Molecular insights into GPCR mechanisms for drugs of abuse.

Substance abuse is on the rise, and while many people may use illicit drugs mainly due to their rewarding effects, their societal impact can range from severe, as is the case for opioids, to promising, as is the case for psychedelics. Common with all these drugs' mechanisms of action are G protein-coupled receptors (GPCRs), which lie at the center of how these drugs mediate inebriation, lethality, and therapeutic effects. Opioids like fentanyl, cannabinoids like tetrahydrocannabinol, and psychedelics like lysergic acid diethylamide all directly bind to GPCRs to initiate signaling which elicits their physiological actions. We herein review recent structural studies and provide insights into the molecular mechanisms of opioids, cannabinoids, and psychedelics at their respective GPCR subtypes. We further discuss how such mechanistic insights facilitate drug discovery, either toward the development of novel therapies to combat drug abuse or toward harnessing therapeutic potential.

A Regional and Projection-Specific Role of RGSz1 in the Ventrolateral Periaqueductal Grey in the Modulation of Morphine Reward.

Opioid analgesics exert their therapeutic and adverse effects by activating µ opioid receptors (MOPR); however, functional responses to MOPR activation are modulated by distinct signal transduction complexes within the brain. The ventrolateral periaqueductal gray (vlPAG) plays a critical role in modulation of nociception and analgesia, but the exact intracellular pathways associated with opioid responses in this region are not fully understood. We previously showed that knockout of the signal transduction modulator Regulator of G protein Signaling z1 (RGSz1) enhanced analgesic responses to opioids, whereas it decreased the rewarding efficacy of morphine. Here, we applied viral mediated gene transfer methodology and delivered adeno-associated virus (AAV) expressing Cre recombinase to the vlPAG of RGSz1fl\fl mice to demonstrate that downregulation of RGSz1 in this region decreases sensitivity to morphine in the place preference paradigm, under pain-free as well as neuropathic pain states. We also used retrograde viral vectors along with flippase-dependent Cre vectors to conditionally downregulate RGSz1 in vlPAG projections to the ventral tegmental area (VTA) and show that downregulation of RGSz1 prevents the development of place conditioning to low morphine doses. Consistent with the role for RGSz1 as a negative modulator of MOPR activity, RGSz1KO enhances opioid-induced cAMP inhibition in periaqueductal gray (PAG) membranes. Furthermore, using a new generation of bioluminescence resonance energy transfer (BRET) sensors, we demonstrate that RGSz1 modulates Gαz but not other Gαi family subunits and selectively impedes MOPR-mediated Gαz signaling events invoked by morphine and other opioids. Our work highlights a regional and circuit-specific role of the G protein-signaling modulator RGSz1 in morphine reward, providing insights on midbrain intracellular pathways that control addiction-related behaviors. SIGNIFICANCE STATEMENT: This study used advanced genetic mouse models to highlight the role of the signal transduction modulator named RGSz1 in responses to clinically used opioid analgesics. We show that RGSz1 controls the rewarding efficacy of opioids by actions in ventrolateral periaqueductal gray projections to the ventral tegmental area, a key component of the midbrain dopamine pathway. These studies highlight novel mechanisms by which pain-modulating structures control the rewarding efficacy of opioids.

Tuberculosis in a weak health system, conflict and fragile zone: The monetary value of human lives lost associated with deaths of persons older than 14 years in Somalia.

BACKGROUND: Low tuberculosis (TB) detection and conflict and fragility have overburdened Somalia. This study estimated economic loss associated with TB deaths among persons aged >14 years. METHOD: Using epidemiologic and economic data, we calculated the cost based on the framework of the World Health Organization guide of identifying the economic consequences of disease and injury. Baseline loss is the product of years of life lost, non-health expenditure, and number of deaths. Adjusting for conflict and fragility conditions and growth of non-health expenditure, we discounted the loss at 3% rate. We conducted a sensitivity analysis of epidemiologic and economic factors. RESULTS: In 2017 values, the 9180 reported deaths result in a loss of US$ 44.77 million, a US$ 4877 per death over the discounted years. Conflict conditions would increase the loss by 5.3%, while simultaneous adjustment for conflict and attunement to growth of non-health expenditure would increase the burden by 54% to US$ 67.28 million. Male fatalities account for 59% of the burden. The baseline result is robust to input variations, although sensitivity analysis suggests conflict and fragility conditions account for greater uncertainty of the loss. CONCLUSION: Stakeholders in the healthcare system should minimise the sizeable economic loss by taking measures to enhance surveillance of TB and security.

