Norwalk Hospital

The Hertzian theory of elastic contact between spheres is extended by considering one of the spheres to be rough, so that contact occurs, as in practice, at a number of discrete microcontacts. It is found that the Hertzian results are valid at sufficiently high loads, but at lower loads the effective pressure distribution is much lower and extends much further than for smooth surfaces. The relevance to the physical-contact theory of friction and electric contact is considered.

The relation between the area of contact and the constriction resistance which holds for a single circular contact spot is widely used in electric contact theory, although the normal mode of contact is by a large number of microcontacts. A method of finding the resistance of a cluster of microcontacts is derived, and it is shown that the resistance may be regarded as the sum of the parallel resistance of the microcontacts and an interaction term often related to the extent of the cluster and not to the number or size of the individual contacts. The resistance is often close to that found by assuming that the entire area covered by the cluster is a single conducting spot.

Acoustic properties of speech have previously been identified as possible cues to depression, and there is evidence that certain vocal parameters may be used further to objectively discriminate between depressed and suicidal speech. Studies were performed to analyze and compare the speech acoustics of separate male and female samples comprised of normal individuals and individuals carrying diagnoses of depression and high-risk, near-term suicidality. The female sample consisted of ten control subjects, 17 dysthymic patients, and 21 major depressed patients. The male sample contained 24 control subjects, 21 major depressed patients, and 22 high-risk suicidal patients. Acoustic analyses of voice fundamental frequency (Fo), amplitude modulation (AM), formants, and power distribution were performed on speech samples extracted from audio recordings collected from the sample members. Multivariate feature and discriminant analyses were performed on feature vectors representing the members of the control and disordered classes. Features derived from the formant and power spectral density measurements were found to be the best discriminators of class membership in both the male and female studies. AM features emerged as strong class discriminators of the male classes. Features describing Fo were generally ineffective discriminators in both studies. The results support theories that identify psychomotor disturbances as central elements in depression and suicidality.

RATIONALE: Survivors of hospitalization for community-acquired pneumonia (CAP) are at increased risk of cardiovascular events, repeat infections, and death in the following months but the cause is unknown. OBJECTIVES: To investigate whether persistent inflammation, defined as elevating circulating inflammatory markers at hospital discharge, is associated with subsequent outcomes. METHODS: Prospective cohort study at 28 sites. MEASUREMENTS AND MAIN RESULTS: We used standard criteria to define CAP and the National Death Index to determine all-cause and cause-specific 1-year mortality. At hospital discharge, 1,799 subjects (77.5%) were alive and vital signs had returned to normal in 1,512 (87%) subjects. The geometric means (+/-SD) for circulating IL-6 and IL-10 concentrations were 6.9 (+/-1) pg/ml and 1.2 (+/-1.1) pg/ml. At 1 year, 307 (17.1%) subjects had died. Higher IL-6 and IL-10 concentrations at hospital discharge were associated with an increased risk of death, which gradually fell over time. Using Gray's survival model, the associations were independent of demographics, comorbidities, and severity of illness (for each log-unit increase, the range of adjusted hazard ratios [HRs] for IL-6 were 1.02-1.46, P < 0.0001, and for IL-10 were 1.17-1.44, P = 0.01). The ranges of HRs for each log-unit increase in IL-6 and IL-10 concentrations among subjects who did and did not develop severe sepsis were 0.95-1.27 and 1.07-1.55, respectively. High IL-6 concentrations were associated with death due to cardiovascular disease, cancer, infections, and renal failure (P = 0.008). CONCLUSIONS: Despite clinical recovery, many patients with CAP leave hospital with ongoing subclinical inflammation, which is associated with an increased risk of death.

BACKGROUND: The effect of procalcitonin-guided use of antibiotics on treatment for suspected lower respiratory tract infection is unclear. METHODS: In 14 U.S. hospitals with high adherence to quality measures for the treatment of pneumonia, we provided guidance for clinicians about national clinical practice recommendations for the treatment of lower respiratory tract infections and the interpretation of procalcitonin assays. We then randomly assigned patients who presented to the emergency department with a suspected lower respiratory tract infection and for whom the treating physician was uncertain whether antibiotic therapy was indicated to one of two groups: the procalcitonin group, in which the treating clinicians were provided with real-time initial (and serial, if the patient was hospitalized) procalcitonin assay results and an antibiotic use guideline with graded recommendations based on four tiers of procalcitonin levels, or the usual-care group. We hypothesized that within 30 days after enrollment the total antibiotic-days would be lower - and the percentage of patients with adverse outcomes would not be more than 4.5 percentage points higher - in the procalcitonin group than in the usual-care group. RESULTS: A total of 1656 patients were included in the final analysis cohort (826 randomly assigned to the procalcitonin group and 830 to the usual-care group), of whom 782 (47.2%) were hospitalized and 984 (59.4%) received antibiotics within 30 days. The treating clinician received procalcitonin assay results for 792 of 826 patients (95.9%) in the procalcitonin group (median time from sample collection to assay result, 77 minutes) and for 18 of 830 patients (2.2%) in the usual-care group. In both groups, the procalcitonin-level tier was associated with the decision to prescribe antibiotics in the emergency department. There was no significant difference between the procalcitonin group and the usual-care group in antibiotic-days (mean, 4.2 and 4.3 days, respectively; difference, -0.05 day; 95% confidence interval [CI], -0.6 to 0.5; P=0.87) or the proportion of patients with adverse outcomes (11.7% [96 patients] and 13.1% [109 patients]; difference, -1.5 percentage points; 95% CI, -4.6 to 1.7; P<0.001 for noninferiority) within 30 days. CONCLUSIONS: The provision of procalcitonin assay results, along with instructions on their interpretation, to emergency department and hospital-based clinicians did not result in less use of antibiotics than did usual care among patients with suspected lower respiratory tract infection. (Funded by the National Institute of General Medical Sciences; ProACT ClinicalTrials.gov number, NCT02130986 .).

