Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13.

Congenital generalized lipodystrophy, or Berardinelli-Seip syndrome (BSCL), is a rare autosomal recessive disease characterized by a near-absence of adipose tissue from birth or early infancy and severe insulin resistance. Other clinical and biological features include acanthosis nigricans, hyperandrogenism, muscular hypertrophy, hepatomegaly, altered glucose tolerance or diabetes mellitus, and hypertriglyceridemia. A locus (BSCL1) has been mapped to 9q34 with evidence of heterogeneity. Here, we report a genome screen of nine BSCL families from two geographical clusters (in Lebanon and Norway). We identified a new disease locus, designated BSCL2, within the 2.5-Mb interval flanked by markers D11S4076 and D11S480 on chromosome 11q13. Analysis of 20 additional families of various ethnic origins led to the identification of 11 families in which the disease cosegregates with the 11q13 locus; the remaining families provide confirmation of linkage to 9q34. Sequence analysis of genes located in the 11q13 interval disclosed mutations in a gene homologous to the murine guanine nucleotide-binding protein (G protein), gamma3-linked gene (Gng3lg) in all BSCL2-linked families. BSCL2 is most highly expressed in brain and testis and encodes a protein (which we have called seipin) of unknown function. Most of the variants are null mutations and probably result in a severe disruption of the protein. These findings are of general importance for understanding the molecular mechanisms underlying regulation of body fat distribution and insulin resistance.

[Obstacles to effective treatment of depression. A general practitioners' postal survey in the north-west region of France]. / Enquête sur la prise en charge des patients dépressifs en soins primaires: les médecins généralistes ont des difficultés et des solutions.

CONTEXT AND AIM: Depression is a quite common condition, and its treatment is mainly provided by General Practitioner (GP). It is already known that detection and treatment requires significant improvement. The well known and high consumption of antidepressant drugs in France, the highest of all other European countries, requires specific studies. The causes of this situation are not clear and seem to be numerous: Patient's demands, social claims; lack of initial and continuous medical education, bad GP demographic trends, and lack of them in rural areas; pharmaceutical company pressure; and organisation of the health care system. GP are the main medical actors of the primary care system in France. The aim of this study was to survey GP perceptions on secondary care services, seek the views and barriers to the provision of good services, and ask them about perceptions and solutions they could suggest. METHODS: A structured postal questionnaire was sent to all GP of the north-west region of France, asking physicians about obstacles perceived when taking care of depressive patients; factors influencing the use of services, specialised advice, treatments, access to psychiatrists and psychological care. Their psychiatric knowledge and demographic data were also assessed. Quantitative data were analysed using Epi-Info software, and qualitative data were transcribed and coded manually. RESULTS: A total of 25% of the GP returned the questionnaire (n=2097 in 8709). The sample profile was the same as the studied population. Less than a third of the GP (28%) were aware of the clinical guidelines on depression, and less than a fifth (18%) had clinical experience of psychiatry during their studies. Lack of time was not the main obstacle assessed by the GP. Their complaints were about lack of mental health services, difficulty in accessing services, and about general liaison between primary and secondary health care services: they reported difficulties obtaining quick and good response from the specialist either for emergency or non emergency cases. Regarding secondary care, they mainly referred to the psychiatrist, rather than to the psychologist, probably because this second option is not reimbursed by the social security system. Not surprisingly, medication was cited as the most frequently used treatment, followed by psychotherapy and cognitive behavioral therapy (CBT), and almost never self help literature and self help groups. Trained GP considered they were much more comfortable coping with depressed patients, less frequently using secondary care providers, and easily alternative solutions rather than antidepressant drugs. This situation suggests the usefulness of medical education, and is attested by many qualitative answers. DISCUSSION: It is not sure that the low rate of knowledge of the guidelines should be judged only as a lack of professionalism. According to the "French Society of Primary Care", clinical guidelines need updating, and it is known that those available could be useful only for half of the situations encountered in primary care. Operational propositions urgently need to be proposed. Recent questioning of the real interest of pharmaceutical options in the treatment of depression is another argument. Nor can we wait for a hypothetic rise in the demographic situation. The GP have several propositions to improve these problems, e.g. continuous medical education (CME) focusing on "patient centred therapy", dedicated hotline or circuit for depressed people, and an adapted sociomedical directory. They also feel that political awareness about lack of physicians is required, but say that improving quality of care does not rely only on improving demographics. They ask for funds for psychological care. When thinking about the circuit of care, the role of all care providers, and their communication, a global vision appears unavoidable, which would get rid of the divisions between out-patients and the hospital. CONCLUSION: Despite an unavoidable questioning on the dysfunctions of the health care system, quality of care and probably pharmaceutical consumption for the depressed patient might be improved by simple tools, such as adapted CME for primary care physicians, and communication improvement between secondary and primary care systems.