Safety and efficacy of dinutuximab in the treatment of neuroblastoma: A review.

Dinutuximab, which is a monoclonal antibody targeting GD2 expressed in neuroblasts, improves survival when included in the therapy regimen. This article reviews the importance of dinutuximab in managing neuroblastoma (NB). Dinutuximab targets high levels of GD2 expression in NB cells, thus increasing event-free survival when used in the maintenance therapy of high-risk patients with NB. Although several collaborative studies have set the standard of care for maintenance therapy, the long-term follow-up and continuous evaluation of the use of antibodies and the co-administration of other pharmacological or immunomodulatory drugs remain to be studied. Trials have shown that the use of dinutuximab for maintenance therapy can prolong the time before the first relapse and improve overall survival. However, there is uncertainty in the function of cytokines co-administered with dinutuximab, which may lead to increased toxicity without additional benefits. Recent studies on relapsed and refractory NB have shown the potential efficacy of dinutuximab. Further research is required to properly incorporate Dinutuximab in current treatment modalities.

Detection of Helicobacter pylori in Gastric Biopsies Among Sudanese Patients with Confirmed Gastric Disorders Using Three Diagnostic Methods.

BACKGROUND: Helicobacter pylori (H. pylori) infection represents one of the most common chronic bacterial infections in developing countries. However, in Sudan, the infection is not well diagnosed with standard laboratory methods in many parts of the country. This study aimed to detect H. pylori in gastric biopsies of patients with gastric disorders, using three diagnostic methods. MATERIALS AND METHODS: A cross-sectional study was conducted among 100 patients in Gezira state, central Sudan. Giemsa stain for histopathological examination (HPE), rapid urease test (RUT), and polymerase chain reaction (PCR) techniques were performed to detect H. pylori from the gastric biopsy samples as per standard assays. RESULTS: Most of the patients were males (66%), from rural areas (72%) and in the age group 31 to 50 years. H. pylori were identified in 85% of the samples by at least one of the three tests. The highest positivity was detected by HPE (83%), followed by PCR (67%) and RUT (63%), while 59% were positive by the three diagnostic methods. PCR showed higher sensitivity (80.72% vs. 73.49%) and specificity (100% vs. 88.24%) than RUT. Positive predictive values were reported as 100% for PCR and 96.83% for RUT. Considering PCR as a gold standard method, HPE revealed higher sensitivity (100%) than RUT (88.06%). On the contrary, RUT showed higher specificity (87.88%) than PCR (51.52%). There were no significant associations between H. pylori infection patients' gender (p = 0.747). Loss of weight (p = 0.007) and nausea (p = 0.032) were significantly associated with H. pylori infection. CONCLUSIONS: There was a high prevalence of H. pylori infection in central Sudan. This highlights the need to analyze epidemiological status, virulence factors, and strain characteristics to control disease transmission. PCR is a reliable and valuable technique in detecting H. pylori infection from gastric biopsy samples.

Zinc oxide nanoparticles prevent multidrug resistant Staphylococcus-induced footpad dermatitis in broilers.

