Improving the quality of the intensive care follow-up of ventilated patients during a national registration program.

OBJECTIVES: The Belgian Public Health Organization is concerned with rates of hospital-acquired infections like ventilator-associated pneumonia (VAP). Implementing best practice guidelines for these nosocomial infections has variable success in the literature. This retrospective study was undertaken to see whether implementation of the evidence-based practices as a bundle was feasible, would influence compliance, and could reduce the rates of VAP. STUDY DESIGN: We utilized easily collectable data about regular care to rapidly assess whether interventions already in place were effectively successfully applied. This avoided cumbersome data collection and review. METHODS: Retrospective compliance rates and VAP ratios were compared using z tests with P-values < 0.05 considered statistically significant. This data review attempted to examine the impact of education campaigns, staff meetings, in-services, physician checklist, nurse checklist, charge nurse checklist implementation, systematic VAP bundle application, and systematic protocols for oral care and sedation protocols. Additionally, VAP ratio could be registered by the participating centers. RESULTS: A total of 10,211 intensive care unit (ICU) patients were included in the study which represents 66,817 ICU days under artificial ventilation with an endotracheal tube. The general compliance for VAP bundle raised from VAP was 61% in February 2012 and 74.16% in December 2012 (P < 0.001). The incidence rate of VAP went from 8.34 occurrences/1000 vent days in 2009 to 4.78 occurrences/1000 vent days in 2012 (P < 0.001-Pearson test). CONCLUSIONS: Efforts to improve physician and staff education, and checklist implementation resulted in an increase in compliance for VAP bundle and a decrease in VAP ratio. This study confirms the applicability of best practice guidelines about regular care but results on VAP incidence have to be confirmed.

Severe ASIA syndrome associated with lymph node, thoracic, and pulmonary silicone infiltration following breast implant rupture: experience with four cases.

Silicone has been considered biologically inert; thus it has been employed in many medical devices and nowadays is commonly used in plastic surgery for mammary prosthesis. It is well tolerated in most cases. However, autoimmune disorders and siliconomas with granulomatous reactions after silicone implant rupture have been described. We report cases of four women who developed systemic disorders following rupture of silicone breast implants resulting in lymph node and thoracic silicone infiltration. The symptoms in these cases, including arthralgia, myalgia, generalized weakness, severe fatigue, sleeping disturbances, cognitive impairment, memory loss, irritable bowel syndrome, and weight loss, clearly match the criteria of the recently defined autoimmune/inflammatory syndrome induced by adjuvants (ASIA).

A safety evaluation of intermittent high-dose inhaled nitric oxide in viral pneumonia due to COVID-19: a randomised clinical study.

High-dose inhaled Nitric Oxide (iNO) has been shown to have anti-inflammatory, vasodilator, and antimicrobial properties, resulting in improved arterial oxygenation as well as a beneficial therapeutic effect on lower respiratory tract infections. This study evaluated the safety and efficacy of 150-ppm intermittent iNO administered with a novel iNO-generator, for treating adults hospitalised for viral pneumonia. In this prospective, open-label, multicenter study, subjects aged 18-80, diagnosed with viral pneumonia received either standard supportive treatment alone (Control-Group) or combined with iNO for 40 min, 4 times per day up to 7 days (Treatment-Group). Out of 40 recruited subjects, 35 were included in the intention-to-treat population (34 with COVID-19). Adverse Events rate was similar between the groups (56.3% vs. 42.1%; respectively). No treatment-related adverse events were reported, while 2 serious adverse events were accounted for by underlying pre-existing conditions. Among the Treatment-Group, oxygen support duration was reduced by 2.7 days (Hazard Ratio = 2.8; p = 0.0339), a greater number of subjects reached oxygen saturation ≥ 93% within hospitalisation period (Hazard Ratio = 5.4; p = 0.049), and a trend for earlier discharge was demonstrated. Intermittent 150-ppm iNO-treatment is well-tolerated, safe, and beneficial compared to usual care for spontaneously breathing hospitalised adults diagnosed with COVID-19 viral pneumonia.

