of using one morphometric as a classification tool, especially with prospects for clinical applications. However, they overcome this using machine learning feeding all shape features into a multilayer perceptron to classify cells. They showed their classifier had good accuracy against high and low cells from the same lineages across cell surfaces and aggregate classes such as high versus low metastatic potential. This early work, and others like it, laid the foundation for computer vision and machine learning techniques to investigate metastatic cells.Using two-dimensional (2D) cell culture has taught us the value of cell appearance and its relation to metastatic ability. Recent work has shown 2D cell shape to be a readout of metastatic cell state . Lyons ein vivo. They implanted each of the seven morphological profiles into the mouse mammary fat pad and examined the metastatic potential of each morphology. They observed that depending on the morphology class, there were differences in metastatic potential and tumorigenesis compared to the parental line. They found a range of aggressiveness of the SCC: low tumorigenicity, tumorigenic, metastatic, and hypermetastatic. While they had several interesting findings regarding metastasis, tumor volume, and circulating tumor cells burden, they identified that cells with a high aspect ratio do not have higher metastatic potential, contradicting other findings in Lyons et al. However, SCCs with the same morphology displayed similar in vivo outcomes of tumorigenicity, circulating tumor cells, and metastatic potential; this highlights the connection between cellular appearance and metastasis. Stratifying the morphologies into high and low metastatic potential with corresponding gene expression profiles allowed Wu et al. to identify potential predictive metastasis genes for their cell line of choice. This highlights the immense impact that homogenous heritable morphological traits condense the heterogeneous genomic landscape to stereotypical cell morphologies.Wu and company have repeatedly continued the exploration of shape features in 2D. Building upon their work in pancreatic ductal adenocarcinoma , they inInstead of using traditional plastic culture dishes or plain glass slides, Hasan et al. used 2D light microscopy of metastatic glioblastoma and astrocytes on functionalized glass coverslips . They trAlizadeh et al. used fluorescent imaging of over a dozen cancer cell lines, with varying metastatic potential, on fibronectin-coated glass coverslips . To discIn contrast, waviness and hull geometry highly overlap all cell lines. This led them to test the morphological features at the single-cell level using an SVM or Perceptron. They found that morphometric-based features are more feature-rich for classification. Based on this, they can discriminate between the high and low metastatic cells of osteosarcoma and breast cancer cell lines. This led them to conclude that there may be stereotypical morphological transformations in the metastatic process. However, based on this study alone, it cannot be concluded how many stereotypical categories there may be for metastatic cells. This leaves an opportunity for long-term morphometric analysis of the development of normal to metastatic cells over many cancer types .Zaritsky et al. used label-free imaging and interpretable deep learning to identify cellular properties that discriminated between high and low metastatic potential patient-derived xenografted (PDX) melanoma cells . While nUsing this latent cell descriptor, they could discriminate between a panel of metastatic melanoma cell lines against fetal foreskin melanocytes. Single-cell clones were created within the metastatic cell lines, and the latent descriptor could discern the parental line from the clonal line. Furthermore, they could successfully discriminate between the cell line and PDX metastatic melanoma panels. Incongruent with the other studies mentioned in this review, cell shape performed worse than the latent cell descriptor, and temporal information did not increase the latent descriptor’s discriminative power. They could discriminate between high and low metastatic melanoma PDXs using the latent cell descriptor and linear discriminate analysis machine learning classifier. While exploring existing deep learning models on a unique physiologically relevant 2D system, the authors investigated the latent descriptor encoded in cell properties. They identified that pseudopodial extensions and interior light scattering properties of the cell discriminate between high and low metastatic melanoma. It is important to note that many studies focused on using machine learning and deep learning methods to identify differences in morphologies of metastatic cells; most studies have not used interpretable methods. This is severely lacking in most investigations, yet it is critical to work backward from phenotype to actionable signaling targets.While static imaging in 2D has profoundly impacted the field, it was always apparent that those studies were missing the mechanical forces that affect the cytoskeleton and, thus, the signaling pathways to which it connects. Furthermore, stereotyped cell behaviors can be identified from cell actions imaged over time . Here weElbez et al. developed a unique approach to image single-cell dynamic morphological phenotypes using machine learning and magneto-rotation, simulating circulating tumor cell morphologies in 3D. . They deRecently it was observed that metastatic breast cancer cell lines embedded in collagen exhibited morphological phenotype transitions that allowed them to efficiently traverse non-uniform matrixes that mimic the ECM . They dein vivo using a mouse model. Indeed, these cell appearance changes identified using A.I. have translated to in vivo metastatic potential. While it may seem evident that anti-cytoskeletal therapies will inhibit metastasis . The pairing of deep learning and machine learning with different imaging technologies, such as IFC, can interrogate the metastatic stage in primary samples as part of the pathology pipeline. Given that these samples can be fragile and genetic engineering can perturb the cell state, IFC can probe the cell using cell light scatter and brightfield images, both of which require no labels and have been used for cancer classification with deep and machine learning.We have highlighted multiple studies investigating cell appearance in varying spatiotemporal imaging modalities as a readout of metastatic potential to accelerate the discovery of metastatic-specific features. Rather than focusing on a specific gene, these works have levied the rich information found in images of metastatic cancer cells, overcoming the limits of using the genetic code for metastatic profiling.