This clinical practice guideline represents a collaborative effort between the American Society of Colon and Rectal Surgeons (ASCRS) and the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES). The ASCRS Clinical Practice Guidelines Committee is composed of society members who are chosen because they have demonstrated expertise in the specialty of colon and rectal surgery. In a collaborative effort, the ASCRS Clinical Practice Guidelines Committee and members of the SAGES Surgical Multimodal Accelerated Recovery Trajectory Enhanced Recovery Task Force and Guidelines Committee have joined together to produce this guideline, written and approved by both societies. The combined ASCRS/SAGES panel worked together to develop the statements in this guideline and approved these final recommendations. Through this effort, the ASCRS and SAGES continue their dedication to ensuring high-quality perioperative patient care. Previous guidelines on perioperative care for colon1 and rectal2 surgery included studies identified up to January 2012 with significant literature published since then. The combined ASCRS/SAGES committee was created to define current best-quality care for enhanced recovery after colon and rectal surgery. This clinical practice guideline is based on the best available evidence. These guidelines are inclusive and not prescriptive. Their purpose is to provide information on which decisions can be made rather than to dictate a specific form of treatment. These guidelines are intended for the use of all practitioners, healthcare workers, and patients who desire information about the management of the conditions addressed by the topics covered in these guidelines. It should be recognized that these guidelines should not be deemed inclusive of all proper methods of care or exclusive of methods of care reasonably directed toward obtaining the same results. The ultimate judgment regarding the propriety of any specific procedure must be made by the physician in light of all of the circumstances presented by the individual patient. STATEMENT OF THE PROBLEM Contemporary colorectal surgery is often associated with long length of stay (8 days for open surgery and 5 days for laparoscopic surgery),3 high cost,3 and rates of surgical site infection approaching 20%.4 During the hospital stay for elective colorectal surgery, the incidence of perioperative nausea and vomiting (PONV) may be as high as 80% in patients with certain risk factors.5 After discharge from colorectal surgery, readmission rates have been noted as high as 35.4%.6 An enhanced recovery protocol (ERP) is a set of standardized perioperative procedures and practices that is applied to all patients undergoing a given elective surgery. In general, these protocols are not intended for emergent cases, but components of them certainly could apply to the emergent/urgent patient. Also known as fast-track protocols or enhanced recovery after surgery (ERAS)1 protocols, the content of these specific protocols may vary significantly, but all are designed as a means to improve patient outcomes. Outcomes of interest to patients and providers include freedom from nausea, freedom from pain at rest, early return of bowel function, improved wound healing, and early hospital discharge.7 Although numerous perioperative protocols currently exist, this clinical practice guideline will evaluate the strength of evidence in support of measures to improve patient recovery after elective colon and rectal resections. A 2011 Cochrane review found that ERPs were associated with a reduction in overall complications and length of stay when compared with conventional perioperative patient management.8 Subsequent studies have shown that ERPs are associated with reduced healthcare costs and improved patient satisfaction.4 ERPs are also associated with improved outcomes regardless of whether patients undergo laparoscopic or open surgery.9 Studies have also shown that ERPs cannot simply be implemented and forgotten but require a continued audit process in place to guide compliance and to continue to improve quality.10–13 There are many different preoperative, intraoperative, and postoperative components in a typical ERP, and it is difficult to identify which are the most beneficial components of the bundle of measures, because they are generally all implemented simultaneously. However, one retrospective review of 8 years of compliance with an ERP identified these items as the strongest predictors of shorter length of stay: no nasogastric tube, early mobilization, early oral nutrition (early discontinuance of intravenous fluids), early removal of epidural, early removal of and This clinical practice guideline will evaluate the evidence ERPs for colorectal surgery. of the SAGES and ASCRS Practice Guidelines Committee worked in of these guidelines from to final were approved by committee and These guidelines were a standardized for the of all of clinical practice which for of a review of the and of the of the of and of the The of specific of studies and of evidence for are available in the but all of the an of and the Cochrane of a of on and were from to and were to of the from the were also in certain and were given in these guidelines. After all of the were a of been identified for and of were for review and evidence with of the evidence based on of the by The final of was the of and by the American of Previous guidelines on perioperative care for colon1 and rectal2 surgery included studies identified up to January with significant literature published since The of and A of and discharge should be with the patient surgery. of based on discharge for patients undergoing colorectal surgery have been in an which that patients are for discharge when is of oral recovery of function, pain with oral to to no evidence of complications or and patient to the Although are studies that at the of regarding and discharge these are a of and have the of an ERP that discharge on hospital length of compliance with an ERP that patient and discharge been shown in and to be associated with length of stay and The to the discharge to for been as a of However, are between the when patients are discharge and with a to days of length of stay high ERP and on should be included in the of based on The of an is an risk for a length of stay after colorectal The of patient to improve of and hospital length of and hospital costs been in and as as a in is beneficial but a demonstrated that patient was most in the and studies have shown that by an of the site and patient was associated with improved postoperative of reduced rates of postoperative and improved patient regardless of and studies have the of an on is an of been shown to be the most of readmission after from to of an in which patients were in management and an enhanced recovery reduced overall from to and for from to a perioperative care been included in a and review of process measures to postoperative and A may be continued of based on high-quality should be to the of because it been shown to be and to improve of clinical have the of elective surgery. These studies have shown that of to of surgery is associated with and at the of surgery. The current practice guidelines of the and Society of support this should be surgery in of based on The use of should be with the purpose to by surgery and A Cochrane review in identified in and as to the or found in or The of the review was that was associated with a reduction in the length of hospital stay when compared with or in patients undergoing elective surgery. was not associated with or perioperative complications when compared with or studies were to because of a of A of studies patients no overall in length of stay all of the included when the of patients undergoing surgery, was a in of length of A of whether the of was and found that both and high of surgery improved length of stay when compared with However, when compared with or not a in the length of to the of complications regardless of the or on this most surgery may provide clinical as bowel oral bowel colorectal surgery is the and is associated with reduced of based on A for perioperative care in elective surgery that bowel should not be in surgery based on the it and a 2011 Cochrane no to in However, evidence regarding the of oral to should be Although to be no of in of a of with a reduction in surgical site infection and site with no in the of infection after elective colorectal These are with In a retrospective of a in the in was associated with overall surgical site and retrospective studies in different and a hospital a reduction in surgical site infection with the of to The Surgical a reduction in surgical site infection and a reduction in postoperative in patients who with patients who no bowel was as of a perioperative care bundle at a significant in surgical site infection was elective surgery may be for patients undergoing elective colorectal surgery with or significant of based on as of the of a been as a for postoperative to a surgical procedure with the to the postoperative and The of is were both and These studies were of to of these and on the of in patients who colorectal not The studies with patient evidence for the of on function, of length of and Studies on colorectal and surgery were in of measures, of the and compliance rates with these which the of and the to However, these studies support the of to improve or surgery. There were retrospective and and that in function, and of with at may have the most to with However, in the of or of in compliance with protocols, and these at postoperative studies no in postoperative rates and hospital length of stay with compared with or postoperative or have been should be as a of the enhanced care of based on ERPs are and require between many different to the care of the surgical patient. to all of these protocols are which include preoperative, intraoperative, and postoperative that care between all and for all The current of not been but all of the studies enhanced recovery conventional care have included as of the However, it is not the of standardized that to improved because a by improved outcomes for patients undergoing who were by enhanced recovery compared with a conventional care that included standardized protocol is The of standardized an ERP is not to outcomes. demonstrated in a that to protocol was high in the and but recovery at a of but length of stay was 5 of patients in that were on and that ERPs were to A collaborative from the Society that patients with protocol compliance length of stay and complications than patients with compliance all of the perioperative A clinical audit that compliance with an ERP was associated with shorter length of However, this not been an because a retrospective ERP compliance in clinical practice compared to a clinical the not any in length of or between the Surgical A bundle of measures should be in place to surgical site of based on A care bundle is a set of practices that have been to improve patient outcomes. In a reduction in surgical site from to after of a measures included a with oral of and of of the surgical with measures included use of a wound and use of a wound and measures included removal of the and of the with and perioperative of were also components of the significant was in and A review and studies that use of an surgical care bundle for patients undergoing colorectal surgery reduced the risk of in bundle in the care Although of the studies in this the care all included from a of and for measures that have been included in are a reduction in intravenous for high of and for 5 days vary between different protocols, and the to which a in difficult to A pain management should be and implemented the of of based on studies have demonstrated that is associated with return of bowel and shorter length of of the to is to as oral and rather than them on an The use of or when not and of or have been shown to improve postoperative and and of their that have been shown to surgical and clinical studies have shown that may the risk of one demonstrated in patients of in the after surgery, the risk of was not This on rates to be and and in patients for a days after surgery. demonstrated a risk of in patients undergoing but not elective colorectal surgery The evidence is and not support the of in patients with perioperative and have also been to improve and and postoperative but and may the and of to be of have also been shown to and improve and postoperative the risk of wound or However, are and with have shown in patients undergoing open and laparoscopic colorectal In that the with a been associated with length of stay compared with in laparoscopic colorectal surgery to provide than at the Although many a the of and to and is for open colorectal surgery, but not for use in laparoscopic colorectal surgery. based on Although is the patient or to pain in patients undergoing open colorectal the by not support a recovery in laparoscopic surgery. and have shown that no or may hospital discharge in laparoscopic surgery. This is to the incidence of and postoperative be in patients at high risk of in postoperative pain management could be patients with a high risk of to an is an of a of a of and been shown to provide than an of or combined with of can provide for long The of as or can be to improve and certain