[Information for patients about hospital infections in psychiatry: An assessment of healthcare professionals' knowledge, opinion and attitude]. / Connaissances, opinions et pratiques des professionnels concernant l'information des patients sur les infections nosocomiales : évaluation en milieu psychiatrique.

INTRODUCTION: French legislation makes mandatory for healthcare providers the disclosure of hospital infection (HI) risk and actual occurrence to the patient. Given the specific diseases encountered in psychiatry, some difficulties may be expected in practical application of this regulation. OBJECTIVES: The aim of our study was to describe the knowledge, declared practices and opinions of healthcare workers (HCW) in psychiatry concerning information for patients about HI. METHODS: We randomly selected doctors, nurses and head nurses from four hospitals with psychiatric activity in Normandy. The HCW were asked to self-complete an anonymous questionnaire, including data describing the responding HCW and questions aiming at describing his/her knowledge, attitude in routine daily practice and opinion about information to patients about HI. RESULTS: One hundred and forty-one HCW were initially selected, of which 114 (80.9%) eventually agreed to complete the questionnaire. Only eight HCW (7.0%) were considered to have a correct overall knowledge of legal obligations. Main errors concerned the obligation to inform the patient of the HI risk according to the medical procedures that are to be performed (43.9% of correct answers) and the obligation to inform the patient of the HI risk according to his/her medical condition (46.5%). The obligation to inform the patient of the occurrence of a HI was largely known (84.2%). HCW usually giving information about the risk of HI to patients without HI accounted for 5.3%. Main reasons advocated for not informing patients were a low level risk of HI in psychiatry (80.4%) and the lack of patients' demand (59.8%). In the case of HI occurrence, the percentage of HCW routinely informing patients was 13.2%. HCW systematically informing the patient's family about the occurrence of HI accounted for 9.6%. A large proportion of HCW supported delivering information to patients about HI (86.0%). HCW expected from information better approval of prevention programs by the patients (87.7%) but feared an increased anxiety in patients (75.4%) and a higher rate of care refusal (48.2%). CONCLUSION: Whereas a very large proportion of HCW in psychiatry support delivering information to patients about HI, our study shows HCW's lack of awareness of regulations and lack of declared practices. Among factors explaining this contrast, a lower perceived HI risk and severity level are to be mentioned. Training programs focusing on risk and mechanisms of HI could be offered to professionals in psychiatry. The issue of specific communication difficulties with psychiatric patients should be addressed as well. In order to develop information on HI, specific methods suited to those patients should be developed.

Production and Characterization of a Conditionally Immortalized Dog Beta-Cell Line from Fetal Canine Pancreas.

Since the 1970s, rodent and human insulin-secreting pancreatic beta-cell lines have been developed and found useful for studying beta-cell biology. Surprisingly, although the dog has been widely used as a translational model for diabetes, no canine insulin-secreting beta cells have ever been produced. Here, a targeted oncogenesis protocol previously described by some of us for generating human beta cells was adapted to produce canine beta cells. Canine fetal pancreata were obtained by cesarean section between 42 and 55 days of gestation, and fragments of fetal glands were transduced with a lentiviral vector expressing SV40LT under the control of the insulin promoter. Two Lox P sites flanking the sequence allowed subsequent transgene excision by Cre recombinase expression. When grafted into SCID mice, these transduced pancreata formed insulinomas. ACT-164 is the cell line described in this report. Insulin mRNA expression and protein content were lower than reported with adult cells, but the ACT-164 cells were functional, and their insulin production in vitro increased under glucose stimulation. Transgene excision upon Cre expression arrested proliferation and enhanced insulin expression and production. When grafted in SCID mice, intact and excised cells reversed chemically induced diabetes. We have thus produced an excisable canine beta-cell line. These cells may play an important role in the study of several aspects of the cell transplantation procedure including the encapsulation process, which is difficult to investigate in rodents. Although much more work is needed to improve the excision procedure and achieve 100% removal of large T antigen expression, we have shown that functional cells can be obtained and might in the future be used for replacement therapy in diabetic dogs.