Applications to augment patient care for Internal Medicine specialists: a position paper from the EFIM working group on telemedicine, innovative technologies & digital health.

Telemedicine applications present virtually limitless prospects for innovating and enhancing established and new models of patient care in the field of Internal Medicine. Although there is a wide range of innovative technological solutions in Europe, there are overarching elements associated with such technologies when applied to the practices of Internal Medicine specialists. The European Federation of Internal Medicine (EFIM) strongly advocates for active leadership and influence from the Internal Medicine societies and specialist physicians across Europe in the development and application of telemedicine and digital technologies in healthcare. This position paper's conclusions were drawn via Delphi method, which was developed collaboratively from July 2021 to December 2023. The panel, consisting of experts in clinical medicine, public health, health economics and statistics, assessed various aspects related to telemedicine. Participants assigned scores on a Likert scale reflecting perceived value and potential risks. The findings were consolidated in a comprehensive checklist aligning with relevant literature and a SWOT analysis. Specifically, key issues that need to be addressed include promoting the professional development of e-health competencies in the healthcare and medical workforce, using educational campaigns to promote digital literacy among patients and caregivers, designing and implementing telemedicine applications tailored to local conditions and needs and considering the ethical and legal contexts under which these applications are employed. Importantly, there is currently no consensus on care models or standardized protocols among European Internal Medicine specialists regarding the utilization of telemedicine. This position paper aims to outline the opportunities and challenges associated with the application of telemedicine in Internal Medical practice in Europe.

Dipeptidyl peptidase-4 inhibitors and their effects on the cardiovascular system.

It is well known that patients with type 2 diabetes mellitus (T2DM) are at increased risk of cardiovascular (CV) disease. Elevated plasma glucose levels that independently lead to increased cardiovascular risk, combined with associated co-morbidities such as obesity, hypertension, and dyslipidemia, further contribute to the development of CV complications. Dipeptidyl peptidase 4 inhibitors (DPP-4 inhibitors) are a relatively new class of drugs used for the treatment of diabetes and recently have been widely used in clinical practice. They exert their actions through degradation inhibition of endogenous glucagon-like peptides (GLP-1) and glucose-dependent insulinotropic peptides (GIP), with a resulting increase in glucose mediated insulin secretion and a suppression of glucagon secretion. Since GLP-1 is known to have an impact not only on plasma glucose levels but also to have cardiovascular protective effects there is increased speculation of whether DPP-4 inhibitors will have similar effects. Though many short-term studies have been encouraging, ongoing long-term clinical trials on humans are needed to provide further clarity to the complete safety profiles of these agents in terms of cardiovascular risk, and whether they may exert potential cardiovascular benefit. This review includes available data on the cardiovascular effects of DPP-4 inhibitors as well as their overall safety profile.

Rapid seroconversion and persistent functional IgG antibodies in severe COVID-19 patients correlates with an IL-12p70 and IL-33 signature.

Despite ongoing efforts to characterize the host response toward SARS-CoV-2, a major gap in our knowledge still exists regarding the magnitude and duration of the humoral response. Analysis of the antibody response in mild versus moderate/severe patients, using our new developed quantitative electrochemiluminescent assay for detecting IgM/IgA/IgG antibodies toward SARS-CoV-2 antigens, revealed a rapid onset of IgG/IgA antibodies, specifically in moderate/severe patients. IgM antibodies against the viral receptor binding domain, but not against nucleocapsid protein, were detected at early stages of the disease. Furthermore, we observed a marked reduction in IgM/IgA antibodies over-time. Adapting our assay for ACE2 binding-competition, demonstrated that the presence of potentially neutralizing antibodies is corelated with IgG/IgA. Finally, analysis of the cytokine profile in COVID-19 patients revealed unique correlation of an IL-12p70/IL33 and IgG seroconversion, which correlated with disease severity. In summary, our comprehensive analysis has major implications on the understanding and monitoring of SARS-CoV-2 infections.

