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Recurrent hypoglycemia leads to impaired awareness of hypoglycemia where the blood glucose threshold that elicits the counterregulatory response is lowered. Hypoglycemia‐induced oxidative stress is hypothesized to contribute to impaired awareness of hypoglycemia development and hypoglycemia‐associated autonomic failure. Our group conducted a randomized, double‐blinded, placebo‐controlled, crossover study in healthy individuals undergoing experimentally induced recurrent hypoglycemia to evaluate the impact of intravenous N‐acetylcysteine (NAC) during experimental hypoglycemia to preserve the counterregulatory response to subsequent hypoglycemia. The work presented herein aimed to characterize the NAC pharmacokinetics and its effects on oxidative stress. Whole blood and plasma samples were collected at specified time points during separate NAC and placebo infusions from 10 healthy volunteers. Samples were analyzed for NAC, cysteine, and glutathione (GSH) concentrations. A 2‐compartment population NAC pharmacokinetic model was developed. Estimates for central compartment clearance and volume of distribution were 19.8 L/h, and 12.2 L, respectively, for a 70‐kg person. Peripheral compartment clearance and volume of distribution estimates were 34.9 L/h and 13.1 L, respectively, for a 70‐kg person. The PK parameters estimated here were different from those reported in the literature, suggesting a higher NAC clearance during hypoglycemic episodes. NAC leads to a significant increase in circulating cysteine concentration in a NAC concentration‐dependent manner, suggesting rapid biotransformation. A transient decrease in plasma GSH was observed, supporting the hypothesis that NAC can act as a reducing agent displacing glutathione from the disulfide bond allowing for increased clearance and/or distribution of GSH.

Background: Rural surgeons operate in an environment significantly different from that of their colleagues, and as such they face unique challenges. We hypothesized the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) research agenda (as identified in the results of the 2014 Delphi study) will differ in its priorities from those identified by rural surgeons. We aimed to pilot a study in Washington state that could be replicated in other areas of the USA and the world. Methods: We identified general surgeons working at rural critical access hospitals in the state of Washington. We then conducted virtual, semi-structured interviews and followed up with surveys and site visits. The survey included the 2014 SAGES Delphi-ranked research priorities. We asked rural surgeons to rank their top 5 of these 40 priorities and to detail any additional which were not on the list. Results: We contacted 79 surgeons with a 30% response rate. We conducted 25 semi-structured interviews and received 18 completed follow-up surveys. These interviews were followed by site visits at 4 of the 23 sites. Of the original Delphi research priorities, those most cited by rural surgeons were #8 (“What is the best method for incorporating new techniques and technology for surgeons of variable levels of experience or training?”) and #1 (“How do we best train, assess, and maintain proficiency of surgeons and surgical trainees in flexible endoscopy, laparoscopy, and open surgery?”). Four surgeons included the last SAGES priority (#40 “Is quality of life improved after ventral hernia repair?”) among their top 5. Conclusion: This study suggests that although rural surgeons’ research priorities align with the published SAGES Delphi survey, these surgeons rank the priorities differently. This may be because the predominant study population of the Delphi is SAGES membership who work in urban and academic centers. Plans for future SAGES Delphi survey could capture these unique priorities by intentional involvement of rural and community surgeons.

When COVID-19 curtailed elective surgeries, our college transitioned to a virtual platform. “Benched” surgeons statewide engaged students online. Third-year students who had completed 2/3 of a longitudinal integrated clerkship (LIC) studied online modules on topics germane to surgery for 1 week. Core entrustable professional activities (EPAs) for entering residency were the backbone of lessons/assignments/assessments. Surgeons coached students around EPAs. Fifty-eight students in consistent small groups, spent 2 hours/day for 4 days with the same pair of surgeon coaches. Off-line, students created a unique hypothetical case/day, practiced and peer-reviewed EPAs. Online, coaches posed scenarios to drill EPAs. Pre/during/post assessments demonstrated progressive proficiency. High level of engagement resulted in 100% attendance and ease of recruitment/retention of faculty. Although variability in students’ clinical settings was high, a virtual week had aided in leveling the learning environment. Prior experience with 2/3 of their total surgery exposure in the LIC allowed for a smooth transition to virtual.