TGF-beta plays a key role in morphogenesis of the pancreatic islets of Langerhans by controlling the activity of the matrix metalloproteinase MMP-2.

Islets of Langerhans are microorgans scattered throughout the pancreas, and are responsible for synthesizing and secreting pancreatic hormones. While progress has recently been made concerning cell differentiation of the islets of Langerhans, the mechanism controlling islet morphogenesis is not known. It is thought that these islets are formed by mature cell association, first differentiating in the primitive pancreatic epithelium, then migrating in the extracellular matrix, and finally associating into islets of Langerhans. This mechanism suggests that the extracellular matrix has to be degraded for proper islet morphogenesis. We demonstrated in the present study that during rat pancreatic development, matrix metalloproteinase 2 (MMP-2) is activated in vivo between E17 and E19 when islet morphogenesis occurs. We next demonstrated that when E12.5 pancreatic epithelia develop in vitro, MMP-2 is activated in an in vitro model that recapitulates endocrine pancreas development (Miralles, F., P. Czernichow, and R. Scharfmann. 1998. Development. 125: 1017-1024). On the other hand, islet morphogenesis was impaired when MMP-2 activity was inhibited. We next demonstrated that exogenous TGF-beta1 positively controls both islet morphogenesis and MMP-2 activity. Finally, we demonstrated that both islet morphogenesis and MMP-2 activation were abolished in the presence of a pan-specific TGF-beta neutralizing antibody. Taken together, these observations demonstrate that in vitro, TGF-beta is a key activator of pancreatic MMP-2, and that MMP-2 activity is necessary for islet morphogenesis.

Influence of infection control report cards on patients' choice of hospital: pilot survey.

The impact on patients' attitudes of quality report cards on infection control in hospitals has never previously been studied. In 2006, the French government implemented a mandatory report card on infection control activity (ICALIN) in all hospitals. This approach was aimed at encouraging professionals to change their routine practices in case they should lose patients due to a low ICALIN score. Our objective was to assess what impact ICALIN could have on patients' attitude as regards hospital choice. We performed a survey of patients and visitors in 14 randomly selected hospitals of various ICALIN scores. A convenience sample of 381 patients and visitors completed an anonymous questionnaire on ICALIN, their reasons for choosing a hospital and attitude in the event of a low ICALIN score. Factors associated with interest in ICALIN and impact of ICALIN on hospital choice were assessed by logistic regression. Our results showed that 77% of participants were interested in ICALIN. ICALIN was ranked sixth as a reason for choosing a hospital. In the case of a low ICALIN, 24.1% of participants would refuse admission and 54.9% would seek advice from their general practitioner. Sociodemographic factors had no influence on patients' attitude. In conclusion, our survey suggests that patients take note of poor performance on infection control report cards. As most patients rely on their general practitioner to interpret these report cards, there is a definite need for further communication with general practitioners on this issue.

Production, Characterization, and Function of Pseudoislets from Perinatal Canine Pancreas.

We evaluated the cell composition and function of canine pancreatic pseudoislets (PIs) produced from 42- to 55-day-old fetuses, 1- to 21-day-old pups, and an adult dog pancreas. After mild collagenase treatment, partially digested tissues were cultured for 2-3 weeks. PI production started on culture day 3, was marked for 6 to 9 days, and then stopped. PI production was greatest with the neonatal specimens, reaching about 12 million aggregates per litter (55-day-old fetus) or per pancreas (1-day-old pup). Cell composition at all stages was similar to that in adult pancreatic islets, with predominant ß cells, scant α cells and, most importantly, presence of δ cells. Among pancreatic markers assessed by quantitative real-time PCR (qRT-PCR) mRNA assay, insulin showed the highest expression levels in PIs from newborn and adult pancreas, although these were more than 1000 times lower than in adult islets. Pdx1 mRNA expression was high in PIs from 55-day-old pancreases and was lower at later stages. Consistent with the qRT-PCR results, the insulin content was far lower than reported in adult dog pancreatic islets. However, insulin release by PIs from 1-day-old pups was demonstrated and was stimulated by a high-glucose medium. PIs were transplanted into euglycemic and diabetic SCID mice. In euglycemic animals, the transplant cell composition underwent maturation and transplants were still viable after 6 months. In diabetic mice, the PI transplants produced insulin and partially controlled the hyperglycemia. These data indicate that PIs can be produced ex vivo from canine fetal or postnatal pancreases. Although functional PIs can be obtained, the production yield is most likely insufficient to meet the requirements for diabetic dog transplantation without further innovation in cell culture amplification.

