Anatomic Location and Mechanism of Injury Correlating with Prehospital Deaths in Sub-Saharan Africa.

INTRODUCTION: Trauma is a large contributor to morbidity and mortality in developing countries. We sought to determine which anatomic injury locations and mechanisms of injury predispose to prehospital mortality in Malawi to help target preventive and therapeutic interventions. We hypothesized that head injury would result in the highest prehospital mortality. METHODS: This was a retrospective analysis of all trauma patients presenting to Kamuzu Central Hospital in Lilongwe, Malawi, from 2008 to 2015. Independent variables included baseline characteristics, anatomic location of primary injury, mechanism of injury, and severity of secondary injuries. Multivariable logistic regression was used to assess the effect of primary injury location and injury mechanism on prehospital death, after adjusting for confounders. Effect measure modification of the primary injury site/prehospital death relationship by injury mechanism (stratified into intentional and unintentional injury) was assessed. RESULTS: Of 85,806 patients, 701 died in transit (0.8%). Five hundred and five (72%) of these patients sustained a primary head injury. After adjustment, head injury was the anatomic location most associated with prehospital death (OR 11.81 (95% CI 6.96-20.06, p < 0.0001). The mechanisms of injury most associated with prehospital death were gunshot wounds (OR 38.23, 95% CI 17.66-87.78, p < 0.0001) and pedestrian hit by vehicle (OR 2.62, 95% CI 1.92-3.55, p < 0.0001). Among head injury patients, the odds of prehospital mortality were higher with unintentional injuries. CONCLUSIONS: Head injuries are the most common causes of prehospital death in Malawi, while pedestrians hit by vehicles are the most common mechanisms. In a resource-poor setting, preventive measures are critical in averting mortality.

Discovery of M3 Antagonist-PDE4 Inhibitor Dual Pharmacology Molecules for the Treatment of Chronic Obstructive Pulmonary Disease.

In this paper, we report the discovery of dual M3 antagonist-PDE4 inhibitor (MAPI) compounds for the inhaled treatment of pulmonary diseases. The identification of dual compounds was enabled by the intuition that the fusion of a PDE4 scaffold derived from our CHF-6001 series with a muscarinic scaffold through a common linking ring could generate compounds active versus both the transmembrane M3 receptor and the intracellular PDE4 enzyme. Two chemical series characterized by two different muscarinic scaffolds were investigated. SAR optimization was aimed at obtaining M3 nanomolar affinity coupled with nanomolar PDE4 inhibition, which translated into anti-bronchospastic efficacy ex vivo (inhibition of rat trachea contraction) and into anti-inflammatory efficacy in vitro (inhibition of TNFα release). Among the best compounds, compound 92a achieved the goal of demonstrating in vivo efficacy and duration of action in both the bronchoconstriction and inflammation assays in rat after intratracheal administration.

Effect of in-hospital delays on surgical mortality for emergency general surgery conditions at a tertiary hospital in Malawi.

Background: In sub-Saharan Africa, surgical access is limited by an inadequate surgical workforce, lack of infrastructure and decreased care-seeking by patients. Delays in treatment can result from delayed presentation (pre-hospital), delays in transfer (intrafacility) or after arrival at the treating centre (in-hospital delay; IHD). This study evaluated the effect of IHD on mortality among patients undergoing emergency general surgery and identified factors associated with IHD. Methods: Utilizing Malawi's Kamuzu Central Hospital Emergency General Surgery database, data were collected prospectively from September 2013 to November 2017. Included patients had a diagnosis considered to warrant urgent or emergency intervention for surgery. Bivariable analysis and Poisson regression modelling was done to determine the effect of IHD (more than 24 h) on mortality, and identify factors associated with IHD. Results: Of 764 included patients, 281 (36·8 per cent) had IHDs. After adjustment, IHD (relative risk (RR) 1·68, 95 per cent c.i. 1·01 to 2·78; P = 0·045), generalized peritonitis (RR 4·49, 1·69 to 11·95; P = 0·005) and gastrointestinal perforation (RR 3·73, 1·25 to 11·08; P = 0·018) were associated with a higher risk of mortality. Female sex (RR 1·33, 1·08 to 1·64; P = 0·007), obtaining any laboratory results (RR 1·58, 1·29 to 1·94; P < 0·001) and night-time admission (RR 1·59, 1·32 to 1·90; P < 0·001) were associated with an increased risk of IHD after adjustment. Conclusion: IHDs were associated with increased mortality. Increased staffing levels and operating room availability at tertiary hospitals, especially at night, are needed.

Less-than-subtotal parathyroidectomy increases the risk of persistent/recurrent hyperparathyroidism after parathyroidectomy in tertiary hyperparathyroidism after renal transplantation.