The caspase 9 inhibitor Z-LEHD-FMK protects human liver cells while permitting death of cancer cells exposed to tumor necrosis factor-related apoptosis-inducing ligand.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis of transformed and cancer cells but not of most normal cells. Recent studies have revealed an unforeseen toxicity of TRAIL toward normal human hepatocytes, thereby bringing into question the safety of systemic administration of TRAIL in humans with cancer. We found that SW480 colon adenocarcinoma, or H460 non-small cell lung cancer cell lines, which are sensitive to TRAIL, were not protected by the caspase 9 inhibitor Z-LEHD-FMK from TRAIL-induced apoptosis. However, a human colon cancer cell line HCT116 and a human embryonic kidney cell line 293, which are sensitive to TRAIL, were protected by Z-LEHD-FMK from TRAIL-mediated death. Both HCT116 and SW480 cells were protected from TRAIL by the caspase 8 inhibitor Z-IETD-FMK, dominant-negative FADD and cellular FLIP-s and interestingly both cell lines displayed caspase 9 cleavage to a similar extent after TRAIL exposure. We confirmed that normal human liver cells are sensitive to TRAIL. Moreover, we found that normal human liver cells could be protected from TRAIL-induced apoptosis by simultaneous exposure to Z-LEHD-FMK. A similar brief exposure to TRAIL plus Z-LEHD-FMK inhibited colony growth of SW480 but not HCT116 cells. Because some cancer cell lines are not protected from TRAIL-mediated killing by Z-LEHD-FMK, we believe that a brief period of caspase 9 inhibition during TRAIL administration may widen the therapeutic window and allow cancer cell killing while protecting normal liver cells. This strategy could be further developed in the effort to advance TRAIL into clinical trials.

Bax is a transcriptional target and mediator of c-myc-induced apoptosis.

The c-Myc oncoprotein is a transcription factor involved in cellular transformation as well as apoptotic cell death. We show here that over-expression of c-Myc delivered by an adenovirus vector up-regulates endogenous proapoptotic bax mRNA and protein expression in human cells. In contrast, the cytotoxic tumor necrosis factor-related apoptosis-inducing ligand induces cell death without up-regulating bax expression. c-Myc/Max heterodimers bind to canonical E-box elements located in the bax promoter region as demonstrated by electrophoretic mobility shift analysis and DNaseI foot-printing assays. Analysis of bax regulatory region mutants suggests a model involving myc-dependent activation as well as relief of repression through distinct E-box elements. c-Myc-null cells are deficient in bax-promoter activation as compared with wild-type c-Myc-expressing cells. Overexpression of c-Myc in serum-starved human or mouse embryonic cells leads to apoptosis which is significantly reduced in the presence of growth factor-containing serum. c-Myc-induced apoptosis appears to be deficient in bax-null as compared with bax-wild-type mouse embryonic fibroblasts. The results suggest that the cell death-promoting gene bax is directly downstream of c-Myc in a pathway leading to apoptosis.

Role of protein kinase C in cholinergic stimulation of lacrimal gland protein secretion.

The purpose of this study was to determine the role of protein kinase C (PKC) isozymes in carbachol-induced protein secretion in the lacrimal gland. Three isoforms of PKC are present in rat lacrimal gland; PKC-alpha, -delta and -epsilon. Carbachol translocated PKC-epsilon during 5 s incubation. Pretreatment with PdBu for 0 to 4 h down-regulated PKC-alpha by 31% at 20 min, PKC-epsilon by 36% at 2 h, and PKC-delta by 37% at 4 h. A 2 h phorbol ester treatment inhibited carbachol-induced secretion completely at 1 min and partially at 5, and 20 min, but did not alter the carbachol-induced increase in the intracellular [Ca2+]. We conclude that PKC-alpha and -epsilon, but not PKC-delta, are implicated in cholinergic agonist-induced protein secretion in rat lacrimal gland.