Management of the child born small for gestational age through to adulthood: a consensus statement of the International Societies of Pediatric Endocrinology and the Growth Hormone Research Society.

OBJECTIVE: Low birth weight remains a major cause of morbidity and mortality in early infancy and childhood. It is associated with an increased risk of health problems later in life, particularly coronary heart disease and stroke. A meeting was convened to identify the key health issues facing a child born small for gestational age (SGA) and to propose management strategies. PARTICIPANTS: There were 42 participants chosen for their expertise in obstetrics, peri- and neonatal medicine, pediatrics, pediatric and adult endocrinology, epidemiology, and pharmacology. EVIDENCE: Written materials were exchanged, reviewed, revised, and then made available to all. This formed the basis for discussions at the meeting. Where published data were not available or adequate, discussion was based on expert clinical opinions. CONSENSUS PROCESS: Each set of questions was considered by all and then discussed in plenary sessions with consensus and unresolved issues identified. The consensus statement was prepared in plenary sessions and then edited by the group chairs and shared with all participants. CONCLUSIONS: The diagnosis of SGA should be based on accurate anthropometry at birth including weight, length, and head circumference. We recommend early surveillance in a growth clinic for those without catch-up. Early neurodevelopment evaluation and interventions are warranted in at-risk children. Endocrine and metabolic disturbances in the SGA child are recognized but infrequent. For the 10% who lack catch-up, GH treatment can increase linear growth. Early intervention with GH for those with severe growth retardation (height sd score, <-2.5; age, 2-4 yr) should be considered at a dose of 35-70 microg/kg x d. Long-term surveillance of treated patients is essential. The associations at a population level between low birth weight, including SGA, and coronary heart disease and stroke in later life are recognized, but there is inadequate evidence to recommend routine health surveillance of all adults born SGA outside of normal clinical practice.

Ontogenesis of thyrotropin-releasing hormone in the human fetal pancreas. A combined radioimmunological and immunocytochemical study.

The ontogenesis of pancreatic thyrotropin-releasing hormone (TRH) in the human fetal gland was studied by radioimmunoassay or immunocytochemistry. The highest TRH concentrations (1,508.5 +/- 382.3 pg/mg wet wt) were detected between 6 and 8 wk of gestation. From 9 to 12 wk, TRH declined to 365.2 +/- 127.4 pg/mg wet wt and remained low thereafter (96.1 +/- 28.9 pg/mg wet wt). The immunocytochemical procedure was performed on semithin and thin sections from 12- to 19-wk-old human fetuses. At the light microscope level, TRH was found interspersed among the islet cell clusters (12 wk), and later (16 wk) inside the typical islets of Langerhans. Consecutive semithin sections treated by TRH and insulin antisera showed the same immunoreactive cells. Electron microscopy showed TRH in B cell secretory granules. These results are consistent with an eventual implication of TRH in the endocrine regulation of metabolism or in the fetal development of pancreas.

Observations on the maturation of thyroid function in early fetal life.