The current experiment was designed to evaluate the effects of dietary supplementations of zinc oxide nanoparticles (ZONPs) on some behavioural, performance, welfare and histopathological changes in broilers exposed to multidrug resistant Staphylococcus aureus (MRSA)-induced footpad dermatitis (FPD). Eighty-four male Indian River (IR) broilers were randomly allotted to six different dietary treatments as follows: C-ve, C+ve, 10, 20, 30 and 40 ppm ZONPs from 7 to 49d of age. At day 28, broilers (n = 70) were sub-cutaneously injected with 0.5 ml of saline containing 5.3 × 107 CFU/ml of S. aureus (MRSA) in each metatarsal foot pad. Control (non-infected) broilers were given 0.5 ml of saline (n = 14). Results clarified that non-infected birds and ZONPs-fed birds had significantly higher standing and feeding activities and lower resting activities in comparison with the infected group. Also, the S. aureus infected group had significantly lower body weight gain (BWG) and higher feed conversion ratio (FCR) than the non-infected group. In addition, the non-infected birds and ZONPs groups had significantly lower object crossing and tonic immobility times (TI) and gait scores (GS) in comparison with the S. aureus group. Only ZONPs 30, 40 ppm and non-infected groups had a significantly higher latency to lie time (LLT) and lower serum cortisol level in comparison with the S. aureus group. Moreover, there were significant changes in the gross lesion score and histopathological lesions between the different groups. In conclusion, the dietary supplementation of ZONPs can reduce S. aureus-induced negative effects of FPD in broilers.

Extracorporeal membrane oxygenation in the management of granulomatosis with polyangiitis.

Granulomatosis with polyangiitis (GPA, also known as Wegener's granulomatosis) is a type of systematic vasculitis that primarily involves the lung and kidney. Diffuse alveolar hemorrhage (DAH) and associated acute respiratory failure are uncommon but devastating complications of GPA. Experience in using extracorporeal membrane oxygenation (ECMO) to manage DAH caused by GPA is limited. We report two GPA patients with DAH that were successfully managed using ECMO support. Examining 13 cases identified in the literature and two of our own, we observed that most patients experienced rapid deterioration in respiratory function in conjunction with a precedent respiratory infection. All 15 patients received veno-venous ECMO support. The median duration of ECMO support was 11 days (interquartile range: 7.5-20.75 days). Bleeding was the most common complication, seen in four (26.7%) cases. All patients were successfully weaned off ECMO after a median length of hospital stay of 42 days (interquartile range: 30-78 days). We demonstrated that the use of ECMO is a reasonable and effective support option in the management of GPA patients with DAH. The risk of bleeding is high but maybe reduced using a lower anticoagulation goal.

Rapid and Tunable Method To Fabricate Angle-Independent and Transferable Structurally Colored Films.

The assembly of monodisperse particles into colloidal arrays that diffract visible light through constructive interference is of considerable interest due to their resilience against color fading. In particular, noniridescent structurally colored materials are promising as a means of coloration for paints, inks, cosmetics, and displays because their color is angle independent. A rapid and tunable assembly method for producing noniridescent structurally colored colloidal-based materials that are pliable after fabrication is described. Structurally colored particle arrays were fabricated by centrifuging highly charged silica particles suspended in deionized water. By tuning the particle diameter, the colors displayed by the arrays spanned the visible spectrum while retaining angle-independent structural color. The color of centrifuged colloids of a single particle diameter was precisely controlled within 50 nm by modulating the particle concentration. The peak wavelength diffracted by the material was further tuned by altering the centrifugal rate and assembly time. Centrifugation assembly of particles in a polymer solution also produces noniridescent colloidal films, and the control of their color is reported. Together, these results offer design considerations for the centrifugation-based assembly of colloidal films with tunable structural color that are transferable after fabrication and are angle independent.

Comparison of comparable scald and contact burns in a porcine model: A preliminary report.

Whether the depth and healing of scalds and contact burns are similar is controversial. Due to water's greater heat capacity, we hypothesized that when exposed to similar temperatures and durations of exposure, burns caused by hot water would be deeper than those caused by contact with hot metal. Forty standardized burns were created in two anesthetized female domestic pigs using a brass bar or circulating heated water. In one pig, the temperature was kept constant (95°C) while the duration of exposure varied (5, 10, 15 seconds) In the second pig, the exposure time was kept constant (10 seconds) while the temperature of exposure varied (70°C, 80°C, 98°C). Periodic punch biopsies were taken to determine burn depth immediately after injury, percentage burns reepithelialized within 21 days, and depth of scar at 28 days. The analysis was performed using analysis of variance. When the temperature was held constant, duration of exposure (5, 10, and 15 seconds) was associated with scar depth (2.1 vs 3.8 vs 5.0 mm, respectively, P = 0.001) but not with burn depth (2.0 vs 2.2 vs 2.3 mm, respectively, P = 0.10). When exposure duration was held constant, temperature (70°C, 80°C, 98°C) was associated with scar depth (0.6 vs 1.7 vs 3.6, P < 0.001) but not with burn depth (1.2 vs 1.5 vs 1.7 mm, respectively, P = 0.21). Burn depths were greater for scald than contact burns although not significantly greater. After controlling for temperature, the difference in scar depth between scalds and contact burns was statistically significant (marginal means 3.0 for contact burns, 4.3 for scalds, P = 0.008). We conclude that burns created in swine with circulating hot water result in deeper scars than those created by contact with a brass bar when controlling for temperature and duration of exposure.