BACKGROUND: The optimal surgical approach for tertiary hyperparathyroidism (HPT) after kidney transplantation is unknown. Existing studies are limited by small sample size, lack of adjustment for kidney function, and no long-term follow-up. METHODS: We retrospectively analyzed 74 patients with tertiary HPT who underwent parathyroidectomy at two centers since 1978. Persistent HPT was defined as parathyroid hormone (PTH) concentrations in excess of the K/DOQI target range for the corresponding estimated creatinine clearance (eCrCl). RESULTS: Seventy-four patients had 83 operations (72 subtotal and 11 less-than-subtotal parathyroidectomies). Mean follow-up time was 5.4 +/- 4.7 years. Calcium concentrations decreased significantly after parathyroidectomy (2.83 vs 2.28 mmol/L, P < 0.001), as did eCrCl (54.5 vs 44.9 mL/min, P < 0.001) and PTH (382 vs 132 pg/mL, P < 0.001). In the multivariable regression analysis, only the type of operation and postoperative eCrCl were significantly correlated with PTH at follow-up. A limited parathyroidectomy was associated with a fivefold increase in risk of persistent or recurrent hyperparathyroidism. CONCLUSIONS: The use of limited parathyroidectomy for tertiary HPT after kidney transplantation has a higher risk of persistent/recurrent HPT. Subtotal parathyroidectomy is recommended for patients with tertiary HPT.

Burns in Nepal: A population based national assessment.

BACKGROUND: Burns are ranked in the top 15 leading causes of the burden of disease globally, with an estimated 265,000 deaths annually and a significant morbidity from non-fatal burns, the majority located in low and middle-income countries. Given that previous estimates are based on hospital data, the purpose of this study was to explore the prevalence of burns at a population level in Nepal, a low income South Asian country. METHODS: A cluster randomized, cross sectional countrywide survey was administered in Nepal using the Surgeons OverSeas Assessment of Surgical Need (SOSAS) from May 25th to June 12th, 2014. Fifteen of the 75 districts of Nepal were randomly chosen proportional to population. In each district, three clusters, two rural and one urban, were randomly selected. The SOSAS survey has two portions: the first collects demographic data about the household's access to healthcare and recent deaths in the household; the second is structured anatomically and designed around a representative spectrum of surgical conditions, including burns. RESULTS: In total, 1350 households were surveyed with 2695 individuals with a response rate of 97%. Fifty-five burns were present in 54 individuals (2.0%, 95% CI 1.5-2.6%), mean age 30.6. The largest proportion of burns was in the age group 25-54 (2.22%), with those aged 0-14 having the second largest proportion (2.08%). The upper extremity was the most common anatomic location affected with 36.4% of burns. Causes of burns included 60.4% due to hot liquid and/or hot objects, and 39.6% due to an open fire or explosion. Eleven individuals with a burn had an unmet surgical need (20%, 95% CI 10.43-32.97%). Barriers to care included facility/personnel not available (8), fear/no trust (1) and no money for healthcare (2). CONCLUSION: Burns in Nepal appear to be primarily a disease of adults due to scalds, rather than the previously held belief that burns occur mainly in children (0-14) and women and are due to open flames. This data suggest that the demographics and etiology of burns at a population level vary significantly from hospital level data. To tackle the burden of burns, interventions from all the public health domains including education, prevention, healthcare capacity and access to care, need to be addressed, particularly at a community level. Increased efforts in all spheres would likely lead to a significant reduction of burn-related death and disability.

Long-term results of less than total parathyroidectomy for hyperparathyroidism in multiple endocrine neoplasia type 1.

BACKGROUND: Our aim was to assess long-term results after less than total parathyroidectomy for hyperparathyroidism in multiple endocrine neoplasia type 1. METHODS: Of 1888 patients undergoing operation at our institution for primary hyperparathyroidism between 1972 and 2001, 83 (4.4%) had multiple endocrine neoplasia type 1. Outcome data were available for 79; 66 underwent subtotal parathyroidectomy, 55 (83%) of these with bilateral thymectomy. In 13 patients, only grossly enlarged glands were resected (mean 1.1 per patient) as the syndrome of multiple endocrine neoplasia type 1 was not yet evident or the initial exploration was performed elsewhere. RESULTS: Follow-up has been 48 +/- 51 months (mean + SD). Intraoperative serum PTH assay decay in 20 patients was suggestive of cure in 18 patients, none of whom required reoperation. Nine patients (11%) required reoperation (3 required reoperation twice) after a mean interval of 77 +/- 53 months. Subtotal parathyroidectomy resulted in a lesser reoperation rate than resection of grossly enlarged glands (7% vs 30%, P =.02). At the time of review, 63 patients (80%) were normocalcemic, 10 (13%) hypocalcemic (2 after unsuccessful delayed autograft), and 7% hypercalcemic (none after reoperation). By Kaplan-Meier analysis, the rate of surgical cure (patients who are nonhypercalcemic) is 60% and 51% at 10 and 15 years, respectively. CONCLUSION: Subtotal parathyroidectomy reduces the need for reoperation. Selective reoperation leads to long-lasting biochemic cure.