Enhanced TRAIL sensitivity by p53 overexpression in human cancer but not normal cell lines.

The cytotoxic ligand TRAIL is a promising anti-cancer agent that is entering into clinical trials. We previously identified a major subgroup of TRAIL resistant cancer cell lines with absent, or reduced DR4 expression containing a K441R polymorphism or harboring elevated levels of the caspase activation inhibitor FLIP. In the present study, we explored the use of a gene therapeutic approach utilizing p53, delivered by an adenovirus-p53 (Ad-p53) vector, which directly controls expression of the TRAIL receptor KILLER/DR5 in a panel of 8 cell lines including normal and TRAIL sensitive or resistant cancers. The functional status of the delivered p53 was monitored by detection of induced p21WAF1 expression by immunocytochemistry. In normal cells, which are TRAIL resistant, TRAIL did not reduce cell viability over and above the effect of Ad-p53 alone. All cancer cell lines were sensitive to Ad-p53 and up-regulated expression of the TRAIL receptor KILLER/DR5. TRAIL-resistant cancer cells became more sensitive to TRAIL at low Ad-p53 multiplicities of infection but TRAIL resistance was not completely overcome in one TRAIL-resistant cell line probably because of a high level of expression of FLIP. The results reveal that Ad-p53 induces the TRAIL receptor KILLER/DR5 and, like radiation or chemotherapy may effectively reverse TRAIL resistance.

Homozygous deletion of the death receptor DR4 gene in a nasopharyngeal cancer cell line is associated with TRAIL resistance.

The family of tumor necrosis factor related apoptosis inducing ligand (TRAIL) receptors, including the pro-apoptotic DR4 and p53-regulated KILLER/DR5, as well as the decoys TRID and TRUNDD, are all located on human chromosome 8p21-22. This region of the genome is frequently altered in head and neck cancer. We previously reported that KILLER/DR5 can be mutationally inactivated in head and neck cancer. Here, we report that the FaDu nasopharyngeal cancer cell line contains an abnormal chromosome 8p21-22 region. In addition, there appears to be a homozygous deletion involving DR4 but not KILLER/DR5 in FaDu cells. The homozygous loss within the DR4 gene encompasses its death domain, which is required for apoptotic signaling. The deletion of DR4 in FaDu cells is associated with resistance to the cytotoxic effects of TRAIL. Re-introduction of wild-type DR4 leads to apoptosis and restores TRAIL sensitivity of FaDu cells. These observations suggest that the death inducing DR4 receptor gene may be a rare target for inactivation in human cancer and that DR4 loss may contribute to resistance to TRAIL therapy.

Thrombosis of the pelvic veins associated with a large myomatous uterus.

BACKGROUND: Deep vein thrombosis is a rare indication for hysterectomy. CASE: A 45-year-old woman presented with a myomatous uterus of 20 gestational weeks' size that was compressing the pelvic veins directly and causing thrombosis. After preparation of the patient with anticoagulants and installation of an umbrella device in the inferior vena cava, we performed an uneventful abdominal hysterectomy. CONCLUSION: Pelvic deep vein thrombosis is a rarely reported complication of myomatous uterus. It can be managed successfully by anticoagulants, placement of an umbrella device in the inferior vena cava, and hysterectomy, as in our case.

Ovarian cyst formation: a complication of gonadotropin-releasing hormone agonist therapy.

