Controlling cleaning agent residues in pharmaceutical manufacturing: A harmonized scientific strategy.

This paper proposes a scientifically justified and harmonized strategy to control cleaning agent ingredients' (CAIs) residues in pharmaceutical manufacturing. Firstly, we demonstrate that worst-case cleaning validation calculations on CAI residues with representative GMP standard cleaning limits (SCLs) are enough to control CAI residues of low concern to safe levels. Secondly, a new harmonized strategy for the toxicological assessment of CAI residues is presented and validated. The results establish a framework applicable to cleaning agent mixtures based on hazard and exposure considerations. This framework is primarily based on the hierarchy of a single CAI's critical effect, where the lowest resulting limit may become the driver of the cleaning validation process. The six critical effect groups are: (1) CAIs of low concern based on safe exposure reasoning; (2) CAIs of low concern based on the mode of action reasoning; (3) CAIs with local concentration-dependent critical effects; (4) CAIs with dose-dependent systemic critical effects for which a route-specific PDE should be calculated; (5) poorly characterized CAIs with unknown critical effect for which a default value of 100 µg/day is proposed; (6) poorly characterized CAIs which should be avoided because of potential mutagenicity and/or potency.

Phase IIa study of the CD19 antibody MOR208 in patients with relapsed or refractory B-cell non-Hodgkin's lymphoma.

Background: This two-stage, phase IIa study investigated the antitumor activity and safety of MOR208, an Fc-engineered, humanized, CD19 antibody, in patients with relapsed or refractory (R-R) B-cell non-Hodgkin's lymphoma (NHL). CD19 is broadly expressed across the B-lymphocyte lineage, including in B-cell malignancies, but not by hematological stem cells. Patients and methods: Patients aged ≥18 years, with R-R NHL progressing after ≥1 prior rituximab-containing regimen were enrolled into subtype-specific cohorts: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), other indolent (i)NHL and mantle cell lymphoma (MCL). Treatment was MOR208, 12 mg/kg intravenously, weekly, for 8 weeks. Patients with at least stable disease could continue treatment for an additional 4 weeks. Those with a partial or complete response after 12 weeks could receive extended MOR208 treatment (12 mg/kg, either monthly or every second week) until progression. The primary end point was overall response rate. Results: Ninety-two patients were enrolled: DLBCL (n = 35), FL (n = 34), other iNHL (n = 11) and MCL (n = 12). Responses were observed in DLBCL, FL and other iNHL cohorts (26%, 29% and 27%, respectively). They lasted ≥12 months in 5/9 responding patients with DLBCL, 4/9 with FL and 2/3 with other iNHL. Responses in nine patients are ongoing (>26 months in five instances). Patients with rituximab refractory disease showed a similar response rate and progression-free survival time to patients with non-refractory disease. The most common adverse events (any grade) were infusion-related reactions (12%) and neutropenia (12%). One patient experienced a grade 4 infusion-related reaction and eight patients (9%) experienced grade 3/4 neutropenia. No treatment-related deaths were reported. Conclusions: MOR208 monotherapy demonstrated promising clinical activity in patients with R-R DLBCL and R-R FL, including in patients with rituximab refractory tumors. These efficacy data and the favorable safety profile support further investigation of MOR208 in phase II/III combination therapy trials in R-R DLBCL. ClinicalTrials.gov number: NCT01685008.

A phase II trial of lenalidomide plus rituximab in previously untreated follicular non-Hodgkin's lymphoma (NHL): CALGB 50803 (Alliance).