Emerging infectious diseases pose an extreme risk for animal populations. Two current devastatingly widespread epizootics, both caused by fungal pathogens, are chytridiomycosis and white-nose syndrome. These infections are responsible for global declines in amphibian and bat populations  highlights the risk of viral infections for bats.Bats are important reservoirs for numerous viruses, including viruses with zoonotic potential  that can cause disease with high mortality rates for humans and non-human primates  of LLOV and reveal transmission pathways.Miniopterus schreibersii) is needed to get a clearer picture about the possible directions of the geographic spreading of the virus.Population genetic study of known hosts  must be prescribed.Wearing personal protective equipment when visiting roosts and handling bats is important. As LLOV is a possible zoonotic pathogen, in case of hazardous situations (e.g. finding of dead Schreiber’s bats), using appropriate personal protective equipment according to the possible presence of a biosafety level 4 agent is critically important.When epizootic event occurs, immediate closing of the site and its neighbouring roosts from humans as well as disinfection of all caving and sampling material is the most important first-step mitigation measure.Regular monitoring of bat roosts must be accompanied at least for Schreiber’s bat colonies, to be able to immediately react when die-offs occur.As a relative of the Ebola virus, communication about LLOV—the only Filovirus naturally occurring in Europe—may lead to biased public perception about bats, and may seriously affect future conservation efforts of habitats and colonies, hence maintaining public awareness must be a priority.A multi-lateral approach must be applied to reduce negative effects on bat populations, and to prevent human infections:To resolve the unknown details of the threats posed by the re-emergence and circulation of LLOV, we encourage a multinational collaboration of researchers from different disciplines , and increased research into this issue. LLOV is not the first and we believe that not the last viral agent that may pose a significant threat to bats and humans; hence, the abovementioned procedures may be applicable to the mitigation of future bat-borne viral epizootics or spillover events as well.