rates have been from to methods to the of the conventional of to identify the as and can be to the of and should be by for risk for postoperative of based on The incidence of postoperative nausea and vomiting (PONV) all of the patients in a care is patients with risk for may have an incidence of as high as hospital costs and patient of been shown to improve patient guideline risk of all patients undergoing and to and the most practice guideline from the not risk have been to identify patients at high risk for Although of and for the use of a protocol for all patients of because to be and A of elective surgical patients that the of a specific for not the incidence in However, a by the same in which risk was combined with a specific for a significant reduction in in all with an reduction in A significant reduction in been with this of risk with a specific in should be in all patients to of based on high-quality Although many have been to postoperative nausea, and the for it that is the best in of patients that a reduced the risk of in the to and that patients a high to for that use of the most on the of in A for patients to be high risk for is the of at of and at from that the of with is to in the of in to patients undergoing A of patients demonstrated that combined with than with and the use of In to A of patients that patients for and pain at Although have regarding associated with in an shown that of 8 of not to a significant when compared with to include the use of intravenous intravenous and There is evidence that the of intravenous with to a is to a with A of patients that the use of intravenous given surgery or in the care reduced the risk of nausea and it was not in given after the of There have been clinical the of as for in surgery, and a that the risk of nausea and vomiting is in patients who the of reduced in the of the use of and it a Although the included studies of and a of were the of evidence is in support of of should be to and of based on or can function, postoperative and hospital based on as or should be because a in the of between different studies the same the to a of have been and surgery have been and the bowel is from the not The by surgical to a reduction of in the of of should not to by not but in the of by complications as However, should not be and it should be or not by because is after a of not intravenous in patients after In these should be with after ensuring that the patient is on these a of of is to the from postoperative which is associated with and hospital should be as in patients undergoing colorectal surgery. of based on from studies in and from of that should be to to the risk of studies have an between the use of and an incidence of postoperative and in surgical In patients and in patients undergoing colorectal surgery associated with significant the use of is of based on intravenous based on measures of as or or based on of or can guide to whether to intravenous of have shown that postoperative and length of hospital in patients undergoing patients have been but have been noted to include patients with a of surgery years with evidence of of one or and However, it must be that the of in patients of the of the included studies was than is currently with a and in the of an ERP have to the same In patients with in perioperative and surgical care to have the demonstrated of The of the patients undergoing surgery colorectal surgery, and the in the of an shown a significant of complications and in patients with risk the of are in the of of the and postoperative of use of in the and perioperative care. can be in at or at when An cannot be because a studies have compared different of These studies on the of different intravenous to with with Their that patients with with than patients with with and that postoperative complications or length of hospital stay were from in patients have about the use of because of the risk of the for and However, and retrospective to these in surgical It is to use rather than in surgical patients at risk of or with Surgical A surgical should be the expertise is available and of based on high-quality There is high-quality evidence in cases, when by laparoscopic of colorectal conditions is beneficial compared with open surgery. of patients with colon the Colon from and the Colon or from the both to be to open in of outcomes return of bowel function, postoperative and shorter hospital of have shown reduced perioperative wound and laparoscopic compared with open that patients undergoing have to reduced use of and improved of early that laparoscopic not provide the of in rates in colon from of rectal are and also reduced and shorter and length of The in these are with the Surgical and the as as The evidence been in high-quality Cochrane and of laparoscopic in colon and in rectal These studies support the of of the early have that outcomes may be with the laparoscopic for rectal clinical to that was to open surgery in a of of these for in of and to the are available from these the outcomes are from have shown that outcomes are for laparoscopic of rectal and outcomes are to open In of colon and rectal with years of rates of and overall of have also about the for but and studies have often shown to be associated with or overall to reduced length of stay and reduced The is the of with an ERP, as demonstrated in the Multimodal The use of and nasogastric for colorectal surgery should be of based on should not be in colorectal surgery and should be for patients who develop postoperative to have demonstrated that patients who not nasogastric in the postoperative have no in nausea, to return of bowel function, or length of stay when compared with patients who nasogastric who not nasogastric also oral days than patients who nasogastric that nasogastric may nutrition in the postoperative the use of nasogastric was associated with a risk of associated are no to support the use of to identify and have been in all have demonstrated no significant in or a of postoperative complications in patients who of published studies no to in patients with or colorectal The of the in to the not to the use of patients with or colorectal who for the have rates of and complications when compared with patients in which a was not of the that may be beneficial for a clinical of patients with rectal After Rectal for Rectal that the use of after rectal not any to the use of also been associated with and as as and patient is associated with shorter length of of based on of include and and The associated with can be reduced with enhanced recovery for colorectal surgery, of early from any at all to 8 by postoperative in ERPs compared with conventional In with from to and was a significant of discharge in most but not Although is associated with shorter hospital studies the of specific to compared with early A review identified 8 in and in surgery, of the studies were in the of an ERP, and overall was There was significant between the different of the 5 studies complications found any and of studies a in length of stay in of the The review that is evidence to guide on best practices to and improve to postoperative after a of with on outcomes. patients to care or a specific with and found no in the of or length of In patients on to on than who not the were no in length of function, or open surgery patients to early early or in the early the hospital but was no significant in A the of to after colorectal surgery an ERP found when of and were was no on hospital stay or complications in the recovery of The that to with were not in an a in to patients colon surgery to a and or to conventional care. The shorter hospital stay and shorter to There were no in or between the should be a after elective colorectal surgery. of based on and demonstrated that early recovery and the hospital length of The of and were also with early in open surgery no significant in any rates of nasogastric length of length of or overall studies demonstrated the in laparoscopic surgery with an The to of early was identified as the in open surgery by colorectal and use of laparoscopic surgery were associated with early postoperative on the both the guidelines and guidelines early in patients undergoing enhanced However, with early oral providers must be that the risk of vomiting for to after colorectal surgery is in in and may be associated with a reduction in the length of hospital of based on high-quality after elective colorectal surgery was as a for and in have been and have been that to postoperative care was associated with to and bowel than postoperative with no significant in postoperative or a shorter hospital length of no significant on length of review an of on bowel of the studies as as of and the A Cochrane review of studies and surgery patients found evidence that who after an return of bowel and were to and have bowel than who not There was a in hospital length of stay but no in complications or overall of care between who or not However, the studies were generally of and surgery and were not to their are the risk and the guidelines for enhanced recovery after elective colorectal surgery after is to recovery after open colorectal surgery, use in surgery of based on The of in open surgery have been generally and to recovery of with and compared with and a shorter hospital length of stay in the compared with for patients undergoing open In the by the of the in hospital and reduced postoperative was in the of an A retrospective review of patients that patients who not the of also the of shorter to hospital and reduction in postoperative compared with not a significant with that was in patients after open surgery compared with the have also the of the studies were in that were no of after laparoscopic A Cochrane review of studies that was than in and and that was and in postoperative but the studies were in open and no ERP was noted in In laparoscopic colorectal surgery, the of are from studies results. studies found return of and shorter length of stay in the found a incidence of postoperative but no in length of hospital stay with or after laparoscopic The collaborative with rates of postoperative in laparoscopic patients who but no significant in length of A of 5 laparoscopic surgery studies by a risk reduction in the of postoperative with no on length of hospital stay or studies have that no in the rates of postoperative or length of stay to laparoscopic colorectal surgery with an to the that the of to an ERP will to in clinical outcomes in patients after open or but not have a after laparoscopic colorectal It may be difficult to the of in laparoscopic surgery in the of an A retrospective review of patients undergoing laparoscopic colorectal surgery not to patient outcomes with a was in this In retrospective of open and laparoscopic were should be in the early postoperative after recovery of based on and different in the postoperative of the of on clinical intravenous should be in the early postoperative recovery and of as after should be when deemed postoperative should be and to It is to because the from studies in patients that of patients are when intravenous are given based on clinical of Although also in the postoperative because clinical and the of of intravenous studies and in surgical patients on surgical are by should be by the and with of after ensuring that the patient is should be of elective or rectal when not a of of based on is in colorectal surgery for and of who undergo for days have the risk of a postoperative infection patients who develop a an will develop a that to hospital stay and risk of studies have the of removal on the postoperative as of an In a of patients who a risk of was with early In of with of patients with on the postoperative by in all A early removal of removal of at the of of after colon and rectal surgery found that was not associated with early and rectal the risk of of This was not to in rates of patients with after or surgery a of patients to early removal compared with removal after of significant in rates between early and removal were identified in this A the of on early postoperative recovery a retrospective of a ERP The of after early removal in patients who elective colorectal surgery was with were in the early postoperative and because of these patients pain on a In this rates of were not different between patients with and It is that may be colon resections. A of patients who elective colon on an ERP it was for management or to and it was at the of the In this was the most the of was and was in of the in of patients and in should be of rectal resections. of based on on the and of to the may the risk of postoperative retrospective studies have identified a risk of after early removal in rectal retrospective studies have An removal after rectal on and 5 found that the rates of were and This was not to identify in with patients compared and 5 removal after rectal and found that rates of were after removal rates of were in the removal A the rectal demonstrated rates of and for and 5 removal this not because of an However, the of in the was to published rates for early removal after In this rates of were with early removal These that patients who undergo rectal surgery may have removal on the postoperative as patients who undergo a who undergo rectal are at an risk of with of removal should be for patients with and