OBJECTIVE--We tested the hypotheses that human brain glycogen is mobilized during hypoglycemia and its content increases above normal levels ('supercompensates') after hypoglycemia. RESEARCH DESIGN AND METHODS--We utilized in vivo [sup.13]C nuclear magnetic resonance spectroscopy in conjunction with intravenous infusions of [[sup.13]C]glucose in healthy volunteers to measure brain glycogen metabolism during and after euglycemic and hypoglycemic clamps. RESULTS--After an overnight intravenous infusion of 99% enriched [1-[sup.13]C]glucose to prelabel glycogen, the rate of label wash-out from [1-[sup.13]C]glycogen was higher (0.12 [+ or -] 0.05 vs. 0.03 [+ or -] 0.06 [micro]mol x [g.sup.-1] x [h.sup.-1], means [+ or -] SD, P < 0.02, n = 5) during a 2-h hyperinsulinemic-hypoglycemic clamp (glucose concentration 57.2 [+ or -] 9.7 mg/dl) than during a hyperinsulinemic-euglycemic clamp (95.3 [+ or -] 3.3 mg/dl), indicating mobilization of glucose units from glycogen during moderate hypoglycemia. Five additional healthy volunteers received intravenous 25-50% enriched [1-[sup.13]C]glucose over 22-54 h after undergoing hyperinsulinemic-euglycemic (glucose concentration 92.4 [+ or -] 2.3 mg/dl) and hyperinsulinemic-hypoglycemic (52.9 [+ or -] 4.8 mg/dl) clamps separated by at least 1 month. Levels of newly synthesized glycogen measured from 4 to 80 h were higher after hypoglycemia than after euglycemia (P [less than or equal to] 0.01 for each subject), indicating increased brain glycogen synthesis after moderate hypoglycemia. CONCLUSIONS--These data indicate that brain glycogen supports energy metabolism when glucose supply from the blood is inadequate and that its levels rebound to levels higher than normal after a single episode of moderate hypoglycemia in humans., Glucose is the primary fuel for the adult brain. During euglycemia and hyperglycemia, the brain receives more glucose from the blood than it utilizes and normal metabolism can be maintained. [...]

OBJECTIVE--Hemipancreatectomy (HPx) for the purpose of organ donation has been associated with a 25% risk of developing abnormal glucose tolerance or diabetes in the year after surgery. Since 1997, the [...]

Abstract:"Neighborhood effects" research has rarely probed how geography influences job success among self-employed individuals in emerging markets. This article explores why two different sub-populations of food vendors in the Nang Loeng neighborhood of Bangkok experience divergent outcomes, using the causal frame of "neighborhood mechanisms." Ultimately, geographically based differences in social exchanges, location choices, and regulatory enforcement matter. Specifically, vendors suffer economically where social exchange is non-reciprocal, where location choice is non-economic, and where regulation is variable and volatile. The spatial landscape, then, has an important place in economic development literature.

Background and Aim. Previous studies have reported 63% of primary inguinal hernia patients present with apparent enlargement of the ilioinguinal nerve beyond the inguinal ring. This may be due to hernia-related pressure on the canal portion of the ilioinguinal nerve, a form of compression neuropathy. The ilioinguinal nerve of 30 patients was resected near the external inguinal ring during herniorrhaphy and histologically characterized to investigate the underlying cause of the size discrepancy. Methods. 30 male patients with primary inguinal hernias undergoing primary inguinal herniorrhaphy were prospectively recruited for ilioinguinal nerve resection and evaluation. Three samples of the resected ilioinguinal nerve (proximal, canal, and distal) were evaluated using Masson’s trichrome stain to measure fascicle and total nerve cross-sectional area and detect changes in collagen. Results. The fascicle cross-sectional area in the canal segment was significantly decreased compared to the proximal control with a large effect size observed (p=0.016,η2 =0.16). There was no significant difference in the nerve cross-sectional area between locations, but there was a moderate to large effect size observed between locations (p=0.165,η2 =0.105). There was no significant difference in collagen content nor effect size observed between locations (p=0.99,η2 =1.503×10−4). Interpretation. The decrease in the fascicle cross-sectional area within the inguinal canal further suggests that there is chronic pressure applied by hernia tissue consistent with axon degeneration. Collagen content is uniformly distributed along the length of the nerve. Further studies with larger samples are needed to confirm the observed effect of nerve location on the total nerve cross-sectional area and axon loss.