Assessing comfort level of organ donation competencies among pediatric intensivists in Saudi Arabia: a national survey.

BACKGROUND: As increasing the number of organ donations presents a global challenge, Saudi Arabia is no different. Intensivists can play a major role in maximizing the organ donation process and minimize the challenges. The purpose of this study was to investigate Saudi pediatric intensivists' comfort and importance levels of organ donation competencies. METHODS: We conducted a cross-sectional survey whose sampling frame included 100 pediatric intensivists. The pediatrician intensivists were identified through an updated list provided by the Saudi Critical Care Society. We assessed 14 competencies categorized into four domains: the general donation, donation after brain death (DBD), neurological determination of death, and medicolegal, religious, and ethical domains. Then we investigated the association between these competencies and physicians' characteristics. RESULTS: With a response rate of 76%, we found that 40-60% of the surveyed pediatric intensivists rated their comfort in 6 out of 14 competencies as high or very high. There was a statistically significant gap in the intensivists' rating of 10 competencies (i.e., high importance but low comfort levels). Ordinal regression showed that comfort levels with the general donation, neurological determination of death, and medicolegal, religious, and ethical domains were higher in intensivists who were frequently involved with DBD than those who had never been exposed. CONCLUSIONS: Pediatric intensivists expressed low comfort levels to organ donation competencies that are essential for maximizing donation rates. Adapting mandatory comprehensive donation education programs and dedicated physician specialists may be beneficial in critical care units aiming to increase donation rates.

Coronavirus Disease 2019 (COVID-19): Potential implications for weak health systems and conflict zones in the Middle East and North Africa region.

This short communication recognizes the underbelly of weak and conflict-prone health systems in the Middle East and North Africa region in the wake of COVID-19 pandemic. The communication highlights how the lack of basic resources, absence of a well-functioning health system and the dearth of well-coordinated communication channels, can bode ill for the successful fight against COVID-19. The article elucidates COVID-19 potential health, social, and economic implications for such countries. The communication cautions that if COVID-19 is left to incubate and makes a home in weak systems, it will have a much better chance of mutating and coming back to infect many people globally. The communication calls on the international institutions in collaboration with developed nations to be prepared to probe up health systems in weak and conflict-prone health systems with much-needed resources in order to nip COVID-19 in the bud.

Combination of High-Calorie Delivery and Organ Failure Increases Mortality Among Patients With Acute Respiratory Distress Syndrome.

OBJECTIVES: Among critically ill patients, the benefits of nutrition support may vary depending on severity of organ dysfunction. The objective of the current article was to explore the relationship between organ failure and calories exposure with hospital mortality during the first week of acute respiratory distress syndrome. DESIGN: Retrospective observational study. SETTING: Single-center ICU. PATIENTS: Adults admitted to the ICU with a diagnosis of acute respiratory distress syndrome. INTERVENTIONS: Calorie delivery from enteral nutrition, parenteral nutrition, propofol, and dextrose containing fluids were collected for 7 days following intubation. Sequential Organ Failure Assessment score was calculated at ICU admit and for the same 7 days to describe organ dysfunction; four different Sequential Organ Failure Assessment variables were created 1) Sequential Organ Failure Assessment at ICU admit, 2) average Sequential Organ Failure Assessment for the first 7 days following intubation, 3) the highest Sequential Organ Failure Assessment for the first 7 days following intubation, and 4) change in Sequential Organ Failure Assessment from intubation to 7 days later. MEASUREMENTS AND MAIN RESULTS: A total of 298 patients were included. Sequential Organ Failure Assessment at ICU admit, average Sequential Organ Failure Assessment for the first 7 days following intubation, highest Sequential Organ Failure Assessment for the first 7 days following intubation, change in Sequential Organ Failure Assessment from intubation to 7 days later, and calorie delivery the first 7 days following intubation were all associated with increased likelihood of mortality. Compared with patients with low organ failure and low-calorie delivery, those with high-calorie delivery and low organ failure, low-calorie delivery and high organ failure, and the combination of both high organ failure with high-calorie delivery were associated with an incremental increase in the likelihood or mortality. CONCLUSIONS: Organ failure appears to modify the relationship between calorie exposure and ICU outcome. Additional research is needed to identify appropriate thresholds for safe calorie exposure with increased organ failure.