Since gonadotropin-releasing hormone (GnRH) analogs were introduced into clinical therapeutic use, several side effects directly related to the hypoestrogenic state have been reported. The authors have encountered a rather infrequent complication, namely ovarian cystic formations, when using these compounds for selected in vitro fertilization and embryo transfer (IVF-ET) cases. In 7 of 24 patients with Decapeptyl (D-Trp6-luteinizing hormone-releasing hormone [LH-RH], Ferring, Kiel, FRG) treatment, and in 5 of 22 patients treated with Buserelin (Superfact, Hoechst A.G., Frankfurt, FRG), solitary ovarian cysts developed during the down-regulation phase. Their growth did not change during ovulation induction with menotropins. Although the mechanism of ovarian cyst formation during GnRH agonist treatment is not clear, their presence does not appear to interfere with the fertility of these women.

In vitro fertilization and embryo transfer in well-controlled, insulin-dependent diabetics.

Five IDD patients achieved strict preconception glycemic control and then underwent nine IVF-ET cycles. All patients had high E2 response with an adequate number of preovulatory oocytes retrieved and normal fertilization and cleavage rates; one conceived. Follicular fluid analysis revealed similar E2, P, A, hCG, PRL, and IGF-I levels to non-IDD controls. The source of the insulin detected in the FF of IDD patients was probably from the insulin doses administered intensively during the tight diabetes management; insulin was absent in non-IDD participants. It seems that patients with IDD have conventional responses to gonadotropin stimulation for IVF and their follicular milieu resembles that of non-IDD patients. Nevertheless, in view of the significant advantages of preconceptional diabetes control in regard to pregnancy outcome, they should be allowed to participate in IVF programs only after tight preconception metabolic control has been obtained.

The impact of long-term gonadotropin-releasing hormone analogue treatment on preclinical abortions in patients with severe endometriosis undergoing in vitro fertilization-embryo transfer.

OBJECTIVE: To examine the relationship between endometriosis and preclinical abortions and to evaluate the effect of gonadotropin-releasing hormone analogue (GnRH-a) therapy on these pregnancies. DESIGN AND PATIENTS: Of 67 women with severe endometriosis referred to us for in vitro fertilization-embryo transfer (IVF-ET), 32 underwent ovarian stimulation for oocyte retrieval with menotropins (protocol A), whereas the other 35 were admitted for the procedure after a 6-month period of hormonal suppression with a GnRH agonist (protocol B). The clinical impact of the preclinical and clinical pregnancies in both treatment protocols were evaluated on the basis of oocyte classification and embryo quality score. SETTING: All patients were treated in our IVF Unit. MAIN OUTCOME MEASURE: Clinical pregnancy was used as our main outcome measure of success. RESULTS: A significantly higher number of preclinical pregnancies (P less than 0.0001) occurred in patients treated by protocol A. After GnRH-a treatment, the preclinical pregnancy rate declined significantly (P less than 0.0001), whereas the clinical pregnancy rate per cycle and per transfer rose significantly (P less than 0.0001 and P less than 0.0001, respectively). Furthermore, clinical pregnancies had a significantly better mean embryo quality score in comparison with preclinical pregnancies (P less than 0.0001). CONCLUSIONS: It is concluded that combining GnRH-a therapy before IVF-ET provides an improved treatment modality for preclinical abortions and infertility associated with severe endometriosis.

Minidose gonadotropin-releasing hormone agonist is the treatment of choice in poor responders with high follicle-stimulating hormone levels.

OBJECTIVE: To investigate the effectiveness of minidose GnRH agonist (GnRH-a) + hMG in poor responders with elevated basal level FSH. DESIGN: Retrospective analysis of IVF cycles. SETTING: IVF Unit, Golda Medical Center, Petah Tikva, Israel. PATIENTS: One hundred six patients who were defined as poor responders on two previous IVF attempts. Three treatment protocols of midluteal Decapeptyl (D-Trp6) were compared: [1] a single-dose of 3.75 mg; [2] 0.5 mg daily until menstruation, followed by 0.1 mg daily; and [3] 0.1 mg daily until menstruation, followed by 0.05 mg daily. MAIN OUTCOME MEASURES: Comparisons were made among the three protocols regarding basal FSH levels, number of oocytes retrieved and fertilized, number of days of stimulation, follicular phase, P levels, and pregnancy and miscarriage rates. RESULTS: Treatment with minidose GnRH-a resulted in higher E2 levels and lower P levels on the day of hCG and lower cancellation rates. Furthermore, a higher number of oocytes recovered and fertilized and embryos transferred were recorded. The trend indicated improved pregnancy and implantation rates with a lower miscarriage rate. CONCLUSION: Minidose GnRH-a is a better choice than regular GnRH-a strategies in poor-responder patients undergoing IVF treatment.