BACKGROUND: This multicenter, phase II trial tested the tolerability and efficacy of lenalidomide plus rituximab in patients with previously untreated follicular lymphoma (FL). PATIENTS AND METHODS: Patients with grade 1-3a FL, stage 3-4 or bulky stage 2, FL international prognostic index (FLIPI) 0-2, and no prior therapy were eligible to receive rituximab 375 mg/m2 weekly during cycle 1 and day 1 of cycles 4, 6, 8, and 10, plus lenalidomide 20-25 mg on days 1-21 for twelve 28-day cycles. The primary objectives were to evaluate response rates [complete (CR) and overall] and time to progression. Secondary objectives included toxicity, response according to polymorphisms in FcgR2A and FcgR3A, and changes in circulating pro-angiogenic cells. RESULTS: From October 2010 to September 2011, 66 patients were enrolled. Median age was 53 years, 34 were female, 15 had bulky disease, 21 were FLIPI 0-1, 43 FLIPI 2, and 2 FLIPI 3. One patient withdrew before receiving treatment. Fifty-one patients completed 12 cycles of lenalidomide. Reasons for discontinuation included withdrawal (n = 6), adverse events (n = 6), progression (n = 2). Grade 3-4 hematologic toxicity included neutropenia (21%), lymphopenia (9%), and thrombocytopenia (2%), infection (11%), and rash (8%). Grade 1-2 toxicity included fatigue (78%), diarrhea (37%), rash (32%), and febrile neutropenia in one patient. The overall response rate was 95%; the CR rate was 72% (95% confidence interval, 60% to 83%). With a median follow-up of 5 years, the 2- and 5-year progression-free survival were 86% and 70%, respectively, and the 5-year overall survival was 100%. There was no association between CR rate or PFS and FLIPI, histological grade, bulky disease, FcgR2A/FcgR3A polymorphism, or change in circulating endothelial cell/hematopoietic progenitor cell. CONCLUSION: Lenalidomide plus rituximab was associated with low rates of grade 3-4 toxicity, yielded a CR rate and PFS similar to chemotherapy-based treatment and may represent a reasonable alternative to immunochemotherapy in previously untreated FL. CLINICALTRIALS.GOV IDENTIFIER: NCT01145495.

[Estimation of the Palliative Care Needs and the Extent of Coverage by Specialized Outpatient Palliative Care Teams in Selected Regions of Westphalia-Lippe]. / Abschätzung des ambulanten palliativmedizinischen Versorgungsgrades regionaler palliativmedizinischer Konsiliardienste in Westfalen-Lippe.

BACKGROUND: Data to estimate the palliative care needs and its outpatient coverage are of public health interest. METHODS: The theoretical palliative care needs were determined on the basis of a population with advanced cancer in selected regions of Westphalia (Germany); information from evaluated death certificates issued in 2011 in the cities of Bochum (BO) and Muenster (MS) and the rural districts of Coesfeld (COE) and Borken (BOR) were used for the analysis. The number of patients thus assessed was linked to anonymized data from the regional palliative home care teams and an estimate was made on the extent of palliative care provision. RESULTS: A total of 12,424 death certificates from 2011 were evaluated. In 22.1% (n=2,751), palliative care needs before death can be assumed. In the same year, 2,396 patients were cared for by the regional palliative home care teams, with 1,288 patients dying of cancer. The coverage of outpatient palliative care was calculated as follows: BO 54.2% (567/1,046), MS 60.6% (385/635), COE 54.4% (210/386), BOR 18.4% (126/684). CONCLUSIONS: One in 5 individuals has a need for palliative care before death. In statistical terms, more than 50% of tumor patients were cared for by regional palliative home care teams in the cities of Bochum and Muenster and the rural district of Coesfeld. By contrast, the degree of palliative care was less than 20% in the rural district of Borken.

Facet tropism and facet joint orientation: risk factors for the development of early biochemical alterations of lumbar intervertebral discs.