Indirect costs associated with deaths of children aged 0-14 years from measles in a weak health system and conflict and fragile zone: the case of Somalia.

This study recognises periodic outbreaks of measles continue to affect conflict and fragile zones in the least developed countries. This study set out to provide evidence for the indirect costs or economic loss associated with measles-related deaths among children aged 0-14 years in Somalia. Using epidemiologic and economic data, the indirect cost was calculated based on the framework of the World Health Organisation guide of identifying the economic consequences of disease and injury. The baseline indirect cost was computed as the product of discounted future productive years of life lost (PYLL), non-health gross domestic product per capita (NHGDPPC) and the estimated total measles deaths (ETMD). The model was adjusted for conflict and fragility conditions and further extension considered a finite and stable upper limit growth of the instability-adjusted NHGDPPC. To discount future costs, a rate of 3% was applied. Using a ±20% variability assumption of the epidemiologic and economic factor inputs, a sensitivity analysis was conducted to account for uncertainty. In 2015 values, the ETMD of 3723 measles deaths of children aged 0-14 years could decrease non-health GDP of the country by $23.46 million, a potential loss of $6303 per death over the discounted PYLL. The loss would increase by 5.3% when adjusted for conflict and fragility conditions. Assuming growth, the future adjusted loss is expected to be $35.91 million in 2015 values. Girl-child deaths accounted for 51.2% of the burden. Results are robust to the variations in the model inputs, although sensitivity analyses suggest the proportion of total measles deaths and the discount rate accounted for greater uncertainty of the loss than do the proportion of growth and instability assumption. Conflict and fragility accounted for the least uncertainty, perhaps confirming their relative perpetuity in Somalia. Results show significant indirect cost related to measles deaths of children, exacerbated by conflict and fragility. This is an economic burden, but one which the health system, policy-makers, government and other stakeholders should be prepared to colossally discount by collectively taking measles surveillance and security measures now to reduce further deaths in the future.

The prevalence of chronic pain and its associated factors among Saudi Al-Kharj population; a cross sectional study.

BACKGROUND: Chronic pain (CP) can be a symptom of many underlying health issues. The consequences of CP may vary from slight discomfort to disruption of quality of life and normal functioning. In this study, we aim to investigate the prevalence of CP and its associated factors in Al Kharj, Saudi Arabia. METHODS: This was a cross-sectional study conducted in Al Kharj, Saudi Arabia. We recruited 1031 participants for our study. Data was collected on socio-demographic, health predictors and anthropometric measurements (such as weight, height and waist circumference). The data analysis was performed on JMP®, Version 12. SAS Institute Inc., Cary, NC, 1989-2007. RESULTS: The prevalence of self-reported chronic pain in Al Kharj population was 19% with a mean age of 26.4 (SD = 8.6) years. The most common locations of pain included; back pain (30%), abdominal pain (26%), headache (13%), and any musculoskeletal pain (56%). Multiple logistic regression revealed that presence of a chronic disease (OR = 3.8; 95% CI = 2.3-6.2), psychological disease (OR = 2.3; 95% CI = 1.2-4.3), high General Health Questionnaire (GHQ)-12 score (OR = 1.06; 95% CI = 1.03-1.1), and pack-years of smoking (OR = 1.05; 95% CI = 1.01-1.08) were significantly related to chronic pain in Al Kharj population. CONCLUSIONS: Our study results found a high burden of chronic pain in this selected Saudi population. The most prevalent pain was low back pain. The presence of chronic and psychological diseases were strongly related to chronic pain. Future prospective studies are needed to establish the temporal relationship of chronic pain with these factors.

