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Antibodies against the CD4 binding site (CD4bs) on the HIV-1 spike protein gp120 can show exceptional potency and breadth. We determined structures of NIH45-46, a more potent clonal variant of VRC01, alone and bound to gp120. Comparisons with VRC01-gp120 revealed that a four-residue insertion in heavy chain complementarity-determining region 3 (CDRH3) contributed to increased interaction between NIH45-46 and the gp120 inner domain, which correlated with enhanced neutralization. We used structure-based design to create NIH45-46 G54W , a single substitution in CDRH2 that increases contact with the gp120 bridging sheet and improves breadth and potency, critical properties for potential clinical use, by an order of magnitude. Together with the NIH45-46-gp120 structure, these results indicate that gp120 inner domain and bridging sheet residues should be included in immunogens to elicit CD4bs antibodies.

INTRODUCTION:Sessile serrated polyps (SSPs) are candidate precursors of most interval colorectal cancers. These mostly right-sided lesions are easily missed, often incompletely removed, and may progress rapidly to malignancy. Accurate histologic distinction between precancerous and non-precancerous polyps is key to choosing appropriate intervals for colonoscopy. Among serrated polyps (SPs), precancerous SSPs are histologically similar to non-precancerous hyperplastic polyps, and disparity among expert pathologists is high with independent reviews of the same specimens. We assessed if this discrepancy would be reflected by significant variability in classification rates of HPs and SSPs among pathologists in a real-world academic clinical setting.METHODS:Using our Colonoscopy Quality Database (UCICQD) at a large academic medical center, we analyzed prospectively-collected data for all polyps removed and examined between 6/2012 and 12/2016. Polyp classification rates of each pathologist were calculated; association between pathologists and polyp classifications were assessed by unconditional logistic regression for multivariate analysis. The rate of classification of each pathologist was analyzed as polyp size increased.RESULTS:Of 8,274 in polyps classified by 9 pathologists, 62.5% were described as adenomas. For 3,103 SPs, a mean of 22.0% was classified as SSPs. SSP classification rate varied among pathologists; a statistically significant association was found between pathologists and type of SP (HP vs SSP) (P < 0.0001). The rate increased for all pathologists with increasing polyp size, although variability was high and pathologists maintained their relative positions when comparing SSPs/SPs between polyp sizes (1–3 mm vs >4 mm), R = 0.8, P = 0.01.CONCLUSION:The SP classification rates of pathologists in the right colons are highly variable. The fraction of SPs classified as SSPs increases with polyp size but variability among pathologists remains high. This suggests that each pathologist is influenced by polyp size but has a different histologic threshold for distinguishing HPs and SSPs in the right colon. This data supports the idea that serrated polyps (HPs or SSPs) proximal to the sigmoid colon should be considered \"surveillance relevant\". This strategy will likely reduce interval cancer rates at the expense of additional colonoscopies in those with true HPs. Novel methodologies are needed to distinguish these morphologically similar but biologically distinct lesions.

INTRODUCTION:Acquired megacolon is a rarely diagnosed condition that may be a source of significant distress in the acutely hospitalized patient. It presents in either gender at any age. Symptoms, when present, are typically abdominal pain with distention, gas distress, and constipation. Reported cases are typically less than 10 cm on diagnostic imaging. Pathology findings vary greatly and include muscularis hypertrophy or degeneration of the smooth muscle, damaged or reduced ganglia, melanosis coli, or chronic inflammation.CASE DESCRIPTION/METHODS:A 19-year-old Hispanic US-born man presented to the ER with severe, progressively worsening abdominal pain and distention for one month and inability to urinate. His last bowel movement (BM) was 3 weeks ago, small and liquid. He stated it was common for him to not have a BM for up to a month. This has occurred since he was six years old, when he began avoiding defecation due to pain he experienced when moving his bowels. Prior treatment with laxatives and enemas had been ineffective in inducing regular bowel movements. He has had difficulty gaining weight. Initial labs were significant for severe iron deficiency anemia with MCV 65, Ferritin 2, TIBC 301, Iron 11, and percent saturation of 4%. CT imaging showed a markedly distended colon and rectum measuring up to 17 cm in the sigmoid colon. There was severe stool burden in the rectum and the distended colon. The colon was causing mass effect and crowding of other organs, including a distended bladder. Initial inpatient management with enemas, disimpaction, and frequent laxatives failed to cause significant reduction in the colonic distention. Under anesthesia, rectal examination found normal rectal tone and required disimpaction and lavage. Full-thickness rectal biopsies were obtained which revealed mild erosion, indeterminate colitis, and hyperplasia of the muscularis mucosa. Calretinin was positive for nerve fibers, however no ganglia were seen. A diverting Brooke ileostomy was created without immediate complications. On 1 month follow up the patient reported significant weight gain, no further abdominal pain, and adequate ostomy output.DISCUSSION:This case demonstrates a severe example of acquired megacolon in a young man due to chronic constipation. Surgery is typically required for very distended cases, but surgical options vary considerably and have been poorly studied. In this patient, due to the extreme nature of his megacolon, surgical diversion was performed to allow eventual resection.