OBJECTIVE: To assess the glycosaminoglycan (GAG) content of lumbar intervertebral discs (IVD) in healthy volunteers with facet tropism (FT) and sagittal facet joint (FJ) orientation using glycosaminoglycan chemical exchange saturation transfer imaging (gagCEST). METHOD: Seventy-five lumbar IVDs of twenty-five young, healthy volunteers without any history of lumbar spine pathologies (13 female; 12 male; mean age: 28.0 ± 4.4 years; range: 21-35 years) were examined with a 3T MRI scanner. Orientation of FT and FJ were assessed for L3/4, L4/5 and L5/S1 using standard T2 weighted images. Biochemical gagCEST imaging was used to determine the GAG content of each nucleus pulposus (NP) and annulus fibrosus (AF). RESULTS: Significantly higher gagCEST values of NP were found in volunteers without FT and normal FJ orientation compared to volunteers with FT and sagittal FJ orientation >45° (P < 0.0001). GagCEST values were significantly higher in volunteers without FT compared to volunteers with moderate or severe FT (moderate FT: P < 0.0001; severe FT: P = 0.0033). Volunteers with normal FJ orientation showed significantly higher gagCEST values compared to those with sagittal FJ orientation >45° (P < 0.001). We found a significant, negative correlation between gagCEST values and higher angels in sagittal FJ orientation (rho = -0.459; P < 0.0001). CONCLUSION: GagCEST analysis indicated lower GAG values of NP in young volunteers with FT and sagittal orientated FJ, indicating that FT and sagittal orientation of the FJ represent risk factors for the development of early biochemical alterations of lumbar IVDs.

Entanglement and Bell Correlation in Electron-Exchange Collisions.

Elastic collisions between initially unpolarized electrons and hydrogenlike atoms are discussed, aiming to analyze the entanglement properties of the correlated final spin system. Explicit spin-dependent interactions are neglected and electron exchange only is taken into account. We show the final spin system to be completely characterized by a single spin correlation parameter depending on scattering angle and energy. Its numerical value identifies the final spins of the collision partners to be either in the separable, entangled, or Bell correlated regions. We emphasize explicit examples for the mixed spin system in order to illustrate the abstract concepts. The analysis of published experimental and numerical data reveals the possibility to create tunable pairs of collision partners with any desired degree of spin entanglement.

Serious pulmonary toxicity in patients with Hodgkin's lymphoma with SGN-30, gemcitabine, vinorelbine, and liposomal doxorubicin is associated with an FcγRIIIa-158 V/F polymorphism.

BACKGROUND: Based on in vitro synergistic cytotoxicity when anti-CD30 antibodies are combined with gemcitabine, the Cancer and Leukemia Group B conducted a double-blind, randomized, phase II trial of SGN-30 with gemcitabine, vinorelbine, and pegylated liposomal doxorubicin (GVD) in patients with relapsed Hodgkin's lymphoma. PATIENTS AND METHODS: In part 1 of the trial, 16 patients received SGN-30 with GVD to assess the safety of the combination. In part 2, patients were randomly allocated to SGN-30 (n = 7) or placebo (n = 7) with GVD to determine overall response rate (ORR). RESULTS: ORR in all 30 patients was 63% (65% with SGN-30 plus GVD, n = 23, and 57% with placebo plus GVD, n = 7). Median event-free survival was 9.0 months, with no difference between the two arms. Grades 3-5 pneumonitis occurred in five patients receiving SGN-30 and GVD, leading to premature closure of the trial. All five patients with pulmonary toxicity had a V/F polymorphism in the FcγRIIIa gene (P = 0.008). CONCLUSIONS: Together with historical data demonstrating a 2% incidence of pulmonary events with GVD, these results indicate that SGN-30 cannot safely be administered concurrently. The risk of pneumonitis with SGN-30 and GVD is greatest in patients with an FcγRIIIa V/F polymorphism.

Effects of autotransplanted lymph node fragments on the lymphatic system in the pig model.