The Influence of Consanguinity on Familial Clefting Among Palestinians.

INTRODUCTION: Orofacial clefts (OFC) are the most common congenital craniofacial anomaly. The relationship between intermarriage (consanguinity) and positive family history for OFC is not well described. Consanguinity rates in developed countries are <1% but are considerably higher in the Middle East (45%). Familial clefting rates in developed countries are under 20% but in the Middle East are reported at 30% or higher. OBJECTIVE: To determine OFC demographics and to clarify the relationship between consanguinity and familial clefting among Palestinians. DESIGN: The Palestinian Congenial Anomalies Database is based on a 700-question survey administered to mothers of children with congenital anomalies. Orofacial clefts were diagnosed in 540 children. All demographic data were analyzed using χ2 tests with a level of significance at α < .05. RESULTS: Demographics for OFC among Palestinians were similar to other published reports. Overall consanguinity rate was 53% and familial clefting rate was 49%. Parental rates of consanguinity were significantly different for patients with cleft palate. Patients with consanguineous parents had a higher rate of positive family history of clefting (67%). Recurrence of clefts in siblings was significantly higher among those born to consanguineous parents (73%) when compared to nonconsanguineous parents. CONCLUSION: Consanguinity rates for Palestinians with OFC were higher than those reported in the Middle East. Familial clefting and sibling recurrence rates were also higher than expected. The risk of OFC may be mitigated with improved education about anticipated genetic consequences of consanguinity in high-risk populations such as the southern West Bank.

Characterizing Palestinian snake melon (Cucumis melo var. flexuosus) germplasm diversity and structure using SNP and DArTseq markers.

BACKGROUND: Crop landraces embody a source of beneficial genes potentially providing endurance to environmental stress and other agronomic qualities including yield. Our study included 88 snake melon accessions (Cucumis melo var. flexuosus) collected from 9 districts in the Palestinian West-Bank. These accessions represent four landraces of Palestinian snake melon: Green, and White Baladi, and Green, and White Sahouri. RESULTS: This is the first report on successful application of genotyping by sequencing in snake melon. Nine thousand seven hundred fifty single-nucleotide polymorphism (SNP) and 7400 DArTseq genetic markers were employed to evaluate genetic biodiversity and population structure of Palestinian snake melon germplasm collection. Clustering based on neighbor-joining-analysis, principle coordinate and Bayesian model implemented in Structure showed that patterns of genetic diversity of snake melon landraces depends on their geographical source and unraveled the presence of two major local landraces (Sahouri, and Baladi) with accessions from each group clustering together. A significant correlation was observed between both types of markers in Mantel correlation test. A significant association between genetic and geographic matrices (P < 0.0001) was also detected. AMOVA indicated that majority of variation (90%) was due to the difference within accessions. CONCLUSION: The Palestinian landraces seem to have unique genes that may allow the enhancement of the global snake melon gene pool and developments of the plant production worldwide. Our subsequent objective is to detect genotypes with promising qualities and to conduct association mapping studies concentrating on Fusarium-wilt resistance, yield, and environmental stresses.

Underlying trend, seasonality, prediction, forecasting and the contribution of risk factors: an analysis of globally reported cases of Middle East Respiratory Syndrome Coronavirus.