Acute pelvic inflammatory disease after oocyte retrieval: adverse effects on the results of implantation.

OBJECTIVE: To determine the impact of pelvic inflammation on the results of IVF after oocyte retrieval. DESIGN: Retrospective analysis of IVF cycles. SETTING: IVF Unit, Golda Medical Center, Petah Tikva, Israel. PATIENTS: Twenty-eight women with a diagnosis of pelvic inflammatory disease (PID) during IVF therapy. MAIN OUTCOME MEASURE: The pregnancy rate (PR) of IVF cycles complicated by PID after oocyte retrieval was compared with our ongoing IVF results. RESULTS: All 28 women with PID during IVF treatment did not conceive, despite the high number of oocytes retrieved, fertilized, and transferred. The PR over the same period was 23% to 31%. CONCLUSIONS: Pelvic infection after IVF treatment might have a detrimental effect on the results of treatment. In an effort to maximize the chances for normal implantation, postponement of ET should be considered when pelvic infection or inflammation is diagnosed.

Severe abdominal complications after transvaginal ultrasonographically guided retrieval of oocytes for in vitro fertilization and embryo transfer.

Severe life-threatening complications as a result of ultrasonically guided ovum pick-up for IVF may rarely occur. We report 14 cases, out of 3,656 patients undergoing the procedure, presenting with a clinical picture of acute abdomen. In 9 patients tubo-ovarian and pelvic abscess were diagnosed; 3 were treated by laparotomy, whereas in the other 6, culdocentesis and drainage were performed. In 3 cases severe intra-abdominal bleeding occurred with 1 requiring laparotomy and hemostasis, whereas in the others laparoscopic drainage and hemostasis were sufficient. Ruptured endometriotic cystic masses caused acute abdomen in 2 patients; partial oophorectomy and drainage were essential operative procedures. We conclude that although severe postovum retrieval complications are rare, one has to be aware of their occurrence with the aim of accurate diagnosis and prompt intervention.

A severe case of ovarian hyperstimulation syndrome despite the prophylactic administration of intravenous albumin.

OBJECTIVE: To evaluate the role of the recently suggested IV administration of human albumin solution as an effective preventive measure of severe ovarian hyperstimulation in high-risk patients. CASE: Presented here is, to the best of our knowledge, the first case of early severe ovarian hyperstimulation necessitating early transabdominal aspiration of ascites and intensive fluid and colloid (dextran and albumin) replacement, which developed despite administration of IV human albumin solution in an attempt to prevent severe ovarian hyperstimulation. CONCLUSIONS: Because IV albumin does not prevent severe ovarian hyperstimulation in absolute terms, its use in high-risk patients should not lead one astray. Further research should be directed at investigating the fundamental cause of ovarian hyperstimulation syndrome and developing a reliable predictive test for this complication.

The value of repeat hysteroscopic evaluation in patients with failed in vitro fertilization transfer cycles.

One hundred ten women with normal initial hysteroscopy who failed to conceive during three or more IVF-ET cycles underwent repeat hysteroscopic evaluation. In 20 patients (18.2%), visualization revealed uterine abnormalities, mainly newly added endometrial lesions, i.e., hyperplasia, polyps, endometritis, and synechiae. Our results indicate that repeat hysteroscopic evaluation, in cases of recurrent IVF-ET failure, is an important adjunctive method for further evaluating and possibly optimizing the IVF-ET procedure.