Species of Clostridium bacteria are notable for their ability to lyse tumor cells growing in hypoxic environments. We show that an attenuated strain of Clostridium novyi (C. novyi-NT) induces a microscopically precise, tumor-localized response in a rat orthotopic brain tumor model after intratumoral injection. It is well known, however, that experimental models often do not reliably predict the responses of human patients to therapeutic agents. We therefore used naturally occurring canine tumors as a translational bridge to human trials. Canine tumors are more like those of humans because they occur in animals with heterogeneous genetic backgrounds, are of host origin, and are due to spontaneous rather than engineered mutations. We found that intratumoral injection of C. novyi-NT spores was well tolerated in companion dogs bearing spontaneous solid tumors, with the most common toxicities being the expected symptoms associated with bacterial infections. Objective responses were observed in 6 of 16 dogs (37.5%), with three complete and three partial responses. On the basis of these encouraging results, we treated a human patient who had an advanced leiomyosarcoma with an intratumoral injection of C. novyi-NT spores. This treatment reduced the tumor within and surrounding the bone. Together, these results show that C. novyi-NT can precisely eradicate neoplastic tissues and suggest that further clinical trials of this agent in selected patients are warranted.

BACKGROUND: Evaluation and interpretation of the literature on obstructive sleep apnea (OSA) allows for consolidation and determination of the key factors important for clinical management of the adult OSA patient. Toward this goal, an international collaborative of multidisciplinary experts in sleep apnea evaluation and treatment have produced the International Consensus statement on Obstructive Sleep Apnea (ICS:OSA). METHODS: Using previously defined methodology, focal topics in OSA were assigned as literature review (LR), evidence-based review (EBR), or evidence-based review with recommendations (EBR-R) formats. Each topic incorporated the available and relevant evidence which was summarized and graded on study quality. Each topic and section underwent iterative review and the ICS:OSA was created and reviewed by all authors for consensus. RESULTS: The ICS:OSA addresses OSA syndrome definitions, pathophysiology, epidemiology, risk factors for disease, screening methods, diagnostic testing types, multiple treatment modalities, and effects of OSA treatment on multiple OSA-associated comorbidities. Specific focus on outcomes with positive airway pressure (PAP) and surgical treatments were evaluated. CONCLUSION: This review of the literature consolidates the available knowledge and identifies the limitations of the current evidence on OSA. This effort aims to create a resource for OSA evidence-based practice and identify future research needs. Knowledge gaps and research opportunities include improving the metrics of OSA disease, determining the optimal OSA screening paradigms, developing strategies for PAP adherence and longitudinal care, enhancing selection of PAP alternatives and surgery, understanding health risk outcomes, and translating evidence into individualized approaches to therapy.