No studies appear to examine potential associations between changes in built environments across childhood and the developmental trajectories of child weight status.Examine the developmental trajectories of child weight status with respect to changes in childhood exposure to the built environments.This study used data of 9589 children with biennial follow-up (2004–2016), retrieved from the Longitudinal Study of Australian Children. Changes in objectively-measured child weight status  were investigated in relation to changes in seven built environments  subjectively reported by caregivers. Group-based discrete trajectory mixture models were used to classify children according to their developmental trajectories of built environments and weight status. Multilevel multinomial logistic regression was employed to examine associations between built environments and child weight status adjusted for confounding.Two, four, and six trajectory groups were developed for built environment variables. Three groups namely “moderate”, “high”, and “extreme increase” were generated for each BMI and waist circumference. Findings from multilevel analyses indicated that growing up in neighbourhoods that are considered highly safe, with better quality of green space nearby, and in areas with low local traffic over time are protective against unhealthy weight increase in childhood. Meanwhile, living with better access to shopping facilities and basic services was associated with an unhealthy increase in BMI and/or waist circumference. No clear associations appeared between the quality of footpath and street conditions, access to public transport, and child weight status.Built environments might act either as a risk or protective factor of an unhealthy increase in child weight status. Enabling health-promoting neighbourhoods  is important to support a healthy weight trajectory across childhood. In Aust century . The tra century . In addi century , 6.There has been growing interest in understanding the potential roles of built environments in influencing child weight-related outcomes. Evidence from previous systematic reviews indicates that built environments, including access to green space , 8 and aSome mechanisms might explain the built environment—child weight association. Built environments might lead to healthy weight among children through health-promoting behaviours. For example, physical activity and/or sedentariness might serve as a pathway in which neighbourhood green space , 13, safTo our knowledge, some longitudinal studies have been designed based on the assumption that built environments remain stable over time –25, ignoGrowing Up in Australia: the Longitudinal Study of Australian Children (LSAC) [This study used data from the nationally representative cohort study, n (LSAC) . Two-stan (LSAC) , 34. ThiWe used caregiver-based biennial assessments on seven aspects of built environments, namely neighbourhood safety; green space; footpaths, roads, and street lighting; public transport; basic shopping facilities; basic services; and heavy traffic Table . These v2) and waist circumference (in cm) were then classified into some groups using the discrete trajectory mixture models .BMI and waist circumference were biennially measured by a trained interviewer. Weight in light clothing was measured to the nearest 50 g using glass bathroom scales ; and height to the nearest 0.1 cm was assessed using a portable rigid stadiometer  . Waist cConfounders were selected based on a conceptualisation that they might influence neighbourhood selection , 43. TheGroup-based discrete trajectory mixture models were employed to develop trajectories of built environments, BMI, and waist circumference across the period of both cohorts combined. This has been used by previous studies in modelling the trajectories of BMI  and mentFollowing the identification of trajectory groups, we examined factors associated with trajectory group membership and confounders-adjusted associations between built environments and weight status. In LSAC, children’s observations were collected multiple times throughout time that were nested within individuals. Therefore, we used multilevel regression models for repeated-measure structured hierarchical data , taking Table Some trajectory groups were developed for each built environment, representing distinctive clusters of changes as children became older. Two and six groups were developed for neighbourhood safety; and footpaths, roads, and street lighting aspects; respectively. Four classes were generated for other built environment variables such as green space quality; public transport; shopping facilities; basic services; and heavy traffic, considering BIC values and none of the groups with less than 5% of the total respondents Table . The perFactors associated with trajectory group membership for built environment variables are presented in Tables Three similar trajectory groups were developed for weight status, namely moderate, high, and extreme increases in BMI or waist circumference Fig. . For botTable Access to public transport that increased or decreased between low and high levels was associated with a lower likelihood of experiencing an extreme increase in weight status, though only decreasing access from high to low showed a statistically significant association. Children with better access to shopping facilities and basic services were more likely to be found with an extreme increase in BMI and/or waist circumference. Compared to those living in areas with low traffic, children growing up in areas with heavy local traffic were more likely to have high and extreme weight increases.To our knowledge, this study is potentially the first that used group-based trajectory models to pattern changes in built environments across childhood and assess whether these changes matter for the developmental trajectories of BMI and waist circumference. Overall, findings indicate that associations between built environments and child weight status varied by the type of the built environments being tested. Favourable changes or stability in exposure to some built environments tended to be protective against unhealthy weight gain in childhood. For example, children living in perceived-safe neighbourhoods over time, and with green space reported, in high quality or, to increase from low to high quality, as they became older, were more likely to maintain healthy weight across childhood. However, better access to basic services  was associated with an extreme increase in BMI. Children experiencing consistent access to shopping facilities at a high level, or changes in access, irrespective of direction or level , relative to low access, were more likely to experience an extreme increase in both BMI and waist circumference. In addition, changes in local traffic conditions from low to moderate, high to low, or stable in high traffic throughout time increased the likelihood of unhealthy weight increase. Associations between changes in footpaths, roads, and street lighting quality; access to public transport; and child weight status were unclear.Caregiver perceptions of high neighbourhood safety over time were associated with healthy weight gain in childhood. Findings