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Upregulated brain glucose transport in response to recurrent hypoglycemia may contribute to the development of hypoglycemia-associated autonomic failure (HAAF) and impaired awareness of hypoglycemia. Whether recurrent hypoglycemia alters glucose transport in the hypothalamus is unknown.

Local excision (LE) of early-stage rectal cancer avoids the morbidity associated with radical surgery but has historically been associated with inferior oncologic outcomes. Newer techniques, including transanal endoscopic microsurgery (TEM) and transanal minimally invasive surgery (TAMIS), have been developed to improve the quality of LE and extend the benefits of LE to tumors in the more proximal rectum. This article provides an overview of conventional LE, TEM, and TAMIS techniques, including indications for their use and pertinent literature on their associated outcomes for rectal cancer.

Abstract:The Palo Verde wetland, one of the most important places for aquatic organisms in Costa Rica, is currently recovering from an invasive expansion of Typha domingensis(cattail). A monitoring program was designed to understand the potential impacts of different management plans on aquatic fauna and flora. Macroinvertebrates were sampled monthly for one year (Aug 2003–Aug 2004) using an artificial substrate method in three plots: Plot A, T. domingensishas been managed since 1987 by manual and mechanical underwater cutting and posterior grazing; Plot B, T. domingensishas been mechanically crushed since 2002; and Plot C, a homogeneous T. domingensisstand without active management. We identified 112 macroinvertebrate taxa from 53 families and 18 orders. Typha domingensisremoval in plots under active management did not increase family or taxa richness. Instead, a greater number of rare taxa persisted in the unmanaged plot, and macroinvertebrate communities differed among plots with less than 60% of taxa shared among them. Furthermore, mean taxa richness was higher in T. domingensiscover (X̅ = 8.56) than in the other vegetation covers (X̅ = 4.6 to 5.54). Macroinvertebrate richness was affected by vegetation cover, sampling date, and depth while abundance was affected by depth and dissolved oxygen. Typha domingensismanagement is necessary to open areas that allow the development of other vegetation types, a variety of communities of macroinvertebrates, and habitat for birds. However, in order to promote a high macroinvertebrates biodiversity and ensure food sources for waterfowl, the Palo Verde wetland should retain some patches of T. domingensisdistributed throughout.

Transanal endoscopic microsurgery, a minimally invasive procedure for treatment of early-stage rectal cancer, carcinoid tumors, and adenomas, is shown to be a safe procedure with very low perioperative morbidity.

Introduction:Pulmonary vein isolation (PVI) alone or in combination with empiric linear ablations (PVI + lines) at the left atrial roof or mitral isthmus (MI) is often performed in patients undergoing first-time atrial fibrillation (AF) ablation despite lack of evidence of benefit from clinical trials and pro-arrhythmic potential, however real-world long-term follow-up is limited.Hypothesis:Patients undergoing PVI + lines will be more likely to experience long-term adverse outcomes as compared to PVI alone.Methods:Patients undergoing AF ablation with either PVI or PVI + lines were included with follow-up data from a single institution between 2005 and 2009. Long-term outcomes included late recurrence of atrial tachyarrhythmias (LRAT), defined as AF, atrial flutter, or atrial tachycardia lasting > 30 seconds after the 3-month blanking period, repeat ablation, and cardioversion. Multivariable adjusted Cox regression was used to evaluate long-term outcomes.Results:Among 516 patients (64 ± 10 years, 68% male, 31% persistent AF) included, 376 (73%) underwent PVI only and 140 (27%) underwent PVI + lines. Of those with lines, 74 (53%) had both roof and MI line, 61 (43%) had a roof line, and 5 (4%) had a MI line. Predictors of PVI + lines included persistent AF, coronary artery disease, and male sex. Over a median follow-up of 1016 (IQR: 385 - 1752) days, approximately 63% of those with PVI only and 53% of those with PVI + lines experienced LRAT. After multivariable adjustment, there was a trend toward higher risk of LRAT in those with PVI + lines as compared to PVI only (HR 1.35, 95% CI 0.99 - 1.85, p = 0.06). There was no difference in the risk of repeat ablation (HR 0.96, 95% CI 0.63 - 1.45), while those with PVI + lines had a significantly higher risk of cardioversion as compared to PVI only (HR 2.50, CI 1.67-3.73, p<0.001).Conclusions:Those receiving linear ablations to complement PVI experienced a trend in higher risk of LRAT as compared with PVI only. While there was no significant difference in the risk of repeat ablations, there was a two-fold higher risk of cardioversion associated with PVI + lines. In line with clinical trial data, these findings suggest that empiric linear ablations are not beneficial, but may also be associated with adverse outcomes in long-term follow-up.