•The majority of patients (80%) with mTNBC in the ASCENT study with available data had high/medium tumor Trop-2 expression.•Survival outcomes and ORRs were numerically higher in SG- versus TPC-treated patients with high/medium Trop-2 expression.•Benefit of SG in patients with high/medium Trop-2 expression was similar to that of overall primary efficacy population.•The small number of patients with low Trop-2 expression prevents definitive conclusions on benefit of SG in this subgroup.•Benefit of SG over TPC was also similar regardless of germline BRCA1/2 mutation status. BackgroundThe pivotal phase III ASCENT trial demonstrated improved survival outcomes associated with sacituzumab govitecan (SG), an anti-trophoblast cell-surface antigen 2 (anti-Trop-2) antibody-drug conjugate linked with the topoisomerase-inhibitor SN-38, over single-agent chemotherapy treatment of physician’s choice (TPC) in previously treated metastatic triple-negative breast cancer (mTNBC). This prespecified, exploratory biomarker analysis from the ASCENT trial evaluates the association between tumor Trop-2 expression and germline BRCA1/2 mutation status with clinical outcomes.Patients and methodsPatients with mTNBC refractory to or progressing after two or more prior chemotherapies, with one or more in the metastatic setting, were randomized to receive SG (10 mg/kg intravenously days 1 and 8, every 21 days) or TPC (capecitabine, eribulin, vinorelbine, or gemcitabine) until disease progression/unacceptable toxicity. Biopsy or surgical specimens were collected at study entry to determine Trop-2 expression level using a validated immunohistochemistry assay and histochemical scoring. Germline BRCA1/2 mutation status was collected at baseline.ResultsOf 468 assessable patients, 290 had Trop-2 expression data [64% (n = 151 SG) versus 60% (n = 139 TPC)] and 292 had known BRCA1/2 mutation status [63% (n = 149 SG) versus 61% (n = 143 TPC)]. Median progression-free survival in SG- versus TPC-treated patients was 6.9, 5.6, and 2.7 months versus 2.5, 2.2, and 1.6 months for high, medium, and low Trop-2 expression, respectively. Median overall survival (14.2, 14.9, and 9.3 months versus 6.9, 6.9, and 7.6 months) and objective response rates (44%, 38%, and 22% versus 1%, 11%, and 6%) were numerically higher with SG versus TPC in patients with high, medium, and low Trop-2 expression, respectively. Efficacy outcomes were numerically higher with SG versus TPC in patients with and without germline BRCA1/2 mutations.ConclusionsSG benefits patients with previously treated mTNBC expressing high/medium Trop-2 compared with standard-of-care chemotherapy and regardless of germline BRCA1/2 mutation status. The small number of patients with low Trop-2 expression precludes definitive conclusions on the benefit of SG in this subgroup. The pivotal phase III ASCENT trial demonstrated improved survival outcomes associated with sacituzumab govitecan (SG), an anti-trophoblast cell-surface antigen 2 (anti-Trop-2) antibody-drug conjugate linked with the topoisomerase-inhibitor SN-38, over single-agent chemotherapy treatment of physician’s choice (TPC) in previously treated metastatic triple-negative breast cancer (mTNBC). This prespecified, exploratory biomarker analysis from the ASCENT trial evaluates the association between tumor Trop-2 expression and germline BRCA1/2 mutation status with clinical outcomes. Patients with mTNBC refractory to or progressing after two or more prior chemotherapies, with one or more in the metastatic setting, were randomized to receive SG (10 mg/kg intravenously days 1 and 8, every 21 days) or TPC (capecitabine, eribulin, vinorelbine, or gemcitabine) until disease progression/unacceptable toxicity. Biopsy or surgical specimens were collected at study entry to determine Trop-2 expression level using a validated immunohistochemistry assay and histochemical scoring. Germline BRCA1/2 mutation status was collected at baseline. Of 468 assessable patients, 290 had Trop-2 expression data [64% (n = 151 SG) versus 60% (n = 139 TPC)] and 292 had known BRCA1/2 mutation status [63% (n = 149 SG) versus 61% (n = 143 TPC)]. Median progression-free survival in SG- versus TPC-treated patients was 6.9, 5.6, and 2.7 months versus 2.5, 2.2, and 1.6 months for high, medium, and low Trop-2 expression, respectively. Median overall survival (14.2, 14.9, and 9.3 months versus 6.9, 6.9, and 7.6 months) and objective response rates (44%, 38%, and 22% versus 1%, 11%, and 6%) were numerically higher with SG versus TPC in patients with high, medium, and low Trop-2 expression, respectively. Efficacy outcomes were numerically higher with SG versus TPC in patients with and without germline BRCA1/2 mutations. SG benefits patients with previously treated mTNBC expressing high/medium Trop-2 compared with standard-of-care chemotherapy and regardless of germline BRCA1/2 mutation status. The small number of patients with low Trop-2 expression precludes definitive conclusions on the benefit of SG in this subgroup.