Promethazine hydrochloride therapy in severely Rh-sensitized pregnancies.

Seventeen severely Rh-sensitized women were treated with promethazine hydrochloride (Phenergan) in 18 pregnancies, according to a protocol described by Gusdon et al. There was an unequivocal amelioration of the disease process in 10 of the pregnancies. In 9 of these 10 pregnancies, the infant survived. In 4 of the pregnancies, promethazine proved an unnecessary therapy as the infants were Rh negative. Promethazine may or may not have been helpful in 2 pregnancies, both of which resulted in live-born infants. One pregnancy resulted in intrauterine fetal death subsequent to an intrauterine transfusion. This infant was later shown to have multiple congenital anomalies incompatible with life. In a subsequent pregnancy, the mother was again treated with promethazine and had a normal infant who survived after exchange transfusions. The one loss of a live-born infant resulted from a cardiac arrest during an exchange transfusion. On the basis of these observations, the authors agree with Gusdon et al that promethazine does have an ameliorating effect on Rh-sensitized pregnancies.

Taxol-induced ceramide generation and apoptosis in human breast cancer cells.

PURPOSE: Taxol has emerged as a valuable antimitotic chemotherapeutic agent, particularly in advanced breast and ovarian cancers. Although much is known about cytotoxic mechanisms, the effectiveness of Taxol cannot be solely explained by microtubular interaction. This study was undertaken to determine whether ceramide generation plays a role in Taxol-induced apoptosis. METHODS: Hormone-independent MDA-MB-468 and hormone-dependent MCF-7 breast cancer cell lines were employed, and ceramide metabolism was characterized using [3H]palmitic acid as lipid precursor. RESULTS: Exposure of cells to Taxol resulted in enhanced formation of [3H]ceramide. Ceramide increased nearly 2-fold in MDA-MB-468 cells exposed to 50 nM Taxol, and more than 2.5-fold in MCF-7 cells exposed to 1.0 microM Taxol. These concentrations mirrored the EC50 (amount of drug eliciting 50% cell kill) for Taxol in the two cell lines. Use of cell-permeable C6-ceramide as a medium supplement revealed that MDA-MB-468 cells were 20-fold more sensitive to ceramide than MCF-7 cells (P < 0.001). Ceramide was generated as early as 6 h after exposure to Taxol in MDA-MB-468 cells, whereas the earliest signs of apoptosis were detected 12 h after treatment, and by 24 h the apoptotic index was six times that of untreated cells. Both fumonisin B1, a ceramide synthase inhibitor, and L-cycloserine, a serine palmitoyltransferase inhibitor, blocked Taxol-induced ceramide generation, whilst sphingomyelin levels remained unchanged, indicating a de novo pathway of ceramide formation. L-Cycloserine reduced Taxol-induced apoptosis by 30% in MDA-MB-468 cells and totally blocked Taxol-induced apoptosis in MCF-7 cells. CONCLUSIONS: These results suggest that Taxol-induced apoptosis is, in part, attributable to ceramide and sphingoid bases. This is of relevance to drug mechanism studies, as ceramide is a known messenger of apoptosis. Clinical use of Taxol with ceramide-enhancing agents may maximize cytotoxic potential.

Female epispadias: report of a case and review of the literature.

Female epispadias is a congenital anomaly representing a mild form of the spectrum of exstrophy of the bladder. Unrecognized an untreated, the handicap associated with the physical malformation can create overwhelming clinical and psychological problems for the affected female. Radiographic findings of spinal dysrhaphism with diastasis of the public bones are often associated with, and can afford the first clue to, the physical findings of absent clitoris, ununited labia and patulous and foreshortned urethra.

Estrogen replacement after menopause. When is it warranted?

As longevity increases, so will the number of women living for many years beyond menopause. The estrogen deprivation that occurs at menopause results in many degenerative changes in a woman's body, some of which cause unpleasant or disabling symptoms. To maintain good health and vitality in menopausal and postmenopausal women, serious consideration should be given to appropriate estrogen replacement therapy. Although such therapy has some risks, the benefits appear to exceed the risks.

The dosing and monitoring of argatroban for heparin-induced thrombocytopenia during extracorporeal membrane oxygenation: a word of caution.