Introduction: Mucosal healing is a primary goal of treatment in ulcerative colitis (UC) and a universal endpoint in therapeutic trials. Endoscopic assessment of mucosal healing, however, is highly subjective with disagreement among experts using standardized scoring systems. The most commonly used scale is the Mayo Endoscopic Subscore (MES). We hypothesized that a convolutional neural network (CNN) could provide a novel means to provide a Mayo UC endoscopic score that is reproducible, unambiguous and operator-independent. Methods: 9,538 images from colonoscopies and flexible sigmoidoscopies from UC patients were scored (0-3) using the MES by consensus between two physicians who completed formal training, one of whom is an established expert in inflammatory bowel disease, resulting in 1,504 MES-0, 4,078 MES-1, 2,860 MES-2, and 1,096 MES-3 images. We developed a CNN built on Tensorflow and pre-trained on ImageNet. Images were partitioned for training (80%) and validation (20%). An Adam optimizer generated a probability between 0 (MES-0) and 1 (MES-3). Results: The model demonstrated very high sensitivity (99.3%), specificity (97.7%), and accuracy (98.7%) for distinguishing MES-0 vs MES-3 (Figure 1). Mean [standard deviation] of prediction scores showed a gradient across MES-0 (0.02 [0.09]), MES-1 (0.13 [0.3]), MES-2 (0.56 [0.46]) and MES-3 (0.97 [0.14]). MES-1 and MES-2 showed a wide and overlapping score distribution. The model processes each frame at 1ms/frame (1000 fps), capable of providing real-time feedback during colonoscopy. Conclusion: This model demonstrates the feasibility of applying CNNs to provide real-time, unambiguous endoscopic scoring of UC. The accuracy of the model for MES 1 and MES 2 can be improved with additional images and training. We believe, however, that the current model will provide much more accurate scoring when results of multiple video frames are averaged during live colonoscopy. Clinical validation studies will soon be underway.

Most post-cholecystectomy biliary strictures can be treated endoscopically as long as stenting is possible. We describe a successful EUS-guided antegrade approach to treatment of a benign post-cholecystectomy stricture, which could not be stented conventionally due to an acute angle alpha loop deformity of the bile duct. A 70 year-old woman with history of laparoscopic cholecystectomy one year ago presented to another hospital with biliary obstruction and cholangitis. She reported a complicated course after surgery with percutaneous drainage of a biliary leak for months. Cholangiogram showed a biliary stricture at the level of hilum and a plastic biliary stent was placed in what was thought to be the right intrahepatic duct. However, she continued to have recurrent biliary obstruction. EUS showed dilated intrahepatics with smooth tapering of the bile duct distally without a mass or a transition point. FNA of perihepatic lymph nodes were negative for malignancy.She was transferred to our institution after recurrent cholangitis. ERCP showed the existing stent to terminate in a tubular structure in the direction of the right intrahepatic duct. Cholangiogram showed faint filling of what looked like a short right hepatic duct beyond the surgical clips as previously described. However occlusion cholangiogram demonstrated an extremely tight and acutely angulated stricture away from the originally seen duct which turned out to be the old percutaneous drainage tract. Although we were able to pass a guidewire to the intrahepatic duct, exhaustive efforts at passing any catheter failed as it impacted in the false tract and flipped the wire out. EUS-guided antegrade approach was performed for biliary stenting. We punctured the left intrahepatic duct under EUS and manipulated a guidewire antegrade to the distal bile duct, again creating an alpha loop within the false tract as with prior attempt during ERCP. The echoendoscope was exchanged for the duodenoscope and the guidewire was secured at the EUS puncture site and at the ampulla and gently pulled to 'straighten out' the bile duct. Retrograde balloon dilation and stenting of the stricture was then performed without difficulty. Repeat ERCP with stent exchange two months later showed healing of the false tract and a patent stricture. This case demonstrates that securing the guidewire at both ends greatly facilities stenting and is helpful in patients with difficult anatomy.