Secondary lymphedema often develops after removal of lymph nodes in combination with radiation therapy, in particular in patients with breast cancer, inguinal cancer, cervical cancer and melanoma. No convincing treatment for the prevention and therapy of acquired lymphedema exists so far, therefore we wanted to show the reintegration of transplanted avascular lymph node fragments in the lymphatic system and positive effects of the transplanted fragments on the restoration of the lymphatic flow in this study. A total of 26 minipigs underwent lymphadenectomy of both groins. A minimum of one lymph node was retransplanted. The lymph nodes were cut into small pieces and retransplanted in the left groin (n = 17) or in both groins (n = 9). Different retransplantation techniques were investigated, transplantation of large versus small fragments, with and without capsule. The lymph flow was evaluated 5 and 8 months after surgery, using SPECT/CT and Berlin Blue. The results were confirmed by dissection. The lymph node transplants were assessed histologically. In contrast to the lymph flow in the transplanted groin, the lymph flow in the non-transplanted groin was often malfunctioning. Large lymph node fragments were found reintegrated in the lymphatic system more often than small slices of lymph node fragments. About 5 months after surgery impairment of lymph flow was seen especially after retransplantation of small slices of lymph node fragments. In seven out of eight minipigs a dermal backflow developed in the non-transplanted groin, 8 months after surgery. Only one minipig of these groups developed dermal backflow in both groins. All lymph node fragments showed an organized structure histologically. Autologous lymph node transplantation has positive effects on the regeneration of lymph vessels and restoration of lymph flow after lymphadenectomy.

[Distances to hospitals performing minimum volume relevant procedures in Germany 2004 to 2006]. / Distanzen zu Krankenhäusern mit Mindestmengen-relevanten Eingriffen 2004 bis 2006.

INTRODUCTION: In 2004, Germany introduced annual minimum volumes nationwide on five surgical procedures (kidney, liver, stem cell transplantation, complex oesophageal, and pancreatic interventions). In 2006, minimum volumes for total knee prosthesis were added and the five established minimum volumes were almost doubled. Since minimum volumes usually result in the regionalisation of procedures, especially patients from rural areas are impeded by geographical access problems. The aim of our study was to analyse regional and time-related differences in the distances patients travelled to hospitals performing minimum volume relevant procedures between 2004 and 2006 in Germany. METHODS: We performed a secondary analysis of data from the Institute for the Hospital Remuneration System (InEK). Using a geographical information system we analysed the distances that patients who underwent one of the six minimum volume procedures travelled to the hospital in the years 2004-2006. We performed t-tests to analyse differences between the 16 German Federal States and the years of observation while correcting for multiple testing. RESULTS: On average patients travelled between 28.6/28.0 km (2004/2006) for knee prosthesis and 78.9 km for stem cell transplantation (2004) and 97.4 km for liver transplantation (2006). In 2004, distances travelled differed up to a factor of 9.9 [comparing distances travelled to stem cell transplantation of patients of the states of Berlin (30.6 km) and Hamburg (303 km)]. In 2006, the maximum difference (factor 12.2) was observed for oesophageal interventions comparing distances travelled in the states of Bremen (7.2 km) and Saarland (88.8 km). For almost all comparisons there were significant differences of the minimum and maximum distances travelled in one of the Federal States compared to the federal average. Comparing distances travelled in 2004 and 2006 we found only small and inconsistent variations. DISCUSSION: We found that geographical access to inpatient care for minimum volume procedures in Germany differs sizably between the Federal States in 2004 and 2006. In spite of doubling the minimum volumes in 2006, the distances patients travelled to hospitals hardly change. This may be caused by an inert implementation of the minimum volume regulation leading to an unchanged number of hospitals providing the respective procedures.

Molecular neuro-biological and systemic health benefits of achieving dopamine homeostasis in the face of a catastrophic pandemic (COVID- 19): A mechanistic exploration.