from a recent meta-analysis indicated that living in unsafe neighbourhoods is associated with a reduction in physical activity and an increase in BMI among children . Unsafe Green space trended from low to high or was in high quality throughout time was less likely to be associated with an extreme increase in BMI and waist circumference as children aged. Mechanisms through encouraging physical activity and/or reducing screen time might help explain the association among children , 13. Air2.5, PM2.5absorbance, PM10, PMcoarse, NOx, and NO2, and the risk of childhood obesity was reported in a recent meta-analysis [decreasing local traffic from high to low was also associated with unhealthy weight gain. This might indicate that heavy local traffic at lower ages might provide adverse impacts on child weight even though the exposure to traffic decreases later in childhood. Young children might be the most vulnerable to the detrimental impacts of heavy traffic due to exposure to air pollution [Unfavourable local traffic conditions  were associated with an unhealthy weight increase. Outdoor physical activity might also explain the association between high traffic and unhealthy weight trajectory . Moreoveanalysis . Other panalysis , total canalysis , and pooanalysis . It is iollution . More emBetter access to basic services and shopping facilities  increased the likelihood of an unhealthy weight trajectory. While high-to-moderate changes in access to shopping facilities might be expected to reduce the likelihood of unhealthy weight increase, a statistically significant association in the opposite direction appeared. The level of changes in the access  was certainly greater when it was compared to the low-level access stable in the reference group. This might explain why children with decreasing access to shopping facilities from high to moderate were more likely to experience an unhealthy weight increase, relative to their counterparts with consistently low access. A current review evaluating the association between the availability of grocery stores and child weight-related behaviours and outcomes suggested mixed findings that might be due to the variations in the study contexts . In our No clear association appeared between caregiver-perceived quality of footpaths, roads, and street lighting and objective measures of weight status. A possible explanation is that different elements of built environments  were combined in a single question. Caregivers might unequally weight each element based on which they viewed as relatively more important before reaching an overall conclusion. More variety in caregivers’ responses to this question might elucidate why more trajectory groups were found to fit with the data compared to other built environment indicators. Nevertheless, previous studies indicated that better access to sidewalks can contribute to neighbourhood walkability which might play important roles in improving active commuting and reducing sedentary behaviour and the risk of overweight or obesity , 67. TheChanges in caregiver perceptions of access to public transport that increased or decreased between low and high levels were associated with lower likelihood of the extreme increase in weight status among children, but only the perception decreasing from high to low showed a statistically significant association in this regard. A previous review reported heterogeneous findings on the association between access to public transport and childhood obesity . Public This study might be among the first that investigated changes in different built environments in relation to changes in weight status  across childhood. Findings from this study enrich the current literature on the importance of the accumulation of exposure to certain built environments. The use of longitudinal data in this study can provide better support for causality compared to previous studies that are cross-sectional in design. Findings from this study can be considered robust by using multilevel models and controlling all confounders, including neighbourhood characteristics that were strongly associated with built environment variables. Same-source bias might be not a concern in this study since the exposure and the outcome were derived from different sources, which may otherwise be a problem when reliant upon subjective reports of weight status that might not correlate particularly well with objective measures, while also permitting contrasting associations with health-related behaviors .Limitations of this study included the measure of built environments. This study used subjective measures of built environments reported by caregivers due to the unavailability of objective measures. Changes reported by caregivers across childhood might not be fully indicative of actual changes in built environments since their perceptions can be influenced by personal values, norms, and socioeconomic background , 35. ThiThe sample was predominantly from high-educated caregivers, two-caregiver families, non-Indigenous, and English-speaking children. The small proportion of some sub-sample groups can indicate less variability in the data that can influence the findings and their generalisability to some extent. This study also did not investigate the effect modifiers the reported associations, indicating further investigation is needed. This is particularly important from an equity perspective, not only based on evidence that communities living with socioeconomic disadvantage may benefit disproportionately more than their more advantaged counterparts from investments in built environment , but alsBuilt environments, such as highly safe neighbourhoods, quality green space nearby, and low local traffic were protective against high and extreme increases in weight status among children. Meanwhile, living close to shopping facilities and basic services increased the likelihood of unhealthy weight gain. However, more studies are needed to understand the influence of footpath and street conditions and access to public transport on child weight status. Ensuring children grow up in neighbourhoods with favourable built environments  is important to help them gain healthy weight.Supplementary Tables


Adopting evidence-based medicine in clinical care of older patients is challenging because the “best” evidence available may not be directly applicable due to exclusion or underrepresentation of older adults in clinical trials. Interventions shown to be beneficial in trial populations therefore often exhibit heterogeneous treatment effects (HTEs) in older adults, particularly among the most vulnerable. This talk will review the concept, causes, and estimation of HTEs. We distinguish clinical heterogeneity from methodologic heterogeneity, defined respectively as the variation in biological mechanisms leading to similar aging phenotypes and variation in study design, measurement, and analysis. We use examples drawn from geriatric medicine to introduce novel study designs and data analytics used to study HTEs. This talk highlights the importance of moving beyond post-hoc subgroup analysis to an approach that integrates theories, observational and experimental data, and data science in the study of HTEs.