While in-vitro fertilization (IVF) was initially developed in women with tubal factor infertility, recent clinical studies have suggested that the presence of hydrosalpinges lowers implantation and pregnancy rates. We postulated that these hydrosalpinges cause impaired endometrial receptivity. A total of 103 women with hydrosalpinges were prospectively evaluated, and compared with 55 infertile and 44 fertile controls. All women had endometrial biopsies during the window of implantation, analysed by conventional histological criteria, and also stained for three integrin markers of endometrial receptivity (alpha1beta1, alpha4beta1 and alpha vbeta3). Women with hydrosalpinges (cases) expressed significantly less of the alpha vbeta3 integrin compared with controls. There was no difference in expression of alpha1beta1 or alpha4beta1 among groups. A significantly greater number of cases had out of phase histology and missing alpha vbeta3 (type I defects) and absent integrin expression despite normal histological maturation (type II) defects, compared with controls. Of 20 women with impaired endometrial receptivity who were also biopsied after hydrosalpinx surgery, 70% demonstrated increased alpha vbeta3 expression. Seventy-seven percent of type I and 57% of type II defects were corrected postoperatively. Using markers of endometrial receptivity, this study demonstrates that inflammatory hydrosalpinges have an adverse effect on endometrial receptivity, which in some cases may be overcome by surgical treatment of the hydrosalpinx.

BACKGROUND: Polyclonal convalescent plasma may be obtained from donors who have recovered from coronavirus disease 2019 (Covid-19). The efficacy of this plasma in preventing serious complications in outpatients with recent-onset Covid-19 is uncertain. METHODS: In this multicenter, double-blind, randomized, controlled trial, we evaluated the efficacy and safety of Covid-19 convalescent plasma, as compared with control plasma, in symptomatic adults (≥18 years of age) who had tested positive for severe acute respiratory syndrome coronavirus 2, regardless of their risk factors for disease progression or vaccination status. Participants were enrolled within 8 days after symptom onset and received a transfusion within 1 day after randomization. The primary outcome was Covid-19-related hospitalization within 28 days after transfusion. RESULTS: Participants were enrolled from June 3, 2020, through October 1, 2021. A total of 1225 participants underwent randomization, and 1181 received a transfusion. In the prespecified modified intention-to-treat analysis that included only participants who received a transfusion, the primary outcome occurred in 17 of 592 participants (2.9%) who received convalescent plasma and 37 of 589 participants (6.3%) who received control plasma (absolute risk reduction, 3.4 percentage points; 95% confidence interval, 1.0 to 5.8; P = 0.005), which corresponded to a relative risk reduction of 54%. Evidence of efficacy in vaccinated participants cannot be inferred from these data because 53 of the 54 participants with Covid-19 who were hospitalized were unvaccinated and 1 participant was partially vaccinated. A total of 16 grade 3 or 4 adverse events (7 in the convalescent-plasma group and 9 in the control-plasma group) occurred in participants who were not hospitalized. CONCLUSIONS: In participants with Covid-19, most of whom were unvaccinated, the administration of convalescent plasma within 9 days after the onset of symptoms reduced the risk of disease progression leading to hospitalization. (Funded by the Department of Defense and others; CSSC-004 ClinicalTrials.gov number, NCT04373460.).