HYPOTHESIS Dissection of subnipple tissue to spare the entire skin envelope of the breast (total skin-sparing mastectomy) is a feasible option in appropriately selected patients and yields an excellent final cosmetic outcome. DESIGN Prospective surgical technique outcomes study. SETTING University-based breast care referral center. PATIENTS Total skin-sparing mastectomy with preservation of the nipple-areola complex was performed in 64 breasts in 43 women. Indications for total skin-sparing mastectomy included prophylaxis (n = 29), invasive carcinoma (n = 24), and ductal carcinoma in situ (n = 11). INTERVENTIONS Preoperative magnetic resonance imaging was used to select patients and to confirm absence of disease within 2 cm of the nipple. Nipple tissue was serially sectioned at pathologic analysis. Circumareolar/nipple-areola free graft, inframammary, crescentic mastopexy, areola crossing, and radial incisions were used. Immediate reconstruction was performed with implant or tissue expander placement or latissimus dorsi muscle, transverse rectus abdominis muscle, or deep inferior epigastric perforator muscle flaps. MAIN OUTCOME MEASURES Nipple-areola complex skin survival, implant loss, skin flap necrosis, wound infection, and occult neoplasm. RESULTS Nipple-areola complex skin survival was complete in 80% of patients (n = 51) and partial in 16% (n = 10); it was highest with the radial incision at 97% survival (n = 34). Occult ductal carcinoma in situ in the nipple-areola complex was found in 2 patients (3%), and the affected nipple-areola complex was subsequently removed. Other complications included implant loss, total skin-sparing skin flap necrosis, and infection. Although follow-up is limited, no patients have exhibited cancer recurrence. CONCLUSIONS Total skin-sparing mastectomy is a viable surgical option in selected patients with breast neoplasm and those who choose prophylactic mastectomy, and may increase the willingness of women to consider mastectomy to reduce their risk of breast cancer.Arch Surg. 2008;143(1):38-45--

Studies show that health education and better access to temporary contraceptives decreases the popularity of sterilization and that most Indian women report no knowledge/no use of other contraceptives prior to sterilization. However, data from this survey of 169 Indian urban and rural women demonstrates that poor women chose sterilization more for personal and socio-economic reasons (low income, dissatisfaction with other methods, achieved parity, poor health and living conditions) than for lack of awareness of other contraceptives. Urban women were significantly more likely to have tried one or more forms of available contraceptives, while rural women were significantly more likely to be unaware of other available methods (p<0.001). Literacy was significantly associated with contraceptive use in both urban and rural groups (p<0.01). At least one child of each sex was desired. A need for improvement of literacy, health education programs, and enhanced family planning services for rural women was evident.

The incidence of breast ductal carcinoma in situ(DCIS) in the USA exceeds that of other countries. This cannot be explained entirely by the frequency of mammographic screening in the USA and may result from differences in the interpretation of mammograms and/or the frequency with which biopsies are obtained. Although the percentage of DCIS patients treated with mastectomy has decreased, the absolute number is unchanged and the use of lumpectomy with whole-breast radiotherapy has increased in inverse proportion to the decrease in mastectomy. Treatment of DCIS with tamoxifen is still limited.