Heparin-induced thrombocytopenia is a serious complication of heparin use. Treatment includes discontinuation of heparin and initiation of alternative anticoagulation therapy. In extracorporeal membrane oxygenation anticoagulation is mandatory, and direct thrombin inhibitors (DTIs) have been approved in these cases. However, the use and monitoring of DTIs in extracorporeal membrane oxygenation patients is not well described. DTI use is also complicated by the imprecision of available monitoring tests and currently recommended dosing has been shown to result in a supratherapeutic anticoagulative state. This case report describes the successful use of the DTI argatroban as an alternative anticoagulant in a patient with heparin-induced thrombocytopenia requiring extracorporeal membrane oxygenation support.

Tracheostomy in the critically ill: the myth of dead space.

Benefits and advantages of tracheostomy have been vigorously debated. There is a lack of consensus as to whether perceived clinical improvement is attributable to fundamental changes in respiratory dynamics. We compare the effect of tracheostomy versus endotracheal tube on dead space, airway resistance and other lung parameters in critically ill ventilated patients. Data collected included patients who were admitted to surgical, burn and neurosurgical intensive care units at the University of North Carolina. Twenty-four intubated patients were included in our analysis with various aetiologies of respiratory failure. Tracheostomy was deemed necessary either for severe neurological devastation or failure to wean from the ventilator. The diameter of the endotracheal tubes ranged from 6-8 mm and the tracheostomy tube diameters were from 6.4-8.9 mm. Internal diameters between endotracheal tube and tracheostomy tubes, ventilator settings and sedation were kept consistent throughout the study. Respiratory parameters were measured using the Respironics' non-invasive cardiac output 2 device (Phillips, Andover, MA) immediately prior to tracheostomy and repeated within 24 hours of tracheostomy. Only two (8%) of the patients had slight improvement (>6% decrease in dead space). The average dead space of endotracheal versus tracheostomy tubes was 41±12.6% and 40±14.6%, respectively (P=0.75). The remaining 22 patients (92%) had no significant change in dead space, compliance or other respiratory parameters. This study shows that there is no significant difference in respiratory mechanics and dead space with a tracheostomy versus endotracheal tube.

Mapping the structural requirements of inducers and substrates for decarboxylation of weak acid preservatives by the food spoilage mould Aspergillus niger.

Moulds are able to cause spoilage in preserved foods through degradation of the preservatives using the Pad-decarboxylation system. This causes, for example, decarboxylation of the preservative sorbic acid to 1,3-pentadiene, a volatile compound with a kerosene-like odour. Neither the natural role of this system nor the range of potential substrates has yet been reported. The Pad-decarboxylation system, encoded by a gene cluster in germinating spores of the mould Aspergillus niger, involves activity by two decarboxylases, PadA1 and OhbA1, and a regulator, SdrA, acting pleiotropically on sorbic acid and cinnamic acid. The structural features of compounds important for the induction of Pad-decarboxylation at both transcriptional and functionality levels were investigated by rtPCR and GCMS. Sorbic and cinnamic acids served as transcriptional inducers but ferulic, coumaric and hexanoic acids did not. 2,3,4,5,6-Pentafluorocinnamic acid was a substrate for the enzyme but had no inducer function; it was used to distinguish induction and competence for decarboxylation in combination with the analogue chemicals. The structural requirements for the substrates of the Pad-decarboxylation system were probed using a variety of sorbic and cinnamic acid analogues. High decarboxylation activity, ~100% conversion of 1mM substrates, required a mono-carboxylic acid with an alkenyl double bond in the trans (E)-configuration at position C2, further unsaturation at C4, and an overall molecular length between 6.5Å and 9Å. Polar groups on the phenyl ring of cinnamic acid abolished activity (no conversion). Furthermore, several compounds were shown to block Pad-decarboxylation. These compounds, primarily aldehyde analogues of active substrates, may serve to reduce food spoilage by moulds such as A. niger. The possible ecological role of Pad-decarboxylation of spore self-inhibitors is unlikely and the most probable role for Pad-decarboxylation is to remove cinnamic acid-type inhibitors from plant material and allow uninhibited germination and growth of mould spores.

The epidemiology, management, outcomes and areas for improvement of burn care in central Malawi: an observational study.

This report describes the epidemiology of burn injuries and quantifies the appropriateness of use of available interventions at Kamuzu Central Hospital, Malawi, between July 2008 and June 2009 (370 burn patients). Burns accounted for 4.4% of all injuries and 25.9% of all burns presenting to the hospital were admitted. Most patients (67.6%) were < 15 years old and 56.2% were male. The most frequent cause was scalding (51.4%). Burns occurred most frequently in the cool, dry season and in the evening. The mean burn surface area (second/third degree) was 14.1% and most burns (74%) presented within 8 h. The commonest procedure was debridement and/or amputation. The mean hospital stay was 21.1 days, in-hospital mortality was 27% and wound infection rate was 31%. Available interventions (intravenous fluids, nutrition therapy, physiotherapy) were misapplied in 59% of cases. It is concluded that primary prevention should address paediatric and scald burns, and secondary prevention should train providers to use available interventions appropriately.