In the face of the global pandemic of COVID 19, approaching 1.75 Million infected worldwide (4/12/2020) and associated mortality (over 108, 000 as of 4/12/2020) as well-as other catastrophic events including the opioid crisis, a focus on brain health seems prudent [1] (https://www.coronavirus.gov). This manuscript reports on the systemic benefits of restoring and achieving dopamine homeostasis to reverse and normalize thoughts and behaviors of Reward Deficiency Syndrome (RDS) dysfunctional conditions and their effects on behavioral physiology; function of reward genes; and focuses on digestive, immune, eye health, and the constellation of symptomatic behaviors. The role of nutrigenomic interventions on restoring normal brain functions and its benefits on these systems will be discussed. We demonstrate that modulation of dopamine homeostasis using nutrigenomic dopamine agonists, instead of pharmaceutical interventions, is achievable. The allied interlinking with diverse chronic diseases and disorders, roles of free radicals and incidence of anaerobic events have been extensively highlighted. In conjunction, the role of dopamine in aspects of sleep, rapid eye movement and waking are extensively discussed. The integral aspects of food indulgence, the influence of taste sensations, and gut-brain signaling are also discussed along with a special emphasis on ocular health. The detailed mechanistic insight of dopamine, immune competence and the allied aspects of autoimmune disorders are also highlighted. Finally, the integration of dopamine homeostasis utilizing a patented gene test and a research-validated nutrigenomic intervention are presented. Overall, a cutting-edge nutrigenomic intervention could prove to be a technological paradigm shift in our understanding of the extent to which achieving dopamine homeostasis will benefit overall health.

Biotechnical development of genetic addiction risk score (GARS) and selective evidence for inclusion of polymorphic allelic risk in substance use disorder (SUD).

Research into the neurogenetic basis of addiction identified and characterized by Reward Deficiency Syndrome (RDS) includes all drug and non-drug addictive, obsessive and compulsive behaviors. We are proposing herein that a new model for the prevention and treatment of Substance Use Disorder (SUD) a subset of RDS behaviors, based on objective biologic evidence, should be given serious consideration in the face of a drug epidemic. The development of the Genetic Addiction Risk Score (GARS) followed seminal research in 1990, whereby, Blum's group identified the first genetic association with severe alcoholism published in JAMA. While it is true that no one to date has provided adequate RDS free controls there have been many studies using case -controls whereby SUD has been eliminated. We argue that this deficiency needs to be addressed in the field and if adopted appropriately many spurious results would be eliminated reducing confusion regarding the role of genetics in addiction. However, an estimation, based on these previous literature results provided herein, while not representative of all association studies known to date, this sampling of case- control studies displays significant associations between alcohol and drug risk. In fact, we present a total of 110,241 cases and 122,525 controls derived from the current literature. We strongly suggest that while we may take argument concerning many of these so-called controls (e.g. blood donors) it is quite remarkable that there are a plethora of case -control studies indicating selective association of these risk alleles ( measured in GARS) for the most part indicating a hypodopaminergia. The paper presents the detailed methodology of the GARS. Data collection procedures, instrumentation, and the analytical approach used to obtain GARS and subsequent research objectives are described. Can we combat SUD through early genetic risk screening in the addiction field enabling early intervention by the induction of dopamine homeostasis? It is envisaged that GARS type of screening will provide a novel opportunity to help identify causal pathways and associated mechanisms of genetic factors, psychological characteristics, and addictions awaiting additional scientific evidence including a future meta- analysis of all available data -a work in progress.

Synergy of ethanol and putative neurotransmitters: glycine and serine.

The putative neurotransmitters, glycine and serine, significantly enhanced the sleeping time (loss of the righting reflex) that was induced by ethanol in mice. The observed synergistic effect between ethanol and the amino acids is probably not related to an alteration of ethanol metabolism, but rather to an interaction of these compounds in the central nervous system.

Reduced leucine-enkephalin--like immunoreactive substance in hamster basal ganglia after long-term ethanol exposure.

Golden Syrian hamsters were placed individually in cages with three drinking bottles--one empty, one containing water, and the third containing water and ethanol. Control hamsters received water only. After 1 year the experimental hamsters showed a significantly lower concentration of leucine-enkephalin-like immunoreactive substance in the basal ganglia than the control hamsters. This finding indicates that the action of ethanol involves endogenous peptidyl opiates.

Evidence for gene recombination in FCGR3 gene variants.