Serum samples were obtained from 21 normal human fetuses after therapeutic abortion for psychiatric indications. Fetal crown-rump length ranged from 5.2 to 22.5 cm, corresponding to the gestational age of 65-168 days.Serum thyroxine, assayed by a modification of the Murphy-Pattee method, was identified in the second smallest fetus examined at 78 days gestation. Thereafter it increased rapidly, maintaining a significant linear correlation with crown-rump length until term (r = 0.800, P < 0.001). Free thyroxine (FT4) also increased in a linear relation to gestational age (r = 0.908, P < 0.001), but reached term levels by 18-20 wk. Radioimmunoassayable thyroid-stimulating hormone (TSH) was detected at 78 days gestation. Levels increased rapidly with advancing gestation, so that by 16 wk almost all were within the range of term infants. After 16 wk gestation, levels were usually greater than 4.0 muU/cc, higher than that seen in normal children. No correlation was demonstrated between the serum TSH levels and total thyroxine. TSH and FT4, however, increased in a parallel manner with a significant positive correlation. This suggested that fetal TSH secretion was responsive to FT4 levels from very early in gestation, possibly as early as 11 wk.Thyroxine-binding globulin (TBG) was detected in a fetus of 78 days gestation (1.4 mug/100 ml). Levels increased rapidly, paralleling the rise in serum thyroxine and maintaining a linear correlation with crownrump length (r = 0.864, P < 0.001). Thyroxine-binding prealbumin binding capacity (TBPA) in fetuses 14-24 wk gestation was comparable with that seen at term. When examining the distribution of tracer amounts of thyroxine-(131)I (T4-(131)I) between the thyroxine-binding proteins, it was found that a major fraction was bound to TBPA and albumin during the early part of gestation. This decreased linearly with maturation of the fetus as the fraction bound to TBG increased. By 20 wk gestation fetal TBG was able to bind 78% of tracer despite a TBG capacity of only 7.7 mug/100 ml. This appeared to be the result of relatively low concentrations of TBPA and albumin during this period of gestation. The theoretical association constant calculated for fetal and newborn TBG was found to be similar to that estimated for normal adult males and females.

Histidyl-proline diketopiperazine (His-Pro DKP) immunoreactivity is present in the glucagon-containing cells of the human fetal pancreas.

Histidyl-proline diketopiperazine (His-Pro DKP) cells in the pancreas of human fetuses aged between 12 and 19 wk were localized by the indirect antibody-enzyme method on semithin sections. To study their fine structure, two techniques were used: a superimposition technique consisting of comparison of the same cells in semithin and electron microscopic preparations, and an immunocytochemical technique on ultrathin sections using the unlabeled antibody peroxidase-antiperoxidase method. Our results show that (a) the same cells are positive for both His-Pro DKP and glucagon/glicentin, (b) His-Pro DKP immunoreactive cells possess extremely electron-opaque secretory granules, implying that these cells correspond to the A cells, and (c) His-Pro DKP immunoreactivity is found over the secretory granules. We hypothesize that the two peptides His-Pro DKP and thyrotropin-releasing hormone (TRH) have independent origins, since TRH is found in the B cells.

Are cysteine-rich and COOH-terminal domains of dystrophin critical for sarcolemmal localization?

It has been hypothesized that the tight localization of dystrophin at the muscle membrane is carried out by its cysteine-rich and/or carboxyl domains. We report the results of biochemical and immunocytochemical investigations of dystrophin in muscle from a 1-yr-old patient with a large deletion that removes the distal part of the dystrophin gene, thus spanning the exons coding for the cysteine-rich and the carboxy-terminal domains, and extends beyond the glycerol kinase and congenital adrenal hypoplasia genes. Immunological analysis of muscle dystrophin shows that the deletion results in the production of a truncated, but stable, polypeptide correctly localized at the sarcolemma. These data indicate that neither the cysteine-rich domain, nor the carboxyl domain, are necessary for the appearance of normal dystrophin sarcolemmal localization.

What factors influence healthcare professionals' opinion and attitude regarding information for patients about hospital infection?

Although informing patients about medical risks is said to decrease the number of malpractice claims, most inpatients receive no information about hospital infection. Using a self-administered questionnaire, we surveyed 1270 healthcare workers randomly selected from 22 French hospitals to assess their opinion on information for patients about hospital infection risks, and their practice of informing patients with, or without, hospital infection. The influence of healthcare worker characteristics on opinion and practice was assessed using logistic regression. Response rate was 87.2%. Although 85.4% supported giving more information, only 17.0% routinely informed non-infected patients and 31.6% informed infected patients about infection. Attitudes were influenced by healthcare worker characteristics and environmental factors. Knowledge of obligations influenced practice when informing non-infected patients, but not those with hospital-acquired infection. Further research is needed to help healthcare professionals improve risk communication and disclosure of hospital infection.

Reassessment of antibiotic therapy in hospitals.