The Na+,K(+)-ATPase alpha subunit has three known isoforms, alpha 1, alpha 2 and alpha 3, each encoded by a separate gene. This study was undertaken to determine the functional status of a fourth human alpha-like gene, ATP1AL2. Partial genomic sequence analysis revealed regions exhibiting sequence similarity with exons 3-6 of the Na+,K(+)-ATPase alpha isoform genes. ATP1AL2 cDNAs spanning the coding sequence of a novel P-type ATPase alpha subunit were isolated from a rat testis library. The predicted polypeptide is 1028 amino acids long and exhibits 76-78% identity with the rat Na+,K(+)-ATPase alpha 1, alpha 2 and alpha 3 isoforms, indicating that ATP1AL2 may encode a fourth Na+,K(+)-ATPase alpha isoform. A 3.9-kb mRNA is expressed abundantly in human and rat testis.

PURPOSE: endothelial progenitor cells (EPCs) and copper-dependent pathways, model the tumor microenvironment. We hypothesized that copper depletion using tetrathiomolybdate would reduce EPCs in high risk for patients with breast cancer who have relapsed. We investigated the effect of tetrathiomolybdate on the tumor microenvironment in preclinical models. EXPERIMENTAL DESIGN: Patients with stage II triple-negative breast cancer (TNBC), stage III and stage IV without any evidence of disease (NED), received oral tetrathiomolybdate to maintain ceruloplasmin (Cp) between 8 and 17 mg/dL for 2 years or until relapse. Endpoints were effect on EPCs and other biomarkers, safety, event-free (EFS), and overall survival (OS). For laboratory studies, MDA-LM2-luciferase cells were implanted into CB17-SCID mice and treated with tetrathiomolybdate or water. Tumor progression was quantified by bioluminescence imaging (BLI), copper depletion status by Cp oxidase levels, lysyl oxidase (LOX) activity by ELISA, and collagen deposition. RESULTS: Seventy-five patients enrolled; 51 patients completed 2 years (1,396 cycles). Most common grade 3/4 toxicity was neutropenia (3.7%). Lower Cp levels correlated with reduced EPCs (P = 0.002) and LOXL-2 (P < 0.001). Two-year EFS for patients with stage II-III and stage IV NED was 91% and 67%, respectively. For patients with TNBC, EFS was 90% (adjuvant patients) and 69% (stage IV NED patients) at a median follow-up of 6.3 years, respectively. In preclinical models, tetrathiomolybdate decreased metastases to lungs (P = 0.04), LOX activity (P = 0.03), and collagen crosslinking (P = 0.012). CONCLUSIONS: Tetrathiomolybdate is safe, well tolerated, and affects copper-dependent components of the tumor microenvironment. Biomarker-driven clinical trials in high risk for patients with recurrent breast cancer are warranted. Clin Cancer Res; 23(3); 666-76. ©2016 AACR.

Perusal of advertisements for oral hypoglycemic agents in this and many other medical journals shows an emphasis on the absolute reduction in HbA1c (A1C). Evidence linking reduction in A1C in diabetic patients to prevention of macrovascular events is weak. However, epidemiological evidence suggests that the risk for cardiovascular disease in this group may actually begin at A1C concentrations well within the normal range (1). This association has led a number of professional organizations to recommend that A1C levels be brought to levels <6.5% (2). An important question to be asked is whether the reduction in A1C differs at lower versus higher baseline levels of A1C. Expectations for the degree of reduction to be attained with a given agent may be excessively optimistic when a person’s initial A1C is already <7.5–8.0%. Some of the deliberations of policy advisory groups are available. The European Agency for the Evaluation of Medicinal Products has published guidelines for diabetes product evaluation suggesting that the change in A1C be utilized as “primary analysis” of drug efficacy, although allowing the baseline A1C to be included as a covariate (3). A meeting of the Center for Drug Evaluation and Research Endocrinologic and Metabolic Drugs Advisory Committee of the U.S. Food and Drug Administration concluded that A1C should be the primary outcome variable for diabetes drugs and suggested an absolute decrease of 0.7% as the minimal acceptable level for approval (4). This may prevent acceptance of agents that are as effective as existing treatments at A1C levels …

BACKGROUND: Despite the development of evidence-based pneumonia guidelines, limited data exist on the most effective means to implement guideline recommendations into clinical practice. OBJECTIVE: To compare the effectiveness and safety of 3 guideline implementation strategies. DESIGN: Cluster-randomized, controlled trial. SETTING: 32 emergency departments in Pennsylvania and Connecticut. PATIENTS: 3219 patients with a clinical and radiographic diagnosis of pneumonia. INTERVENTIONS: The authors implemented a project-developed guideline for the initial site of treatment based on the Pneumonia Severity Index and performance of evidence-based processes of care at the emergency department level. Guideline implementation strategies were defined as low (n = 8), moderate (n = 12), and high intensity (n = 12). MEASUREMENTS: Effectiveness outcomes were the rate at which low-risk patients were treated on an outpatient basis and the performance of recommended processes of care. Safety outcomes included death, subsequent hospitalization for outpatients, and medical complications for inpatients. RESULTS: More low-risk patients (n = 1901) were treated as outpatients in the moderate-intensity and high-intensity groups than in the low-intensity group (high-intensity group, 61.9%; moderate-intensity group, 61.0%; low-intensity group, 37.5%; P = 0.004). More outpatients (n = 1125) in the high-intensity group received all 4 recommended processes of care (high-intensity group, 60.9%; moderate-intensity group, 28.3%; low-intensity group, 25.3%; P < 0.001); more inpatients (n = 2076) in the high-intensity group received all 4 recommended processes of care (high-intensity group, 44.3%; moderate-intensity group, 30.1%; low-intensity group, 23.0%; P < 0.001). No statistically significant differences in safety outcomes were observed across interventions. LIMITATIONS: Twenty percent of eligible patients were not enrolled, and data on effectiveness outcomes were not collected before the trial. CONCLUSIONS: Both moderate-intensity and high-intensity guideline implementation strategies safely increased the proportion of low-risk patients with pneumonia who were treated as outpatients. The high-intensity strategy was most effective for increasing the performance of the recommended processes of care for outpatients and inpatients.