Administration of N‐acetyl cysteine (NAC) during hypoglycaemia will preserve the counterregulatory response to subsequent hypoglycaemia in healthy humans. This was a randomized double‐blind cross over study where humans were given either a 60‐minute infusion of NAC (150 mg/kg) followed by a 4‐hour infusion of NAC (50 mg/kg) or saline starting 30 minutes before the initiation of a 2‐hour hypoglycaemic (HG) clamp at 8 am. After rest at euglycaemia for ~2 hours, subjects were exposed to a 2nd HG clamp at 2 pmand discharged home in euglycaemia. They returned the following day for a 3rd HG clamp at 8 am. Twenty‐two subjects were enrolled. Eighteen subjects completed the entire protocol. The epinephrine response during clamp 3 (171 ± 247 pg/mL) following clamp 1 NAC infusion was lower than the response during the clamp 1 NAC infusion (538 ± 392 pg/mL) (clamp 3 to clamp 1 NAC: P= .0013). The symptom response during clamp 3 (7 ± 5) following clamp 1 NAC infusion was lower than the response during the clamp 1 NAC infusion (16 ± 10) (clamp 3 to clamp 1 NAC: P= .0003). Nine subjects experienced rash, pruritus or nausea during NAC infusion. We found no difference in the hormone and symptom response to experimental hypoglycaemia measured in subjects who were administered NAC as opposed to saline the day before. This observation suggests that further development of NAC as a therapy for impaired awareness of hypoglycaemia in patients with diabetes may be unwarranted. Infusion of the antioxidant N‐acetyl cysteine during hypoglycaemia in healthy humans did not preserve the counterregulatory response to hypoglycaemia the next day. This observation suggests that further development of NAC as a therapy for impaired awareness of hypoglycaemia in patients with diabetes may be unwarranted.

Fournier's gangrene (FG) is an aggressive necrotizing soft tissue infection of the perineum. FG takes hold as a mixture of pathogenic organisms enter the host via injured gastrointestinal or genitourinary mucosa. After soft tissue insult, a synergistic, polymicrobial infection destroys tissue through an obliterative endarteritis. FG particularly affects older, obese men with type 2 diabetes mellitus, but can affect everyone. Special populations at risk include patients who have undergone gender reassignment surgery. Early, aggressive debridement and fluid resuscitation are mandatory. Careful decisions must be made regarding the fecal stream, antibiosis, topical coverings and the use of adjunctive therapy. While untreated FG is certainly fatal, with effective diagnosis and treatment survival rates approach 95%.

Although regular human U‐500 insulin (U‐500) is frequently used for insulin resistant type 2 diabetics, pharmacokinetic and pharmacodynamic studies in these individuals are lacking. We set out to determine the rate of onset, duration of action and total glucose lowering effect of two doses of U‐500 insulin in obese insulin resistant subjects with type 2 diabetes. Randomized double‐blind crossover study was designed to study subjects who were administered either 100 or 200 units SQof U‐500 insulin once and then were provided intravenous glucose as necessary to maintain euglycaemia. A total of 12 subjects were studied. The time during which intravenous glucose was required to maintain euglycaemia following a 200‐unit dose of U‐500 insulin was significantly greater than the time following a 100‐unit dose. No differences were found between doses in measures related to the rate of onset or in the total amount of intravenous glucose required to maintain euglycaemia for the duration of the study. The duration of action of U‐500 increases when dose is increased from 100 to 200 units. Neither dose of U‐500 insulin has an onset of action before 2.5 hours after administration. This suggests that U‐500 should not be used as a premeal bolus insulin to lower glucose two hours after a meal and that dosing intervals might need to be extended as dose is increased to avoid hypoglycaemia. We performed a randomized double‐blind crossover study in which obese insulin resistant subjects with type 2 diabetes were administered either 100 or 200 units SQof U‐500 insulin once and then were provided intravenous glucose as necessary to maintain euglycaemia to determine the rate of onset, duration of action and total glucose lowering effect of the two doses. We found that the duration of action of U‐500 increases when dose is increased from 100 to 200 units and that neither dose had an onset of action before 2.5 hours after administration. This suggests that U‐500 should not be used as a premeal bolus insulin to lower glucose two hours after a meal and that dosing intervals might need to be extended as dose is increased to avoid hypoglycaemia.

Small bowel tumors and other rare intestinal disorders are often exceedingly difficult to identify. Even cutting-edge technologies, such as push enteroscopy and capsule endoscopy, can fail to determine the cause of a patient’s symptoms. At our institution magnetic resonance enterography (MRE) has become an increasingly reliable tool in the difficult-to-diagnose or difficult-to-monitor patient. In this retrospective case series, we discuss four patients with four rare intestinal disorders that were successfully diagnosed using MRE after failing to be diagnosed using more routine technologies, such as CT scans and flexible sigmoidoscopies. With the discussion of these four cases we demonstrate that MRE is a useful diagnostic modality in patients whose surveillance is difficult or to diagnose rare colorectal disease phenomena, colloquially referred to as “zebras.”