The purpose of this study was to examine the protective effect of trait resilience, a positive personality characteristic that enhances individual adaptation to life events and adversity, in the face of declining social relationships in later life. Social relations have a significant effect on our development and well-being throughout life. However, it is known that a decline in physical, cognitive, and mental functioning makes it difficult to maintain active participation in society and leads to shrinking social networks in later life. Therefore, it is important to identify protective factors that enable people to maintain positive social relations when functioning in daily life declines in old age. We analyzed longitudinal survey data from a representative sample of older Japanese adults aged 74 to 86 years (N=1064). The interaction effect of resilience in the relationship between functions  and relationships with friends  was examined using multi-group Structured Equation Modeling (SEM). Respondents were divided into upper quartile and lower quartile groups according to their Resilience Scale (RS-14) scores. The results showed significant group differences for the effect of cognitive function on friendship. The positive correlation between cognitive functioning and friendship was stronger among respondents with low resilience. For high resilience participants, cognitive functioning was not associated with friendship. The results suggest that resilient older adults cope well with poor cognitive health and maintain positive social relationships in very late life.


Ischemic preconditioning (IPC) has been reported to augment exercise performance, but there is considerable heterogeneity in the magnitude and frequency of performance improvements. Despite a burgeoning interest in IPC as an ergogenic aid, much is still unknown about the physiological mechanisms that mediate the observed performance enhancing effects. This narrative review collates those physiological responses to IPC reported in the IPC literature and discusses how these responses may contribute to the ergogenic effects of IPC. Specifically, this review discusses documented central and peripheral cardiovascular responses, as well as selected metabolic, neurological, and perceptual effects of IPC that have been reported in the literature. This tourniquet-induced ischemia and reperfusion is then repeated for a prespecified number of intervals (most commonly 3–4 times) before commencing exercise (Ischemic preconditioning (IPC) is a potential ergogenic technique that involves administering brief repeated episodes of non-lethal ischemia and reperfusion to the limb(s) prior to engaging in exercise. IPC is performed by temporarily occluding the flow of blood through the limb(s) exercise . Althougexercise —which tyexercise .Previously, IPC has been demonstrated to have protective properties against the injurious effects of ischemia-reperfusion injury in mammalian animal models  and has It has previously been suggested that the training status or sex of the participant may influence the probability of IPC ergogenicity , althougvia IPC and how they may contribute to enhancing exercise performance outside of the laboratory. The primary objective of this review is to provide the reader with an up-to-date report on the physiology of IPC-exercise that will help to inform future IPC practitioners when using IPC for the purposes of performance enhancement during exercise.There is no doubt that there has been growing interest from sport and exercise researchers and practitioners in IPC as a promising ergogenic aid, and there is also no doubt that the mechanistic explanations for the observed performance enhancing effects of the treatment are incompletely understood. Thus, a comprehensive understanding of the physiology of IPC and exercise is imperative to maximizing the likelihood of a positive ergogenic response occurring. While several published reviews have summarized the observed ergogenic effects or methodological variations in IPC exercise studies, at the time of preparing this paper we could find no review that has collated the myriad physiological mediators purported to be the mechanisms that explain the observed ergogenic effects attributed to IPC. Therefore, this narrative review aims to summarize the current evidence of the effects of an acute bout of IPC on the physiological responses to exercise, regardless of whether an ergogenic effect was elicited. Specifically, this report discusses the documented cardiovascular, metabolic, neural, and perceptual responses that occur Much of the foundational work on underlying IPC mechanisms arose from clinical and animal models that investigated the role of remote IPC (RIPC) in preventing or remediating ischemia-reperfusion injury in various tissue types . The proIt is important to consider