INTRODUCTION: French national guidelines state that antibiotic therapies should be reassessed between 48 and 72hours after treatment initiation and that reassessment of antibiotic therapy (RA) must be recorded in patients' files. OBJECTIVE: To determine whether RA is performed and recorded in patients' files in hospitals in a region of France. METHODS: Setting: hospitals participating in the National nosocomial infection point- prevalence survey (NPS) in Upper-Normandy, France. Patients included those receiving antibiotic therapy (excluding antibiotic prophylaxis) on NPS day, started in the hospital in which the survey was conducted and ongoing for more than 72hours. Data collected included characteristics of participating hospitals and, for each included patient, characteristics of ward, infection and antibiotic therapy, and mention in the patients' files of explicit or implicit RA. The rate of explicit and implicit RA was calculated and factors associated with explicit or implicit RA were evaluated using a univariate analysis. RESULTS: Thirty-three hospitals representing 87% of hospital beds region-wide were included in the study. In addition, 933 prescriptions were assessed for 724 infections in 676 patients. The overall rate of RA was 67.6% (49.3% of explicit RA and 18.3% of implicit RA). The rate of RA differed significantly according to infection and antibiotic class but not according to hospital or ward characteristics. CONCLUSION: Our study provides new and reassuring results regarding reassessment of antibiotic therapy.

A transient microenvironment loaded mainly with macrophages in the early developing human pancreas.

We have previously shown that the human developing pancreas, as a tissue under construction and remodeling, is composed of epithelial ducts and differentiated endocrine cells surrounded by mesenchyme. The physiologic importance of resident tissue leukocytes, expected to enter through the mesenchyme in remodeling functions, prompted us to investigate human developing pancreases for the presence of leukocyte lineages and for expression of cytokines and receptors involved in their recruitment and differentiation. Immunohistochemistry studies were performed on 69 human, paraffin-embedded pancreases at 6-12 weeks of development (WD). Cytokines and receptor transcripts were monitored by reverse transcription (RT)-PCR, by immunohistochemistry when antibodies were available or by in situ hybridization (ISH). We show that numerous cells expressing CD45RA, HLADR and CD68 antigens are cellular components of the mesenchyme of all the pancreases at 6-12 WD. So-called constitutive chemokines (SLC (CCL19), stromal-derived factor 1 (SDF1) (CXCL12)) and a macrophage-specific growth/survival factor, colony-stimulating factor 1 (CSF1), were detected in epithelial duct cells. Both epithelial and mesenchymal cells expressed chemokine receptors, suggesting a role in leukocyte recruitment and possibly in early pancreatic development. In conclusion, we demonstrated the presence of CD45RA resident leukocyte-derived lineages, mostly macrophages, in the early human pancreatic mesenchyme. These cells may have migrated in the tissue through the vascular system, attracted by constitutively expressed chemokines, and locally surviving through CSF1 signaling. The role of macrophages in epithelium/mesenchyme interaction-mediated pancreatic development remains to be demonstrated.

Alcohol-based hand rub: influence of healthcare workers' knowledge and perception on declared use.

Handrubbing with alcohol-based hand rub (AHR) is a validated alternative to handwashing. The aims of this study were to compare knowledge and declared use of AHR between different categories of healthcare worker (HCW), and to assess factors associated with the use of AHR. A standardized questionnaire was sent to all HCWs in a tertiary care university hospital. The following data were collected for each HCW: job title (physician, nurse, nursing assistant or other), sources of information about AHR; knowledge and perception of AHR and declared use of AHR in daily practice instead of unmedicated or antiseptic soap. Of 5238 questionnaires, 1811 were returned. Physicians had better knowledge about AHR than other HCWs. HCWs' knowledge of AHR efficacy and skin tolerance were independently associated with the use of AHR instead of unmedicated or antiseptic soap. The declared use of AHR differed according to professional category.

Surgical hand rubbing compared with surgical hand scrubbing: comparison of efficacy and costs.

The aim of this study was to compare the efficacy of surgical hand rubbing (SHR) with the efficacy of surgical hand scrubbing (SHS), and to determine the costs of both techniques for surgical hand disinfection. A review of studies reported in the literature that compared the efficacy of SHS and SHR was performed using MEDLINE. The costs of SHR and SHS were estimated based on standard hospital costs. The literature showed that SHR had immediate efficacy that was similar to that of SHS, but SHR had a more lasting effect. SHR reduced costs by 67%. In conclusion, SHR is a cost-effective alternative to SHS.