This study set out to identify and analyse trends and seasonal variations of monthly global reported cases of the Middle East respiratory syndrome coronavirus (MERS-CoV). It also made a prediction based on the reported and extrapolated into the future by forecasting the trend. Finally, the study assessed contributions of various risk factors in the reported cases. The motivation for this study is that MERS-CoV remains among the list of blueprint priority and potential pandemic diseases globally. Yet, there is a paucity of empirical literature examining trends and seasonality as the available evidence is generally descriptive and anecdotal. The study is a time series analysis using monthly global reported cases of MERS-CoV by the World Health Organisation between January 2015 and January 2018. We decomposed the series into seasonal, irregular and trend components and identified patterns, smoothened series, generated predictions and employed forecasting techniques based on linear regression. We assessed contributions of various risk factors in MERS-CoV cases over time. Successive months of the MERS-CoV cases suggest a significant decreasing trend (P = 0.026 for monthly series and P = 0.047 for Quarterly series). The MERS-CoV cases are forecast to wane by end 2018. Seasonality component of the cases oscillated below or above the baseline (the centred moving average), but no association with the series over time was noted. The results revealed contributions of risk factors such as camel contact, male, old age and being from Saudi Arabia and Middle East regions to the overall reported cases of MERS-CoV. The trend component and several risk factors for global MERS-CoV cases, including camel contact, male, age and geography/region significantly affected the series. Our statistical models appear to suggest significant predictive capacity and the findings may well inform healthcare practitioners and policymakers about the underlying dynamics that produced the globally reported MERS-CoV cases.

How do patient demographics, time-related variables, reasons for cancellation, and clinical procedures affect frequency of same-day operating room surgery cancelation? A maximum likelihood method.

BACKGROUND: Cancelation of same-day surgery is a common global problem, wasting valuable hospitals' operating room (OR) times and imposing significant economic costs. There is limited evidence to support the association between frequency of same-day surgery cancelation and patient demographics, time-related variables, healthcare provider reasons for cancelation, and clinical procedures in Saudi Arabia. The aim of this study was to explore this relationship, providing an understanding of the local context. METHODS: A retrospective cross-sectional study that retrieved medical records to examine the association between the frequency of same-day surgery cancelation and covariates including patient demographics, time-related variables, healthcare provider reason for cancelation, and clinical procedures. The data covered from January 2014 to December 2014 at King Fahad National Guard Hospital in Riyadh. We considered 440 patients that met the inclusion criteria for final analysis. The cancelation was regarded less frequent if a patient canceled once in the12 months and more frequent if a patient canceled two times or more in the same period. We used descriptive statistics to summarize data and employed a probit regression to estimate the association of frequency of same-day surgery cancelation and covariates via maximum likelihood method. King Abdullah International Medical Research Center granted the institutional approval. RESULTS: Our study suggests that while reasons of unavailability of OR time were associated with less frequent same-day surgery cancelation, scheduling issues were linked to more frequent cancelations, compared with reasons for patients being unwell on the day of surgery. Waiting time of more than six hours and morning sessions were associated with less frequent cancelations compared to shorter waiting time and afternoon sessions. Compared to general procedures, specialized clinical procedures were associated with cancelations that are more frequent. Further, female patients were more likely to have more cancelations. Finally, being married was associated with the less frequent cancelation of same-day surgery. CONCLUSION: Our findings provide evidence of determinants of the frequency of same-day surgery cancelations. This study draws several important implications for hospitals, especially on optimal utilization of resources and minimization of same-day surgery cancellations. The study also offers several recommendations that we believe will spur future research.

G Protein-Coupled Receptors Contain Two Conserved Packing Clusters.

G protein-coupled receptors (GPCRs) have evolved a seven-transmembrane helix framework that is responsive to a wide range of extracellular signals. An analysis of the interior packing of family A GPCR crystal structures reveals two clusters of highly packed residues that facilitate tight transmembrane helix association. These clusters are centered on amino acid positions 2.47 and 4.53, which are highly conserved as alanine and serine, respectively. Ala2.47 mediates the interaction between helices H1 and H2, while Ser4.53 mediates the interaction between helices H3 and H4. The helical interfaces outside of these clusters are lined with residues that are more loosely packed, a structural feature that facilitates motion of helices H5, H6, and H7, which is required for receptor activation. Mutation of the conserved small side chain at position 4.53 within packing cluster 2 is shown to disrupt the structure of the visual receptor rhodopsin, whereas sites in packing cluster 1 (e.g., positions 1.46 and 2.47) are more tolerant to mutation but affect the overall stability of the protein. These findings reveal a common structural scaffold of GPCRs that is important for receptor folding and activation.