BACKGROUND AND OBJECTIVES: The genes encoding the Fcgamma receptors (FcgammaR) IIIa and IIIb (FCGR3A and FCGR3B) are clustered on chromosome 1 band q23-24 and exhibit allelic polymorphism. We investigated the molecular basis of additional new FCGR3 genomic variation. MATERIALS AND METHODS: A segment shared by FCGR3A and FCGR3B containing the polymorphic nucleotide positions 141, 147, 227, 266, and 277 in exon 3 was cloned and sequenced from genomic DNA of 30 donors and 3 bacterial artificial chromosome (BAC) clones. A mixture consisting of isolated FCGR3B*2- and FCGR3A- plasmids was cloned and sequenced as well. Additionally, nucleotide databases were screened for clones with variant FCGR3 sequences. RESULTS: A total of 12 FCGR3 variants defined by the polymorphic positions were detected in whole blood genomic DNA from 23 of 24 FCGR3B*2 and/or FCGR3B*3 positive donors, the DNA from two of three BAC clones and in the DNA mixture of isolated FCGR3B*2- and FCGR3A- plasmids. CONCLUSION: Nucleotide exchanges of the variants were non-random and resulted from two alternative nucleotides present in one of the polymorphic position of the basic FCGR3 forms. Polymerase chain reaction (PCR) artefacts cannot be excluded as origin of new variants, but there is strong evidence that at least two variants are the result of a somatic recombination.

[Influence of minimum volumes on the structure of inpatient care]. / Auswirkung der Mindestmengenvereinbarung auf die stationäre Versorgungsstruktur.

OBJECTIVE: In 2004 five minimum volumes were introduced for the first time into German hospitals. The structural effects of these minimum volumes are presented as the first part of a health service research to evaluate the minimum volume regulation. DESIGN/METHODOLOGY/METHODS: The investigation is based on the mandatory hospital quality reports for 2004. Data were extracted from 1710 quality reports, descriptively analysed and applied to the modified minimum volumes for 2006. RESULTS: In 2004, 485 out of 1710 German hospitals providing acute care and approximately 23,128 cases, i.e., 0.14% of all hospital cases, were affected by at least one minimum volume regulation. The number of affected hospitals varies considerably between the German Federal Sates with 16% in Bavaria and 75% in Bremen. In 2004 (and presumably 2006) the following hospital numbers will comply with the minimum volume regulation: liver transplantation 100% (63%), kidney transplantation 91% (84%), stem cell transplantation 84% (65%), complex oesophageal interventions 71% (40%), complex pancreatic interventions 82% (51%). On a case level, 4% of kidney transplantation cases and up to 22% of complex oesophageal interventions were to be redistributed. Viewing the hospital size by number of beds, smaller (100-300 beds) and medium size hospitals (300-600 beds) are affected in complex oesophageal and pancreatic interventions, whereas in transplantations medium and large hospitals (>600 beds) are affected. Considering the regional distribution on a district level, the number of districts with at least one hospital providing the respective service will decrease from 2004 to 2006, with the strongest reduction in complex oesophageal interventions from 172 to 82 districts (-53%). CONCLUSION: In 2004 the minimum volume regulation has moderate structural effects on the care setting. In 2006 these effects will be stronger due to the doubled number of interventions required for most of the minimum volumes. The effects on transplantations have to be differentiated from those on oesophageal and pancreatic interventions since the former are already highly centralised whereas the latter are mainly provided on a medium hospital care level and will be shifted on to the maximum hospital care level. This process should stimulate a debate on geographically equal access to care within and among the Federal Sates.

[Minimum hospital volumes for total knee replacement]. / Mindestmengen bei Knie-TEP-Implantationen.