Opioids cause constipation by binding to specific opioid receptors in the enteric and central nervous systems. First-pass glucuronidation limits systemic bioavailability of oral naloxone. This study was designed to determine if oral naloxone could reverse opioid-induced constipation without precipitating abstinence or recrudescence of pain in opioid-dependent individuals. Concentrations of unmetabolized and total naloxone, including naloxone glucuronide, were measured by radioimmunoassay. A dose-related increase in symptoms of laxation resulted in all three opioid-dependent patients studied that paralleled the increase in active and total naloxone plasma levels. Withdrawal symptoms occurred with plasma naloxone area under the plasma concentration-time curves above 550 ng.min/ml and with dosing intervals less than 3 hours. Peak plasma levels did not predict withdrawal. Oral naloxone ameliorates opioid-induced constipation in opioid-dependent persons. Titration of dose to a maximum of 12 mg at least 6 hours apart may be needed to avoid adverse reactions.

Economies are fueled by energy produced in excess of the amount required to drive the energy production process. Therefore any successful society’s energy resources must be both abundant and exploitable with a high ratio of energy return on energy invested (EROI). Unfortunately most of the data kept on costs of oil and gas operations are in monetary, not energy, terms. Fortunately we can convert monetary values into approximate energy values by deriving energy intensities for monetary transactions from those few nations that keep both sets of data. We provide a preliminary assessment of EROI for the world’s most important fuels, oil and gas, based on time series of global production and estimates of energy inputs derived from monetary expenditures for all publicly traded oil and gas companies and estimates of energy intensities of those expenditures. We estimate that EROI at the wellhead was roughly 26:1 in 1992, increased to 35:1 in 1999, and then decreased to 18:1 in 2006. These trends imply that global supplies of petroleum available to do economic work are considerably less than estimates of gross reserves and that EROI is declining over time and with increased annual drilling levels. Our global estimates of EROI have a pattern similar to, but somewhat higher than, the United States, which has better data on energy costs but a more depleted resource base.

Crossed immunoelectrophoresis of Triton X-100 solubilized proteins from normal and abnormal platelets was performed with rabbit antibodies raised against normal platelets. In Bernard-Soulier platelets protein 13 was not detected, and neither the amphiphilic (probably GP Ib) nor the hydrophilic (glycocalicin) glycocalicin-related proteins were seen when monospecific antiglycocalicin antiserum was used. The most prominent precipitate, 16, and platelet fibrinogen, 24 were not detected in platelets of two patients with type I thrombasthenia, whereas in one patient with type II thrombasthenia fibrinogen was clearly detected, but the amount of protein 16 remained severely reduced. Protein 16 was heavily labeled after lactoperoxidase-catalyzed (125)I iodination of normal platelets, and was precipitated by IgG-L, an alloantibody from a polytransfused thrombasthenic patient. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) or protein 16 cut out from immunoplates showed two (125)I-labeled glycoprotein bands, which migrate as GP IIb and GP IIIa. SDS-PAGE of (125)I-labeled type I thrombasthenic platelets showed no periodic acid-Schiff bands or peaks of radioactivity in the GP IIb and GP IIIa regions, whereas in the GP I region both the periodic acid-Schiff band intensity and the radiolabeling were within the normal range. Autoradiography after crossed immunoelectrophoresis of iodinated thrombasthenic platelets showed that the bulk of radioactivity was bound to protein 17. This glycoprotein, which was also present in normal and Bernard-Soulier platelets, migrates in the GP I region on SDS-PAGE. Thus, the bulk of radioactivity observed in the GP I region after SDS-PAGE is associated with protein 17 and not with glycocalicin.

The aim of this study was to determine the potential of screening breast ultrasound to improve breast cancer detection in women with mammographically normal, but dense breasts. Six Connecticut radiology practices with 12 total sites participated in a retrospective chart review. The total number of screening mammograms, screening ultrasounds broken down by BIRADS (Breast Imaging Reporting and Data System) codes, and the number of positive and negative biopsies were collected from November 2009 through November 2010. Demographic data on the patients with positive biopsies as well as cancer staging were also collected. Sensitivity, Specificity, Positive Predictive Value, and Negative Predictive Value were calculated. A total of 72,030 screening mammograms and 8,647 screening ultrasounds were performed at the research sites during the study period. Relevant research indicates that 41% of the female population has dense breasts. In this study, 12% (8,647/72,030) underwent follow-up breast ultrasound screening. A total of 86% (7,451/8,647) of the ultrasounds were BIRADS 1 or 2, 9% (767/8,647) were BIRADS 3, 5% (429/8,647) were BIRADS 4 or 5. Of those 429 recommended to undergo biopsy 418 were performed and 28 cancers were found. There was one false negative. Screening breast ultrasound in women with mammographically normal, but dense breasts has a Positive Predictive Value (PPV) of 6.7% (28/418), Negative Predictive Value (NPV) of 99.9% (7,450/7,451), sensitivity of 96.6% (28/29), and a specificity of 94.9% (7,450/7,851). Screening ultrasound had an additional yield of 3.25 per 1,000 cancers in women with dense breasts and normal mammograms and no additional risk factors. As with all screening tests, time, cost, and false positive risk must be considered.

If the real area of contact between surfaces is determined by ideal plastic flow of the microcontacts, then the proportionality between the area of contact and the load follows immediately. If the deformation mode is elastic, or elastic-plastic, or plastic with work-hardening, which will be the usual cases, then the proportionality is harder to explain. However, by considering the statistical distribution of heights of the surface asperities, it can be shown that the average size of a microcontact is almost constant, independent of load; consequently, the fact that the contact pressure at a single micro-contact may vary with contact size becomes irrelevant. If the real origin of the laws of friction is in the statistics of surface roughness and not in a particular mode of deformation, the applicability of the Bowden and Tabor theory of friction to plastics and other nonmetals becomes more readily understandable.