if the well-documented cardioprotective effects of RIPC  mean tha˙O2max) . During ˙O2max)  and incr˙O2max) . Another˙O2max) . While svia 3 min of post exercise muscle ischemia, Similarly, when examining the effects on blood pressure responses, a minority of studies listed in Collectively, even with the sound theoretical basis for speculating that IPC before exercise should influence central cardiovascular responses during exercise, there is very limited supporting empirical evidence that such is the case. Thus, it is likely that physiological mechanisms other than central cardiovascular effects of IPC are primarily responsible for the ergogenic effects of IPC, while central cardiovascular responses may contribute modestly in some cases.2 delivery, and deoxygenation kinetics at the muscle capillary interface . External compression of the peripheral blood vessels in the limb via IPC may augment local feedforward and feedback responses at the site of ischemia that may persist for some time following the cessation of the treatment  marked increases in total haemoglobin [tHb] which is an indicator of total blood volume , 2017, aresponse . It is nThe peripheral hemodynamic response may be less robust during RIPC compared to local IPC, although the limited available evidence should be acknowledged here. One study found modest changes to hemodynamic variables following RIPC , whereas2 at the muscle-capillary interface  activity during IPC-exercise have found no effect on neuromuscular function, regardless of whether performance enhancement was found . Conversvia group III/IV muscle afferents have been shown to initiate the exercise pressor reflex, which is an essential response governing the cardiovascular response to exercise (One neural mechanism that has been previously hypothesized to contribute to the ergogenic effect of IPC involves the desensitization of metabolically sensitive metabo-nociceptive neurons known as group III/IV muscle afferents . Brieflyexercise . The exeexercise , inhibitexercise , and modexercise . TheoretFew studies have sought to directly investigate the relationship between IPC on discharge from group III/IV muscle afferents. One study found an attenuated hemodynamic response to metaboreflex activation during dynamic handgrip exercise preceded by IPC , whereasPerhaps lending further support to the muscle afferent hypothesis is the evidence of IPC inducing hypoalgesic effects in humans. Indeed, previous investigations have demonstrated IPC techniques to reduce pressure pain ratings, pain under ischemia, perceived pain following eccentric exercise induced muscle damage, and time spent under pain during cold-water immersion tests . IPC-indIndeed, activation of opioid and endocannabinoid receptors in the central and peripheral sites of the pain pathway such as the spine and peripheral nerves can modulate ascending and descending pain signalling . Specifiversus supramaximal intensities where perceived effort should already be maximized. Nevertheless, most research efforts show no effect of IPC on RPE.Pain perception serves an important function in protecting the body from deleterious stimuli through promoting avoidance behaviours . SimilarThe effects of IPC on neural and perceptual responses to exercise are still being probed. Currently, there is no consistently reported effect of IPC on neural responses, however, a notable body of evidence suggests some relationship. Moreover, the majority of studies that have examined IPC and RPE have found no evidence to postulate that IPC modulates the perception of discomfort during exercise. Future research efforts should aim to generate more data on the neural effects of IPC to better characterize the potential contribution to IPC ergogenicity.The present review aimed to summarize the myriad physiological responses measured during acute IPC exercise interventions and to contemplate how such responses may contribute to enhancing exercise performance. Acute bouts of IPC have been demonstrated to modulate cardiovascular, hemodynamic, metabolic, neurological, and perceptual responses during subsequent acute exercise. However, the reproducibility and synchroneity among these responses to IPC are equivocal for reasons that remain unclear. Based on the widely varying mechanisms reported in this review as primarily responsible for mediating IPC-induced ergogenic effects, it is tempting to speculate that an “entourage” effect, i.e., a combined effect of several mediators is the explanation for observed performance enhancements. Future efforts should aim to assess the relative importance and contributions of the identified physiological and biochemical mediators as well as the necessary methodological strategies for optimizing the conditions for the most important mediators to maximize the efficacy of the treatment on performance outcomes.