BACKGROUND: As requested by the Federal Joint Committee, the German Hospital Institute and the Heinrich-Heine University of Düsseldorf carried out an investigation of the minimum volume regulation for hospitals based on the Social Legislation Code. Total knee replacement forms one minimum volume field. Since 2006 hospitals with a performance rate of less than the minimum volume of 50 patients a year with knee replacement are no longer permitted to conduct this procedure. The object of the present analysis is to investigate the impact of the minimum volume regulation for total knee replacement. METHODS: The results are based on two hospital surveys on the application of the minimum volume regulation for total knee replacement. 279 hospitals (response rate: 41,8%) participated in 2006 and 297 hospitals in 2007 (response rate: 47,5%). The results are representative of General hospitals with total knee replacements. RESULTS: As expected, hospitals above and below the minimum volume cut-off differ in size. To date the minimum volume regulation has led to a rather selective exclusion of hospitals from care. In the case of total knee replacement 13,7% of the hospitals have been excluded. Most hospitals that do not reach the minimum volume are still participating in care. A decisive reason for this is the existence of exception rules. In hospitals exceeding the minimum volume, certain quality management tools for knee replacement are more widely spread than in hospitals that do not reach the minimum volume. As a consequence of the minimum volume regulation, the participating hospitals improved their position in the market. Vice versa, the excluded hospitals are more concerned about the damage to their image that may result from being excluded from care. With respect to the further development of the minimum volume regulation, the hospitals do not share the same point of view. DISCUSSION: Because, as yet, only few hospitals with low case numbers have been excluded from care, the immediate effects of the minimum volume regulation on the affected hospitals and hospital care in general are limited. The surveys showed a considerable uncertainty among all participants about the application and effects of the minimum volume regulation in hospitals.

[Hospitals failing minimum volumes in 2004: reasons and consequences]. / Unterschreitungen der Mindestmengen 2004: Begründungen und Konsequenzen.

BACKGROUND: In 2004 Germany introduced annual minimum volumes nationwide on five surgical procedures: kidney, liver, stem cell transplantation, complex oesophageal, and pancreatic interventions. Hospitals that fail to reach the minimum volumes are no longer allowed to perform the respective procedures unless they raise one of eight legally accepted exceptions. The goal of our study was to investigate how many hospitals fell short of the minimum volumes in 2004, whether and how this was justified, and whether hospitals that failed the requirements experienced any consequences. METHOD: We analysed data on meeting the minimum volume requirements in 2004 that all German hospitals were obliged to publish as part of their biannual structured quality reports. We performed telephone interviews: a) with all hospitals not achieving the minimum volumes for complex oesophageal, and pancreatic interventions, and b) with the national umbrella organisations of all German sickness funds. RESULTS: In 2004, one quarter of all German acute care hospitals (N=485) performed 23,128 procedures where minimum volumes applied. 197 hospitals (41%) did not meet at least one of the minimum volumes. These hospitals performed N=715 procedures (3.1%) where the minimum volumes were not met. In 43% of these cases the hospitals raised legally accepted exceptions. In 33% of the cases the hospitals argued using reasons that were not legally acknowledged. 69% of those hospitals that failed to achieve the minimum volumes for complex oesophageal and pancreatic interventions did not experience any consequences from the sickness funds. However, one third of those hospitals reported that the sickness funds addressed the issue and partially announced consequences for the future. The sickness funds' umbrella organisations stated that there were only sparse activities related to the minimum volumes and that neither uniform registrations nor uniform proceedings in case of infringements of the standards had been agreed upon. DISCUSSION: In spite of the high number of hospitals that failed to achieve the minimum volumes in 2004, only few hospitals experienced consequences from the sickness funds. The reluctance of the payers may be explained, amongst others, by the small number of patients affected and the percentage of cases where legally accepted exceptions applied. In view of the partly unclear definitions of the exceptions and difficulties in the interpretation and execution of the minimum volumes in the hospitals and at the sickness fund level, it may be helpful to formulate more concrete instructions for the implementation of the standards.

Would induction of dopamine homeostasis via coupling genetic addiction risk score (GARS®) and pro-dopamine regulation benefit benzodiazepine use disorder (BUD)?