Intestinal tuberculosis (ITB) and Crohn’s disease (CD) very closely resemble each other in symptomatology, imaging, appearance, and pathology. While ITB is rare in the United States, its prevalence is significantly higher in endemic areas, thus presenting a diagnostic dilemma in immigrant populations from high-risk countries. This patient was diagnosed with CD and treated with anti-TNF agents after indeterminate screening for latent tuberculosis. He was then admitted with septic shock and intestinal perforation due to disseminated tuberculosis. This case demonstrates the importance the consideration of ITB when a patient with risk factors for TB fails to respond to treatment for CD.

Passive transfer of broadly neutralizing HIV antibodies can prevent infection, which suggests that vaccines that elicit such antibodies would be protective. Thus far, however, few broadly neutralizing HIV antibodies that occur naturally have been characterized. To determine whether these antibodies are part of a larger group of related molecules, we cloned 576 new HIV antibodies from four unrelated individuals. All four individuals produced expanded clones of potent broadly neutralizing CD4-binding-site antibodies that mimic binding to CD4. Despite extensive hypermutation, the new antibodies shared a consensus sequence of 68 immunoglobulin H (IgH) chain amino acids and arise independently from two related IgH genes. Comparison of the crystal structure of one of the antibodies to the broadly neutralizing antibody VRC01 revealed conservation of the contacts to the HIV spike.

Passive immunotherapy with a combination of neutralizing monoclonal antibodies is shown to be effective in suppressing HIV replication in a humanized mouse model. A boost for HIV-1 therapy Broadly neutralizing antibodies to human immunodeficiency virus-1 (HIV-1) are slow to develop and are found in only a fraction of patients, but they can prevent infection and so are of great importance for HIV therapy design. Previous work has shown that the virus can quickly evolve resistance against these antibodies; however, more potent antibodies are now available. Michel Nussenzweig and colleagues therefore re-examined the potential of antibody therapy in 'humanized' mice. They demonstrate that passive immunotherapy with combinations of broadly neutralizing antibodies effectively controls HIV-1 infection. The authors suggest that it is time to re-examine monoclonal antibodies as therapeutics in HIV-1-infected individuals. Human antibodies to human immunodeficiency virus-1 (HIV-1) can neutralize a broad range of viral isolates in vitro and protect non-human primates against infection 1 , 2 . Previous work showed that antibodies exert selective pressure on the virus but escape variants emerge within a short period of time 3 , 4 . However, these experiments were performed before the recent discovery of more potent anti-HIV-1 antibodies and their improvement by structure-based design 5 , 6 , 7 , 8 , 9 . Here we re-examine passive antibody transfer as a therapeutic modality in HIV-1-infected humanized mice. Although HIV-1 can escape from antibody monotherapy, combinations of broadly neutralizing antibodies can effectively control HIV-1 infection and suppress viral load to levels below detection. Moreover, in contrast to antiretroviral therapy 10 , 11 , 12 , the longer half-life of antibodies led to control of viraemia for an average of 60 days after cessation of therapy. Thus, combinations of potent monoclonal antibodies can effectively control HIV-1 replication in humanized mice, and should be re-examined as a therapeutic modality in HIV-1-infected individuals.