Prescriptions for Benzodiazepines (BZDs) have risen continually. According to national statistics, the combination of BZDs with opioids has increased since 1999. BZDs (sometimes called "benzos") work to calm or sedate a person by raising the level of the inhibitory neurotransmitter GABA in the brain. In terms of neurochemistry, BZDs act at the GABAA receptors to inhibit excitatory neurons, reducing VTA glutaminergic drive to reduce dopamine release at the Nucleus accumbens. Benzodiazepine Use Disorder (BUD) is very difficult to treat, partly because BZDs are used to reduce anxiety which paradoxically induces hypodopaminergia. Considering this, we are proposing a paradigm shift. Instead of simply targeting chloride channel direct GABAA receptors for replacement or substitution therapy, we propose the induction of dopamine homeostasis. Our rationale is supported by the well-established notion that the root cause of drug and non-drug addictions (i.e. Reward Deficiency Syndrome [RDS]), at least in adults, involve dopaminergic dysfunction and heightened stress. This proposition involves coupling the Genetic Addiction Risk Score (GARS) with a subsequent polymorphic matched genetic customized Pro-Dopamine Regulator known as KB220ZPBM (Precision Behavioral Management). Induction of dopamine homeostasis will be clinically beneficial in attempts to combat BUD for at least three reasons: 1) During detoxification of alcoholism, the potential induction of dopamine regulation reduces the need for BZDs; 2) A major reason for BZD abuse is because people want to achieve stress reduction and subsequently, the potential induction of dopamine regulation acts as an anti-stress factor; and 3) BUD and OUD are known to reduce resting state functional connectivity, and as such, potential induction of dopamine regulation enhances resting state functional connectivity. Future randomized placebo-controlled studies will investigate this forward thinking proposed novel modality.

Insurance Companies Fighting the Peer Review Empire without any Validity: the Case for Addiction and Pain Modalities in the face of an American Drug Epidemic.

The United States are amid an opioid overdose epidemic; we are challenged to provide non-addicting/non-pharmacological alternatives to assist in pain attenuation. There are proven strategies available to manage chronic pain effectively without opioids. Utilization review providers for insurance companies often ignore medicine based scientific peer-reviewed studies that warn against the chronic use of opioid medications, as well as the lack of evidence to support long-term use of opioids for pain. This paradigm must change if we are to indeed change the drug-embracing culture in American chronic pain management. A barrier to treatment is pushback on the part of insurance companies especially as it relates to fighting against pain relief alternatives compared to classical analgesic agents. Pain specialists in the U.S., are compelled to find alternative solutions to help pain victims without promoting unwanted tolerance to analgesics and subsequent biological induction of the "addictive brain." It is noteworthy that reward center of the brain plays a crucial role in the modulation of nociception, and that adaptations in dopaminergic circuitry may affect several sensory and affective components of chronic pain syndromes. Possibly knowing a patient's genetic addiction risk score (GARS™) could eliminate guessing as it relates to becoming addicted.

Clinical use of PI3K inhibitors in B-cell lymphoid malignancies: today and tomorrow.

INTRODUCTION: PI3K inhibitors are an important new therapeutic option for the treatment of relapsed and refractory B-cell lymphoid malignancies. Idelalisib is a PI3Kδ inhibitor that has been approved for the treatment of lymphoma and chronic lymphocytic leukemia in the relapsed/refractory setting, and several other PI3K inhibitors are being developed targeting other isoforms of the PI3K enzyme, which results in distinct toxicities and variable efficacy in the clinical setting. Areas covered: We provide a general overview of PI3K inhibitors, recommended applications, and the mechanism and management of toxicities. We further review trials, ongoing and completed, leading to the approval of idelalisib as well other PI3K inhibitors currently in development. Articles were obtained from PubMed, and abstracts were searched for the past 5 years from the websites for ASCO, ASH, EHA, and ICML/Lugano. Expert commentary: PI3K inhibitors provide an important and powerful pharmacologic tool in the armamentarium against hematologic malignancies, especially for relapsed/refractory B-cell lymphoid malignancies. Unique toxicities are associated with inhibition of different isoforms of the PI3K enzyme, as demonstrated with the infectious and autoimmune toxicities associated with the PI3Kδ inhibitor, idelalisib. Due to these unique toxicities, PI3K inhibitors should only be used in formally approved combinations and settings.